Current Developments in Glaucoma Surgery and Migs

ISBN 978-90-62992-76-8
9 789062 992768
NEW CONCEPTS IN GLAUCOMA SURGERY SERIES
VOLUME 1
About the series
New Concepts in Glaucoma
and Glaucoma Surgery
These series has been conceived as a recurring project. It is neither book nor journal. Books are infrequently
edited and rarely up-to-date for more than a year or two; journals are really devoted to the standard experimental
format and no longer permit authors to wander into speculation or lengthy discussions of what might come next.
There is room for a plurality of publishing approaches. All of these formats have their place and all have different
purposes in moving a field forward.
This series is designed to allow us to consolidate new information and hold forth on speculation in glaucoma.
It does so in both the basic sciences and clinical sciences.
It is our hope that this consolidation of hypotheses and theories, along with identifying new information
and new speculation will propel us toward a more rapid cure for glaucoma.
ISSN: 2542-5595
ISSN 2589-7632 (Surgery Series)
New Concepts in Glaucoma Website

Visit our website at newconceptsinglaucoma.com for access to the videos discussed in this book, captured content
from our annual congress, and all articles published within the series.
Published by Kugler Publications

www.kuglerpublications.com
New Concepts in Glaucoma
Surgery Series:
Volume 1
Editors
John R. Samples
Iqbal Ike K. Ahmed
Kugler Publications/Amsterdam/The Netherlands

New Concepts in Glaucoma Website
Visit our website at newconceptsinglaucoma.com for access to the videos discussed in this book, captured
content from our annual congress, and clinical science and research articles published within the series.
Videos
Videos can be accessed directly through:
newconceptsinglaucoma.com/surgery1/videos/chapter-number
e.g. for chapter 10 go to to newconceptsinglaucoma.com/surgery1/videos/10)
New Concepts in Glaucoma Surgery Series - Volume 1

ISSN 2589-7632
ISBN 978-90-6299-276-8
Kugler Publications
P.O. Box 20538
1001 NM Amsterdam, The Netherlands
www.kuglerpublications.com
© 2020 Kugler Publications, Amsterdam, The Netherlands

All rights reserved. No part of this book may be translated or reproduced in any form by print, photoprint,
microfilm, or any other means without prior written permission of the publisher.
Kugler Publications is an imprint of SPB Academic Publishing bv, P.O. Box 20538, 1001 NM Amsterdam,
The Netherlands
Cover design by: Willem Driebergen, Rijnsburg, The Netherlands

Table of contents
Foreword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii
About the editors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . viii
About the authors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . x
1. Anatomy of the conventional aqueous outflow pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Haiyan Gong, David L. Swain
2. Patents in an age of innovation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

William Noonan
3. Which minimally invasive glaucoma surgery should one choose for a specific patient? . . . . . . . . . . . . . . 55
Jithin Yohannan, E. Randy Craven
4. In defense of the trabeculectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

Ryan Machiele, Makena Parker, Leon W. Herndon
5. On the use of curcumin as a multimodal antifibrotic agent for glaucoma surgery . . . . . . . . . . . . . . . . . . 71

Nicholas M. Pfahler, Michael C. Giovingo, Paul A. Knepper
6. The future of MIGS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85

Thiago A. Moulin, Arsham Sheybani
7. Gonioscopy-assisted transluminal trabeculotomy (GATT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .95

Ronald L. Fellman, Davinder S. Grover
8. Hydrus® microstent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107

9. The iStent devices: iStent, iStent inject, and iStent Supra . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
Antonio M. Fea, Simona Scalabrin, Carlo Lavia
10. Ab interno trabecular meshwork incision, ablation, and disruption . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137

Hamed Esfandiari, Si Chen, Ralitsa T. Loewen, Susanna Waxman, Kevin Kaplowitz, Nils A. Loewen
11. iTrack™ ab interno canal-based glaucoma surgery: the next evolution in MIGS . . . . . . . . . . . . . . . . . . . 157
Mahmoud Khaimi, David Lubeck
12. XEN: the evolution of the stent and technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167

Vanessa Vera, Daniel Lee, Natasha N. Kolomeyer, M. Reza Razeghinejad, Jonathan S. Myers
13. An ab externo minimally invasive aqueous shunt comprised of a novel biomaterial . . . . . . . . . . . . . . 181
Leonard Pinchuk, Isabelle Riss, Juan F. Batlle, Henny Beckers, Ingeborg Stalmans
vi
14. Laser trabeculoplasty and micropulse: evolution from trabecular photocoagulation,

to trabecular photothermolysis, to trabecular photostimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
Giorgio Dorin, Ted S. Acott, Antonio M. Fea, John R. Samples
15. Cyclophotocoagulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211

Michael Giovingo, Shyam Patel, Shweta Chaudhary, Amar Mannina, Thomas Patrianakos
16. Excimer laser trabeculostomy: the laser-based MIGS procedure for open-angle glaucoma . . . . . . . . 231
Michael S. Berlin, Marc Töteberg-Harms, Jonathan Shakibkhou, Alyssa Francesca Ahorro, Ryan Lamrani, Antonio
Moreno Valladares, Ulrich Giers
17. Mixing and combining MIGS procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245

Steven R. Sarkisian, Jr.
18. Trabeculectomy with suprachoroidal derivation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249

Rodolfo A. Pérez-Grossmann, Daniel Grigera, Alan Wenger, Rodolfo A. Pérez-Simons
19. Modern retinal laser for neuroprotection in open-angle glaucoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255

Jeffrey K. Luttrull, David Kent
20. What is the ideal conjunctival bleb and how to achieve it?
Learning from the Microfistula-XEN procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275
Dao-Yi Yu, Stephen John Cringle, William H. Morgan, Er-Ning Su
21. Special considerations for pediatric glaucoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289

Peter A. Netland, John R. Samples
Foreword
Successful interventional glaucoma remains a sought-after goal for the glaucoma clinician for many reasons.
Medical costs, compliance, and adherence remain major barriers for the treatment of our patients. A truly
definitive treatment for glaucoma is most likely to be largely surgical, as it is doubtful that patients will continue to
use glaucoma drugs in the future for anything other than transient lowering of intraocular pressure. In the coming
era, it seems probable that neuroprotection and neurorestoration will be combined with MIGS to lower pressure.
Cost and access to medications, as well as cost-effectiveness are all reasons pushing towards surgery becoming
the prime method of treating adult glaucoma, as is already the case for pediatric glaucoma. However, this could
change if medications were to have a demonstrable beneficial effect upon the cells of the eye, whether corneal or
trabecular. Cytoprotection, trabecular protection, and even canaloprotection may lie ahead to join the concept
of neuroprotection. In fact, if medications were actually regenerative, it is likely that that they would become a
routine component when MIGS is performed. At present, no such beneficial cellular treatment is known, but new
medications based on neuroprotection and trabecular meshwork restoration may be on the immediate horizon. It
has been suggested that netarsudil would have beneficial effects for both the trabecular meshwork and the optic
nerve. Nitric oxide compounds may offer a similar possibility; much remains to be learned as of this writing.
Additional good news is that the different types of MIGS are increasing in proportion to their efficacy. To
date, there are no fewer than 12 choices available to glaucoma specialists. Choice of procedure depends on the
underlying anatomy as well as the patient’s individual characteristics. Truthfully, the number of available surgeries
depends upon their taxonomy. Most are based on the outflow system and the canal, as illustrated in Chapter 1 of
this book.
Since our last book on the topic, Surgical Innovations in Glaucoma, the surgical landscape has shifted consid-
erably; in only a few years, much has become obsolete, replaced by more recent findings and techniques. Due
to significant improvements, MIGS are increasingly finding their place in patient management to such a degree
that a monograph is no longer a suitable format to keep track of all the developments in this area. This collection
of articles is intended to be the first of a series of planned books on glaucoma surgery. It follows the format and
citability of another glaucoma series from Kugler Publications, Glaucoma Research and Clinical Advances, soon to
publish its third volume.
Comments and contributions to this new surgical series are very much welcome. We hope that this volume will
not only enhance the reader’s clinical care, but will also spark a dialogue that aids us all in increasing the quality
of care we render to our patients.
John R. Samples, MD
Clinical Professor, Washington State University Floyd Elson College of Medicine, Spokane, WA, USA
Director, Western Glaucoma Foundation, Sisters, OR, USA
Founder and Organizer, Trabecular Meshwork Study Club
Iqbal Ike K. Ahmed, MD, FRSC (C)

Assistant Professor, University of Toronto, Toronto, ON, Canada
Clinical Professor, Salt Lake City, University of Utah, UT, USA
Director, Glaucoma & Advanced Anterior Segment Surgery (GAASS) Fellowship, University of Toronto, Toronto,
ON, Canada
Research Director, Kensington Eye Institute, University of Toronto, Toronto, ON, Canada
Division Head, Ophthalmology, Trillium Health Partners, Mississauga, ON, Canada
Medical Director, Prism Eye Institute, ON, Canada
Co-Medical Director, TLC Oakvillle, Oakville, ON, Canada
About the editors
John R. Samples, MD
John R. Samples practices at both the Olympia Eye Clinic of Olympia, WA and the Eye
Clinic in Portland, OR, USA. He is the Chief Scientific Officer for EyeGenetix, Director of
the Western Glaucoma Foundation, and Clinical Professor at Washington State Univer-
sity’s Elson S. Floyd College of Medicine in Spokane, WA, USA.
For over thirty years, Dr. Samples has been actively involved within the professional
community including the American Academy of Ophthalmology (AAO), the American
Glaucoma Society, and the American Society for Cell Biology. He has also organized
and/or co-chaired numerous meetings since 2003, including an annual mini fellowship
in glaucoma held in Napa Valley in collaboration with the University of California San
Francisco, the Oregon Academy of Ophthalmology, the Pacific Coast Oto-Ophthalmo-
logical Society annual meeting, the International Society for Eye Research (ISER), and
a Trabecular Meshwork Study Club held annually in conjunction with the American Society for Cell Biology.
He has been active in ophthalmology research with funding from the National Eye Institute and has over
150 peer-reviewed publications to his credit, as well as numerous books on glaucoma. Dr. Samples’ research
has focused on the trabecular meshwork, cytokines, aspects of wound healing, and glaucoma genetics; he has
also worked on the development of several new glaucoma-related drugs and several new laser and surgical
procedures. He consults on new drug and device development, as well as legal intellectual property issues within
ophthalmology.
Iqbal Ike K. Ahmed, MD, FRCSC
Ike Ahmed is a fellowship-trained glaucoma, cataract, and anterior segment surgeon

with a practice focus on the surgical management of glaucoma, complex cataract and
intraocular lens complications. He is board-certified in ophthalmology in Canada and
the USA, and is an active member of numerous national and international societies.
Dr. Ahmed has become world renowned for his skills and groundbreaking work in the
diagnosis and surgical treatment of highly complex eye diseases, including glaucoma
and surgical complications. He is recognized as being one of the most experienced
complex eye surgeons in the world and has trained numerous surgeons in innovative
surgical techniques.
He is currently an Assistant Professor at the University of Toronto, and a Clinical
Professor at the University of Utah. He is the Director of the Glaucoma and Advanced
Anterior Segment Surgery (GAASS) fellowship at the University of Toronto, and Director of Research at the
Kensington Eye Institute, University of Toronto. He has trained glaucoma specialists who are now practicing in
Canada and around the world, as well as residents and medical students. Dr. Ahmed has a large tertiary glaucoma/
cataract practice at Prism Eye Institute in the Greater Toronto Area, and primarily performs surgery at Trillium
Health Partners, Mississauga, Ontario, the Kensington Eye Institute, University of Toronto, Toronto, Ontario, and
TLC Oakville.
Dr. Ahmed has a keen interest in the development of advanced microsurgical devices and techniques in
glaucoma surgery and complicated cataract extraction, and is actively involved in research and medical education
at a national and international level. He has received research grants to study glaucoma medications, glaucoma
ix
laser and surgical devices/techniques, angle-closure glaucoma, anterior segment and retinal/optic nerve imaging
in glaucoma, cataract surgical techniques and devices, and intraocular lens designs. Dr. Ahmed has designed
innovative glaucoma diamond scalpels for surgery, microsurgical instrumentation, and devices, implants, and
techniques for the management of the dislocated cataract, iris reconstruction, and glaucoma implant devices.
He has done pioneering work in innovative glaucoma surgery, developing and coining the term “microinvasive
glaucoma surgery” (MIGS) as a new genre of surgical approaches and devices.
About the authors
Ted Acott, MD, PhD
Dr. Acott is Research Professor of Ophthalmology and of Biochemistry & Molecular Biology
at the Casey Eye Institute, Oregon Health & Science University, OR, USA. His team’s long-term
research interests are centered on identifying therapeutic targets to treat glaucoma via
lowering intraocular pressure. They have recently identified the homeostatic mechanism
of intraocular pressure, which normally maintains the aqueous humor outflow resistance at
the appropriate levels, protecting most people from ever developing glaucoma. In addition,
they have been studying the molecular and biomechanical properties that are responsible
for this homeostatic mechanism and for maintaining the highly segmental nature of aqueous
humor outflow. Their work has recently demonstrated that the IOP homeostatic mechanism
is compromised in glaucoma, and both high and low segmental flow regions exhibit different
biomechanical and flow properties. The team has also identified individual extracellular
matrix proteins that may be important therapeutic targets in the treatment of glaucoma.
Alyssa Francesca Ahorro, BA

Alyssa Francesca Ahorro received a Bachelor of Arts in Psychology at the University of
California, Riverside in June of 2018. Currently, she is conducting research at the Glaucoma
Institute of Beverly Hills and Cedars-Sinai Medical Center in Los Angeles, CA, USA. Her
current interests lie within the scopes of Ophthalmology and Oncology. Upon gaining further
research experience, she will pursue a medical degree.
Juan F. Batlle, MD
Dr. Batlle is founder and President of the multi-specialty private practice Centro Laser in
Santo Domingo, Dominican Republic. He is a Distinguished Member of Vision 2020/Interna-
tional Agency for the Prevention of Blindness, Chief of Ophthalmology at the charity clinic
Elias Santana Hospital, and Medical Director of one of the most prestigious residency train-
ing programs of ophthalmology in Latin America associated with Instituto Tecnológico de
Santo Domingo. He has dedicated his professional life to the prevention of blindness in Latin
America, with an interest in cataract, glaucoma, cornea, and refractive surgery. Dr. Batlle
has more than 20 years of experience in research and collaborates with well-known oph-
thalmic companies for the development and design of ophthalmic devices and medications,
supporting submissions and approvals to world-wide regulatory agencies in his areas of
interest.
xi
Henny J.M. Beckers, MD, PhD, FEBOphth

Dr. Beckers is Associate Professor, Head of the Glaucoma Clinic, and Director of the Ophthal-
mology Residency Program at the University Eye Clinic of the Maastricht University Medical
Center+ in the Netherlands. She is the Secretary of the Dutch Glaucoma Group, an active
committee of Dutch ophthalmologists with a special interest in glaucoma. Her main research
interest is glaucoma surgery, with a focus on studying new glaucoma devices. Research lines
also include progression of glaucoma, prognostic factors in glaucoma, diagnosis of nar-
row-angle glaucoma, glaucoma treatment and adherence, and cost-effectiveness studies.
Michael S. Berlin, MD, MSc

Dr. Michael Berlin is a Professor of Clinical Ophthalmology at the UCLA Stein Eye Institute.
His professional contributions are in laser surgery and in the research and treatment of
glaucoma. He is the founder and director of the Glaucoma Institute of Beverly Hills (GIBH)
in Los Angeles, CA, USA, where he has maintained a private clinical practice for over 30
years and is the director of the GIBH Research Foundation. Dr. Berlin received his bachelor’s
degree, medical degree, and his Master of Sciences degree in ophthalmology from the
University of Michigan. He completed an internship in Internal Medicine at the Harbor –
UCLA Medical Center, followed by an ophthalmology residency at the University of Michigan
and subsequent subspecialty glaucoma fellowship training at the Mount Sinai Medical
Center in New York. His research interests focus on the development of novel therapies
for the treatment of glaucoma. He holds multiple patents for innovative laser and surgical
procedures, publishes extensively and lectures internationally.
Shweta Chaudhary, MD
Shweta Chaudhary is an ophthalmology resident at Cook County Health and Hospitals,
Chicago, IL, USA. She has completed an ophthalmology residency in India and a corneal neu-
robiology research fellowship at the University of Illinois at Chicago. Her research interests
include surgical and laser inventions in the field of glaucoma, especially mechanisms of
action of different types of glaucoma lasers and minimally invasive glaucoma surgery.
Si Chen, MD
Si Chen is a PhD student from Central South University, Xiangya School of Medicine,
Changsha, China. She is currently a visiting international scholar in the Loewen Lab in
the Department of Ophthalmology at the University of Pittsburgh, PA, USA. Her research
interests involve the role of microincisional glaucoma surgeries in the cause, treatment, and
prevention of glaucoma. Her PhD is concerned with factors that influence outflow in the
distal outflow tract.
xii
E. Randy Craven, MD
Dr. Craven specializes in glaucoma and complex anterior segment cases, such as iris
problems and lens issues. He is an Associate Professor at Johns Hopkins University School
of Medicine (Baltimore, MD, USA). Dr. Craven is currently also the Medical Director of the
Wilmer Eye Institute Bethesda (Bethesda, MD, USA) and serves as the Vice-Chair for the
Wilmer Eye Institute Practice Network.
From 2013 to 2016, Dr. Craven served as the Chief of Glaucoma and Glaucoma Fellowship
Director at the King Khaled Eye Specialist Hospital in Riyadh, Saudi Arabia. He also served
as the Residency Coordinator there.
Dr. Craven was involved with the development and implementation of risk-management
programs for ophthalmologists while serving on the Board of Directors for the Ophthalmic
Mutual Insurance Company in the USA. He participated in over 120 clinical research trials
and was the first US surgeon in the US Food and Drug Administration (FDA) trial to implant
the iStent, as well as the first US surgeon to implant the CyPass; as a result, he is active
in expanding and educating about the role of minimally invasive glaucoma surgeries
throughout Europe, the Middle East, Africa, and the USA. He has extensive experience with
optical coherence tomography for glaucoma and served as an advisor for the development
of imaging in glaucoma.
Stephen John Cringle, BSc, PhD

Dr. Cringle is Professor of the Lions Eye Institute, Center for Ophthalmology and Visual Science
at The University of Western Australia in Nedlands, Australia. His research involves basic
studies of retinal oxygen metabolism, vascular biology, laser applications in ophthalmic
research, and the development of new diagnostic and therapeutic techniques in glaucoma
and retinal diseases. He has worked with Professor Yu and made a significant contribution
to the XEN Gel Stent technology for glaucoma filtration surgery that is now in clinical use.
Dr. Cringle has a background in physics and 35 years of experience in ophthalmic research.
xiii
Giorgio Dorin
Giorgio Dorin has been devoted to the development of clinical laser systems for the treatment
of glaucoma, retinal, and refractive disorders since 1969. In 1983, in recognition of his contri-
butions to the ocular applications of lasers, he was awarded with the Honorary Membership
by the Italian Society of Laser in Ophthalmology (S.I.L.O.).
During the past two decades, he has developed micropulse laser emission techniques to
master the control of the photothermal effects during ocular laser treatments, to the end of
minimizing and avoiding the treatment’s iatrogenic damage and collateral complications,
while maintaining and optimizing both clinical outcomes and therapeutic benefits.
He has pioneered the clinical use of sub-visible-threshold nondamaging micropulse laser
procedures for the treatment of retinovascular disorders and glaucoma. This has led to new
subthreshold laser micropulse photostimulation (SLMP) treatment protocols that have been
fine-tuned in pilot studies and validated in prospective randomized clinical trials, which
have provided the evidence that SLMP is at least as effective as the conventional destructive
threshold laser photocoagulation and can result in superior outcomes and unprecedented
functional benefits thanks to the absence of the treatment’s morphologic and functional
damage. This evidence is now leading a pivotal swing from laser photocoagulation to laser
photostimulation, a seminal paradigm-shift with intrinsic unprecedented safety profile and
benefit-to-risk ratio. He is now advocating the ban of destructive photocoagulation and the
use of photostimulation for the treatment of ocular chronic degenerative progressive neu-
rotrophic disorders.
He has been granted three patents on sub-threshold laser applications by the US Patent
Office, has authored/coauthored numerous publications in peer-reviewed medical journals,
has contributed with chapters in ophthalmology books, and has presented posters and given
podium presentations at ophthalmology meetings, congresses, and courses throughout the
world. He is currently serving as the Senior Development Scientist and COO for ALeyeGN
Technologies, Saratoga, CA, USA.
Hamed Esfandiari, MD
Hamed Esfandiari is an Assistant Professor of Ophthalmology at Shahid Beheshti University
of Medical Science in Tehran, Iran. He completed a research fellowship with Dr. Loewen at
the University of Pittsburgh (PA, USA) focusing on the clinical outcomes of novel techniques
to increase conventional outflow. He is now on the Pediatric Ophthalmology service at
the Northwestern University in Chicago, IL, working extensively in the field of childhood
glaucoma. His research interests encompass success factors in traditional and new
glaucoma surgeries and how they relate to recent insights into the conventional aqueous
outflow tract. He has also conducted studies on pediatric glaucoma, optic neuropathies,
and novel glaucoma medications.
xiv
Antonio Maria Fea, MD, PhD

Dr. Antonio Maria Fea is an Aggregate Professor at the University of Turin, Italy and an adjunct
scientist at SERI. He holds a PhD in electrophysiology. He developed and propagated the
use of several psychophysical techniques to test visual function in infants and children. Dr.
Fea was part of several humanitarian missions in Madagascar, Namibia and, India. In recent
years, he has been involved in the development and clinical evaluation of several minimally
invasive techniques for the treatment of glaucoma. He has been part of several multicenter
trials performing and teaching MIGS surgery in Armenia, India, Colombia, and Chile, and is
part of the Advisory Board of several companies involved in the development of novel and
minimally invasive methods for the treatment of glaucoma. He serves as reviewer and is part
of the editorial board of several peer-reviewed journals.
Ronald L. Fellman, MD
Ronald Fellman is an Attending Surgeon and Clinician at Glaucoma Associates of Texas in
Dallas, Adjunct Professor of Ophthalmology at North Texas Eye Research Institute (NTERI)
University of North Texas Health Science Center Fort Worth and Associate Clinical Professor
Emeritus, Department of Ophthalmology, University of Texas Southwestern Medical Center,
Dallas (UTSWMC) in TX, USA. Dr. Fellman attained his medical degree from Tulane University,
residency at University of Texas Southwestern Medical Center, and glaucoma fellowship at
Wills Eye Hospital. He is involved in clinical research concerning the surgical management of
glaucoma including wound healing, new devices and techniques for canal surgery and the
factors associated with canalogenesis. Dr. Fellman serves on the board of Cure Glaucoma, a
foundation dedicated to translational research in glaucoma and the reduction of blindness
from glaucoma on a global level and is active in various roles for the American Glaucoma
Society.
Ulrich Giers, MD
Dr. Ulrich Giers is the Founder, Director, and Head of the anterior segment surgery department
of the OWL Eye Clinic in Detmold, Germany. He graduated and earned his medical doctorate
degree from Marburg University. He then completed his residency and fellowship at the
University Eye Hospital in Ulm, Germany. His research interests focus on clinical outcomes
of refractive and glaucoma procedures.
Michael Giovingo, MD
Michael Giovingo is the director of Glaucoma Service for Cook County Health and Hospital
System in Chicago, IL, USA. He is a board-certified ophthalmologist and fellowship trained
glaucoma specialist. His research interests include the pathophysiology of glaucoma,
development of new medical interventions for glaucoma, and minimally invasive glaucoma
surgery and lasers. Dr. Giovingo is also active in training medical and surgical management
of glaucoma to the Ophthalmology residents at Cook County Health and Hospital System.
xv
Haiyan Gong, MD, PhD, FARVO

Dr. Gong is Professor of Ophthalmology, Anatomy, and Neurobiology at Boston University
School of Medicine (MA, USA). Her research is focused on understanding the mechanisms
that regulate aqueous humor outflow resistance in normal eyes and how this resistance is
increased in eyes with primary open-angle glaucoma, using physiological and morpholog-
ical methods to provide new insights for the development of new therapeutic strategies to
treat this disease. Dr. Gong’s current research is supported by National Institutes of Health/
National Eye Institute, BrightFocus Foundation, Aerie Pharmaceuticals, Inc., and Massachu-
setts Lions Eye Research Fund.
Daniel Grigera, MD
Dr. Grigera earned his medical degree from the University of Buenos Aires, Buenos Aires,
Argentina. He currently serves as a consultant in the Glaucoma Service at Santa Lucía Eye
Hospital and as Assistant Professor of Ophthalmology at the Faculty of Medicine of Salvador
University in Buenos Aires, Argentina.
He is a former President of the Latin American Glaucoma Society and the Pan American
Glaucoma Society, member of the World Glaucoma Association Council, and founding
member and first president of the Argentine Association of Glaucoma. Dr. Grigera has partic-
ipated as coordinator or speaker in more than 90 congresses and symposiums in Argentina,
America, and Europe. He is a reviewer of Journal of Glaucoma and has published
23 works on glaucoma in Argentinian and international peer-reviewed publications.
Davinder S. Grover, MD, MPH

Dr. Grover is Attending Surgeon and Clinician at Glaucoma Associates of Texas, Dallas,
Adjunct Assistant Professor at North Texas Eye Research Institute (NTERI), University of
North Texas Health Science Center, Fort Worth, and Clinical Assistant Professor at University
of Texas Southwestern Medical School in Dallas, TX, USA. His interests include innovative
glaucoma surgeries, complex glaucoma, cataract, and anterior segment surgeries, as well
as clinical research outcomes in medical and surgical glaucoma. He is widely published and
has helped develop innovative surgical techniques and has designed several novel surgical
instruments.
Dr. Grover received his medical degree from the Johns Hopkins School of Medicine, residency
at the Wilmer Eye Institute, and glaucoma fellowship at the Bascom Palmer Eye Institute.
Additionally, he received a Master of Public Health degree at the Harvard University School
of Public Health. He also serves on the Board of Directors for the Cure Glaucoma Foundation,
a charitable organization with a mission to improve access to quality care, fund transforma-
tional research, and disseminate knowledge through global outreach efforts.
Leon W. Herndon, Jr., MD

Dr. Herndon is Professor of Ophthalmology at Duke University Medical Center in Durham,
NC, USA. He currently serves as Chief of the Glaucoma Division at the Duke University Eye
Center, where he has trained 74 clinical fellows. Dr. Herndon is the recipient of the Distin-
guished Medical Alumnus Award from the UNC School of Medicine, and was the Surgery Day
Lecturer at the American Glaucoma Society Annual Meeting in 2019.
Dr. Herndon’s research interests include studying novel treatment approaches in the
diagnosis and management of glaucoma. He has ongoing research projects evaluating the
high prevalence of primary open-angle glaucoma in Ghana, West Africa.
xvi
Kevin Kaplowitz, MD
Kevin Kaplowitz is an Associate Professor in the Department of Ophthalmology at the VA
Loma Linda with Loma Linda University, CA, USA. One of his main research interests is
evaluating the outcomes and success factors for glaucoma surgery.
David Kent, FRCOphth

Dr. Kent is a vitreoretinal surgeon practicing in The Vision Clinic, Kilkenny, Ireland. His
research interests include the therapeutic use of light to modulate and promote repair in the
aging retina. He has been a member of ARVO since 1996 and currently serves as a director of
LIGHT: The International Retinal Laser Society.
Mahmoud A. Khaimi, MD
Dr. Khaimi is Clinical Professor and Glaucoma Fellowship Director of the Dean McGee Eye
Institute at the University of Oklahoma in Oklahoma City, OK, USA. His clinical focus lies in
the field of glaucoma, with special emphasis in innovations in MIGS, glaucoma filtration and
drainage surgery, and complex cataracts. His research interests also include clinical phar-
macology studies and glaucoma clinical trials.
Paul A Knepper, MD, PhD

Dr. Knepper is Associate Professor of Ophthalmology at the Feinberg School of Medicine,
Northwestern University Medical School, IL, USA, as well as a Research Scientist at the
University of Illinois at Chicago, IL, USA. His research interests focus on improved diagnostic
modalities and treatment of primary open-angle glaucoma, Alzheimer’s disease, and
age-related macular degeneration.
Natasha N. Kolomeyer, MD
Dr. Kolomeyer is a glaucoma specialist at Wills Eye Hospital, Philadelphia, PA, USA. She has
published 20 peer-reviewed papers and has served on committees for the Association for
Research in Vision and Ophthalmology (ARVO) and The American Academy of Ophthal-
mology (AAO). Dr. Kolomeyer’s research interests include clinical outcomes, public health,
imaging, big data, and telemedicine.
xvii
Ryan Lamrani, BS
Ryan Lamrani started working at the Glaucoma Institute of Beverly Hills in Los Angeles, CA,
USA after graduating in May 2018 from New York University with a BS degree in Public Health
and Chemistry. He will be applying to medical school in the summer of 2019 with the intent
of becoming an ophthalmologist. His research interests include the glaucomatous eye, epi-
demiology, and stem cells.
Carlo A Lavia, MD
Dr. Lavia completed his five-year residency at the Department of Ophthalmology of the
University of Turin, Italy in 2018. During his residency, he took part in several clinical trials
in the field of medical retina and glaucoma, with Professor Antonio Fea as main researcher.
Dr. Lavia spent six months pursuing a research fellowship in medical retina, subsequently
working for a year as a retina specialist at the Department of Ophthalmology of the Laribois-
iere Hospital in Paris, France. He is a fellow of the European Board of Ophthalmology.
Dr. Lavia has published approximately twenty original articles and reviews in peer-reviewed
journals. His current interests involve MIGS and the clinical applications of OCT angiography.
He currently works in the Department of Ophthalmology of the ASL TO5, Chieri-Carmagno-
la-Moncalieri-Nichelino, Italy.
Daniel Lee, MD
Dr. Lee is an Assistant Professor and the Director of the Glaucoma Research Center at the
Wills Eye Hospital, Philadelphia, PA, USA. After obtaining his medical degree from Rutgers
University’s Robert Wood Johnson Medical School, ophthalmology residency at the Yale
School of Medicine, and glaucoma fellowship at the Wills Eye Hospital, Dr. Lee serves as an
assistant attending surgeon on the Glaucoma Service.
Dr. Lee has authored and coauthored numerous articles and lectured at local and national
meetings. He is actively involved in teaching residents and fellows at Wills Eye Hospital.
His current research interests include novel glaucoma treatments and the role of ocular
perfusion in glaucoma pathogenesis.
Nils A. Loewen, MD, PhD

Nils Loewen is an Associate Professor in the Department of Ophthalmology at the University
of Pittsburgh, PA, USA. Clinically, he is specialized in glaucoma and cataract care and micro-
incisional glaucoma procedures that are bleb-free. He has comprehensive experience
with Trabectome surgery and published extensively on factors and outcomes. In his basic
research, his laboratory is focused on bioengineering of the ocular outflow system with a
particular interest in the distal outflow tract.
xviii
Ralitsa Loewen, MD
Ralitsa Loewen is a physician-scientist who investigates aqueous humor outflow both
clinically and in the laboratory, based in the Department of Ophthalmology at the University
of Pittsburgh, PA, USA. She has developed porcine ex vivo eye models for lentiviral transduc-
tion, established methods to visualize and measure aqueous humor flow, and generated
techniques to visualize microscopic aspects of the distal outflow system at high resolution
and in 3D.
David Lubeck, MD
David Lubeck is a founder and world-renowned surgeon at Arbor Centers for EyeCare (IL,
USA), specializing in cataract, cornea and refractive surgery. Dr. Lubeck is passionate about
surgery, teaching and innovation. Dr. Lubeck teaches cataract and refractive surgery to
ophthalmologists all over the world, focusing on new technologies and safe and efficient
eye surgery. He is regularly a first to perform complex procedures providing patients with
outstanding surgical outcomes.
In addition to a busy clinical practice, Dr. Lubeck is an Assistant Clinical Professor of Oph-
thalmology at the University of Illinois, Chicago and lectures regularly worldwide. He has
developed curricula that have been integrated into surgical teaching programs across the
USA and abroad. He has hosted and participated in live surgery programs in China, India,
Vietnam, Korea, Australia, the Philippines, and the USA.
Jeffrey K. Luttrull, MD
Dr. Luttrull is a vitreoretinal surgeon and clinical researcher practicing in Ventura, CA, USA.
His interests and publications include medical and surgical retina, with a special interest in
retinal laser therapy. He is founder and director of LIGHT: The International Retinal Laser
Society.
Ryan Machiele
Ryan Machiele is a 4th-year medical student at Campbell University, NC, USA. His research
interests include evidence-based treatment modalities for various types of glaucoma. Other
research interests include the relationship between intraocular pressure and systemic
illness as well as eliminating barriers to care in disease-burdened areas. He will start his
residency training in 2020.
xix
Amar Mannina, MD
Amar Mannina is an ophthalmology resident at Cook County Health and Hospital Systems in
Chicago, IL, USA. His research interests include treatment modalities for glaucoma, including
micropulse trans-scleral diode and minimally invasive glaucoma surgery.
William Morgan, MBBS, PhD, FRANZCO

Dr. Morgan is Professor of the Lions Eye Institute, Center for Ophthalmology and Visual
Science at The University of Western Australia in Nedlands, Australia. His research involves
basic studies of pressure gradients in and around the optic nerve, with specific interest in the
effect of cerebrospinal fluid (CSF) pressure. Derived from this, he has been recently pursuing
a greater understanding of retinal venous pulsation and its relationship to CSF pressure and
glaucoma. Dr. Morgan was involved with Professor Yu’s team in the development of gelatin
microfistula surgery for glaucoma therapy, the XEN Gel Stent, which is currently being widely
used internationally. He has a clinical and research interest in glaucoma surgery.
Thiago A. Moulin, MD
Dr. Moulin holds a medical degree from the University of São Paulo, Brazil. He is currently
working with Dr. Arsham Sheybani from Washington University in St. Louis, MO, USA in
the statistical modeling of glaucoma patients’ outcomes using large datasets. Since his
graduation in 2015, he has also worked with big data analyses in the Saint Louis University
Center for Outcomes Research. He is interested in advancing the specialty through data
science, which includes the implementation of sophisticated analyses and also the proper
use of machine-learning techniques in ophthalmology.
Jonathan S. Myers, MD
Dr. Myers is the Chief of the Glaucoma Service at Wills Eye Hospital and an Associate Professor
of Ophthalmology, Sidney Kimmel Medical Center in Philadelphia, PA, USA. Dr Myers has par-
ticipated in research involving many aspects of the diagnosis and management of glaucoma,
but has particular interests in investigations involving surgical procedures, pharmaceutical
options, and perimetry.
.
xx
Peter A. Netland, MD, PhD
Dr. Netland received his undergraduate degree at Princeton University, his PhD from
Harvard University, and his medical degree from the University of California, San Francisco.
He completed his residency in Ophthalmology, followed by a clinical fellowship in glaucoma,
at the Massachusetts Eye and Ear Infirmary, Harvard Medical School. Currently, Dr. Netland
is the Vernah Scott Moyston Professor and Chair, Department of Ophthalmology, University
of Virginia School of Medicine, Charlottesville, VA, USA. He has written numerous peer-re-
viewed publications and delivered numerous named and invited lectures on clinical and
surgical management of glaucoma. He has received the Life Achievement Honor Award from
the American Academy of Ophthalmology and was elected to the American Ophthalmolog-
ical Society.
William D. Noonan, MD, JD

Dr. Noonan is both a physician and a patent attorney who specializes in the protection of
medical inventions. During his postgraduate training he participated in an ophthalmolo-
gy residency. He is a partner and the Chair of the Life Sciences Patent Group at Klarquist
Sparkman, LLP in Portland, OR, USA. During a 37-year career he has represented cor-
porations, research institutes, universities, and individuals in both patent litigation and
prosecution matters. For the last 20 years he has also represented the National Institutes
of Health and other government agencies, making his firm the second largest supplier of
legal services to the United States government over the last decade. He is listed in the Best
Lawyers in America (2014-2019), IAM Patent 1000 World’s Leading Patent Practitioners (2015-
2019), and Chambers USA Best Patent Practitioners (2010-2019).
Makena Parker, BA
Makena Parker holds a BA from the University of North Carolina at Chapel Hill (NC, USA). She
is currently a second year Master of Physiology student at North Carolina State University
and works as a clinical lead technician at a retina practice. Her research interests include
ophthalmology with a focus on increased surgical success rates for glaucoma patients and
retinal diseases.
Shyam Patel, MD
Shyam Patel is currently a cornea and external disease fellow at the Eye Consultants of
Atlanta (GA, USA). He completed medical and business school at the University of Alabama
at Birmingham (AL, USA), followed by ophthalmology residency at Cook County Health in
Chicago, IL, USA. In addition to glaucoma, his previous research interests have included
retina, oculoplastics, and pediatric ophthalmology.
xxi
Thomas Patrianakos, DO
Thomas D. Patrianakos is the Chair of Ophthalmology for Cook County Health and Hospitals
System in Chicago, IL, USA. He is a board-certified ophthalmologist and a fellowship-train-
ing glaucoma specialist. His research interests include optic nerve head imaging techniques,
microinvasive glaucoma surgery, and glaucoma laser surgery.
Rodolfo A. Pérez-Grossmann, MD
Dr. Perez-Grossmann graduated in Ophthalmology from the National Institute of Oph-
thalmology (Instituto Nacional de Oftalmología) in Lima, Perú. He completed a glaucoma
fellowship at the Glaucoma Research and Education Group in San Francisco, CA, USA. He
currently serves as Medical Director of the Glaucoma and Cataract Institute (Instituto de
Glaucoma y Catarata) in Lima, Perú.
He is former President of the Pan American Glaucoma Society and the Latin American
Glaucoma Society, founding member and first president of the Peruvian Glaucoma
Society, and a member of the Steering Committee of the World Glaucoma Association. Dr.
Perez-Grossmann has participated as coordinator or speaker in numerous congresses and
symposiums worldwide. He holds a US patent involving the method and apparatus for tra-
beculectomy and suprachoroidal shunt surgery. He was one of the founders of the Hospital
de la Familia volunteer group in Guatemala.
Rodolfo A. Pérez-Simons
Rodolfo A. Perez Simons is a medical student at the Scientific University of the South
(Universidad Científica del Sur) in Lima, Perú. He volunteers at the the Glaucoma and
Cataract Institute (Instituto de Glaucoma y Catarata) in Lima, Perú. He also took part in the
foundation of the Hospital de la Familia volunteer group in Guatemala. His research interests
involve medical and surgery treatments of glaucoma.
Nicholas M. Pfahler, BS
Nicholas M. Pfahler holds a BS from the University of Illinois at Chicago, IL, USA and is
currently a Research Associate at the same university. His research interests include cellular
mechanisms of neurodegeneration, identification of therapeutic targets in Alzheimer’s
disease, primary open-angle glaucoma, and age-related macular degeneration, as well as
visual processing.
xxii
Leonard Pinchuk PhD, DSc (h.c.), NAE

Dr. Pinchuk is a Distinguished Research Professor of Biomedical Engineering at the University
of Miami (FL, USA). He is also the founder, Chairman Emeritus, and Chief Scientific Officer
of InnFocus, Inc., a Santen Company (FL, USA). Dr. Pinchuk is a biomaterials scientist with
seminal patents in the area of angioplasty balloons, coronary stents, stent grafts, drug-elut-
ing stents, biomaterials (including polycarbonate urethane and SIBS), the PRESERFLO
MicroShunt, and the next-generation intraocular lens materials. He is also the 2019 Russ
Prize Laureate. His current interests involve the interpretation of clinical results of the
PRESERFLO MicroShunt, developing new methods of preserving the bleb, reinterpreting
the drainage system from the glaucomatous eye based upon new information gleaned from
MIGS and OCT, and other ocular devices.
M. Reza Razeghinejad, MD
Dr. Razeghinejad currently serves as Associate Professor of Ophthalmology at Wills Eye
Hospital, Sidney Kimmel Medical College, Thomas Jefferson University in Philadelphia, PA,
USA, and Co-Director of glaucoma fellowship of the Glaucoma Service. Dr. Razeghinejad’s
research focuses on the medical and surgical management of glaucoma. His research has
been published in over 100 peer-reviewed publications, including major ophthalmology
journals, and several book chapters.
Isabelle Riss, MD
Professor Riss is Director of the Ophthalmology Department at Clinique Mutualiste de Pessac
in Pessac, France. Her research interests focus on glaucoma surgical techniques, methods
of maintaining blebs, and clinical trials, as well as studies involving new glaucoma devices,
including Alcon’s ExPress Shunt and the PRESERFLO MicroShunt.
Steven R. Sarkisian, Jr., MD

Dr. Sarkisian is founder and CEO of Oklahoma Eye Surgeons in Oklahoma City, OK,Dr.
Sarkisian is founder and CEO of Oklahoma Eye Surgeons in Oklahoma City, OK,USA. He has
an active clinical practice with a particular interest in surgical innovation for the treatment
of glaucoma and cataracts, with extensive research involvement in numerous FDA clinical
trials, particularly involving MIGS. He was part of pivotal FDA trials for the CyPass, iStent
Inject, iStent Supra, and iDose.
xxiii
Simona Scalabrin, MD
Dr. Scalabrin is currently a Resident in the Ophthalmology Unit at the Department of Surgical
Sciences of the City of Health and Science University Hospital of Turin (Italy).
She received her summa cum laude medical degree from the University of Turin in 2015 and
attended the Scuola di Studi Superiori “Ferdinando Rossi”, an elite Italian institution of
higher education.
Her current interests involve the etiopathogenesis of optic nerve disorders, with particular
attention to the impact of sex hormones, medical and surgical glaucoma therapy, and
stem-cell treatment of eye disease.
Jonathan Shakibkhou
Jonathan Shakibkhou graduated from UCLA and is the research manager at the Glaucoma
Research Institute of Beverly Hills in Los Angeles, CA, USA. Mr. Shakibkhou is interested
in the development and efficacy of novel surgical methods in the treatment glaucoma.
He was worked with Dr. Michael Berlin on excimer laser trabeculectomy research, testing
the efficacy of this procedure in comparison to other surgical and non-surgical treatment
options. Further, he has been actively involved in raising awareness about glaucoma and
presenting data that is comprehensible to the general population.
Arsham Sheybani, MD
Dr. Arsham Sheybani completed his medical degree at Washington University School
of Medicine in St. Louis, MO, USA. He then completed his residency in Ophthalmology at
Washington University in St. Louis and was selected to remain on faculty as Chief Resident.
During that year, Dr. Sheybani was responsible for ophthalmologic trauma and emergencies
as well as all adult inpatient ophthalmology consultations at Barnes Jewish Hospital. He
was the primary surgical teacher for the beginning residents and implemented a didactic
system that is still used at Washington University. He then completed a fellowship with Ike
Ahmed in Glaucoma and Advanced Anterior Segment Surgery in Toronto, Canada.
Dr. Sheybani subsequently returned to Washington University School of Medicine as faculty
in the Department of Ophthalmology and Visual Sciences where he serves as Residency
Program Director and Assistant Professor of Ophthalmology. He has presented research
internationally and is currently involved in device design aiming to make glaucoma surgery
safer amongst many other endeavors. He is an avid surgical teacher, winning the resident
selected faculty teaching award early in his career. He has also helped create one of the
highest volume surgical glaucoma fellowships in the country serving as the fellowship
director.
xxiv
Ingeborg Stalmans, MD, PhD

Professor Dr. Ingeborg Stalmans heads the Laboratory of Ophthalmology at the Catholic
University of Leuven (KU Leuven), as well as the Glaucoma Unit of the University Hospitals in
Leuven (UZ Leuven) in Belgium. The subject of her PhD was the role of vascular endothelial
growth factor (VEGF) in retinal angiogenesis and in the pathogenesis of DiGeorge syndrome.
This work resulted in several high-impact papers published in journals such as Nature, Cell,
and PNAS, and was rewarded by the prestigious GlaxoSmithKline prize.
The current focus of her basic and clinical research work is medical glaucoma therapy,
glaucoma surgery, and retinal imaging as a biomarker for systemic diseases. She has
published in Cell, Ophthalmology, Journal of Glaucoma, IOVS, etc. Her work has been
awarded with prizes from the Funds for Research in Ophthalmology (FRO) and the Pfizer
Glaucoma Research Award. As a glaucoma specialist and researcher, she frequently lectures
both nationally and internationally, including at ARVO, WGC, ISGS, EVER, EGS, ESCRS, SOE,
and ESASO. Within the European Glaucoma society, she is a member of the Executive
Committee, treasurer, chair of the Communication Committee, as well as co-chair of the
program-planning committee. She also serves on the Board of Governors of the World
Glaucoma Association (WGA) and in the Glaucoma Expert Committee of the European Vision
Institute Clinical Research Network (EVICR.net). She is the Treasurer of the Belgian Glaucoma
Society and a member of the Royal Academy of Medicine of Belgium.
Er-Ning Su, MD, PhD

Dr. Su is Associate Research Professor of the Lions Eye Institute, Center for Ophthalmol-
ogy and Visual Science at The University of Western Australia in Nedlands, Australia. Her
research mostly involves in vitro studies of vasoactivity of retinal arteries and veins. Dr. Su
has developed a microperfusion system that allows vasoactivity to be assessed in real time
whilst perfusing or bathing the vessels with putative vasoactive compounds. The aim is to
better understand the mechanisms of blood flow control in the eye and look for potential
vasoactive compounds that could be useful clinically. She has also developed a custom-built
system to produce a bioengineered cross-linked gelatin microfistula for experimental use in
new forms of glaucoma filtration surgery.
David L. Swain, BA
David L. Swain holds a BA in Biology and English from Boston University (MA, USA). During
his undergraduate studies he participated in the investigation of morphological differences
in the scleral spur between normal and glaucoma eyes. Currently, he is an MD/PhD candidate
in the department of Anatomy and Neurobiology at Boston University School of Medicine,
and is completing his PhD thesis in the laboratory of Dr. Gong. His research interests include
mechanisms of increased resistance in the aqueous outflow pathway of eyes with primary
open-angle glaucoma, and the structure and function of the inner wall endothelial cells of
Schlemm’s canal.
xxv
Marc Töteberg-Harms, MD, FEBO

Dr. Töteberg-Harms is a glaucoma specialist and attending physician at the University Hospital
Zurich, Department of Ophthalmology and a clinical instructor and lecturer (Privatdozent)
with the University of Zurich in Switzerland. He went to Charité Medical School, Humboldt
University Berlin, Germany and to the University of Kiel, Germany, where he graduated
from. He earned his medical doctorate degree and the venia legendi at University of Zurich
Medical School. Later, he completed clinical and basic research glaucoma fellowships at the
Massachusetts Eye and Ear Infirmary, Boston, MA, and Case Western Reserve University,
Cleveland, OH, in the United States. His research interests focus on glaucoma diagnosis
(OCT, visual field testing, and different tonometry techniques) and efficacy and safety of
surgical procedures, especially MIGS procedures.
Vanessa Vera, MD
Dr. Vera is a glaucoma specialist and a surgical consultant for Kelotec, Fs-Eye, and Allergan.
She has published numerous peer-reviewed papers and book chapters, and has over ten
patents and patent applications in the USA. Her research interests include novel medical
and laser treatments, as well as new devices and surgical options for glaucoma.
Susannah Waxman, BA
Susannah Waxman is the Laboratory Manager of the Loewen Lab for Outflow Tract
Engineering at the Department of Ophthalmology of the University of Pittsburgh, PA, USA.
Her research interest is the conventional outflow tract. Her background in plant physiology
and food safety has led to increasingly translational research interests in human physiology.
She is set to start a PhD in the Interdisciplinary Biomedical Graduate Program at the
University of Pittsburgh.
Alan Wenger, MD
Dr. Wenger is Chief of the Glaucoma Service at Hospital San Juan de Dios in Santiago, Chile.
He graduated in Ophthalmology from the National Institute of Ophthalmology (Instituto
Nacional de Oftalmología) in Lima, Perú and then completed a fellowship in Clinical and
Surgical Glaucoma at Hadassah University Medical Center in Jerusalem, Israel. His current
interests involve glaucoma clinical research and development of novel glaucoma surgeries.
xxvi
Jithin Yohannan, MD, MPH

Jithin Yohannan is an Assistant Professor of Ophthalmology at the Wilmer Eye Institute,
Johns Hopkins University School of Medicine (Baltimore, MD, USA). His practice specializes
in medical, laser, and surgical treatment of glaucoma, with a focus on minimally invasive
glaucoma surgery and new glaucoma surgical devices. He also performs both routine
and complex cataract surgery. Furthermore, Dr. Yohannan specializes in the surgical
management of complex problems of the anterior segment; these problems include issues
that arise after trauma or prior surgery gone wrong, such as dislocated intraocular lenses, or
iris and pupil defects.
Dr. Yohannan earned his bachelor’s degree in biochemistry from New York University, where
he graduated summa cum laude. He then received his medical and Master of Public Health
degrees from Johns Hopkins University and completed an ophthalmology residency at the
Wilmer Eye Institute, Johns Hopkins University School of Medicine. From there, he served as
a fellow in glaucoma and advanced anterior-segment surgery at the University of Toronto,
Canada, with Ike Ahmed. Subsequently, he returned to serve as Assistant Chief of Service at
the Wilmer Eye Institute.
Dr. Yohannan’s research focuses on using artificial-intelligence algorithms to improve the
tests that are used to diagnose and monitor glaucoma. His background in biostatistics,
epidemiology, and mathematics enables this effort. The ultimate goal of this research is
to detect glaucoma and determine when it is worsening more accurately. The results of
this work will ultimately help guide doctors who are managing glaucoma to make better
treatment decisions. Dr. Yohannan also has a clinical and research interest in novel surgical
devices used to treat glaucoma. These devices hold the promise of making glaucoma surgery
safer and easier to recover from.
Dao-Yi Yu, MD, PhD

Dr. Yu is Professor of the Lions Eye Institute, Center for Ophthalmology and Visual Science
at The University of Western Australia in Nedlands, Australia. His research interests cover
many fields in ophthalmology, including glaucoma, retinal diseases, vascular biology, and
retinal metabolism. He leads a highly innovative team and has established more than ten
laboratories performing experimental research and transferring to clinical therapeutics
and diagnostics. As lead inventor, he has worked with his team to develop a new glaucoma
surgery including a crossed-linked gelatin microfistula, an ab interno implantation and
needle type implanter to perform MIGS, now in clinical use under the name XEN Gel Stent.
Currently, the team is interested in further improving the outcomes of glaucoma filtration
surgery.
1. Anatomy of the conventional aqueous outflow
pathway
Haiyan Gong, David L. Swain
Department of Ophthalmology, Boston University School of Medicine, Boston, MA, USA
Abstract
A better understanding of the anatomy of the outflow Keywords: aqueous outflow pathway, collector channel,
pathways can be useful in knowing how each class of Schlemm’s canal, segmental outflow, trabecular
minimally invasive glaucoma surgery (MIGS) devices meshwork
works. This article reviews the anatomy of the aqueous
drainage pathways, emphasizing the trabecular
meshwork. Experimental evidence of the location of 1. Introduction
the major sources of outflow resistance in this pathway
and their contribution to glaucoma pathogenesis are Intraocular pressure (IOP) is maintained within a normal
discussed. The segmental outflow pattern around the range from a dynamic balance between aqueous
circumference of the eye, structural differences in high- humor formation and drainage. Dysfunctional aqueous
and non-flow areas, and morphological changes that drainage results in elevated IOP, which is a causative
are responsible for the reduction of effective filtration risk factor for the development and progression of
area (EFA) with increased intraocular pressure (IOP) primary open-angle glaucoma (POAG).1 An under-
and glaucoma are also discussed. Lowering IOP can be standing of how to lower IOP using minimally invasive
achieved by medical and surgical treatments, through glaucoma surgery (MIGS) begins with an understanding
increasing EFAs in the trabecular meshwork and in the of the normal anatomy of the structures related to the
episcleral veins. Anatomically, much more remains to drainage of aqueous humor and changes in POAG.
be investigated to better understand how structural Aqueous humor is secreted by the ciliary body, enters
changes along this pathway contribute to the regulation the posterior chamber, flows anteriorly through the
of segmental outflow, how anatomical structures distal pupil, circulates around the anterior chamber by con-
to Schlemm’s canal, including the collector channels vective flow, and exits through two pathways, the con-
and their ostia and scleral venous plexus, contribute ventional or trabecular outflow pathway and the uve-
to the regulation of distal outflow resistance. Further oscleral outflow pathway. The conventional outflow
development of in vivo assessment of the segmental pathway is the major drainage pathway (80-90%), which
outflow pattern with optical coherence tomography is comprised of the uveal and corneoscleral portions
and aqueous angiography could provide better, indi- of the trabecular meshwork (TM), the juxtacanalicular
vidualized treatment plans and outcomes for MIGS connective tissue (JCT), Schlemm’s canal (SC), the col-
surgery. lector channels (CCs), the scleral venous plexus, and
the aqueous veins (AVs). Most aqueous humor drains
from the anterior chamber through progressively
Correspondence: Haiyan Gong, M.D., Ph.D., Department of Ophthalmology, Boston University School of Medicine, 72 East Concord
Street, L-905, Boston, MA 02118, USA.
E-mail: [email protected]
New Concepts in Glaucoma Surgery Series: Volume 1, pp. 1-38

Edited by John R. Samples and Iqbal Ike K. Ahmed
2 H. Gong and D.L. Swain
smaller channels of the TM into a circumferentially the views from two perspectives — the view obtained
oriented channel called SC. From this canal, aqueous from meridional sections (Fig. 2), and the en face and
humor drains from external CCs, through the circuitous gonioscopic views obtained of the anterior chamber
scleral venous plexus, ultimately joining the episcleral angle (Fig. 3). In Figure 3a, the light reflection from
vasculature into the venous system. Flow through this Schwalbe’s line and the TM below it, overlying the
system is driven by a bulk-flow pressure gradient, and blood-filled SC, can be clearly seen. Below SC, the lighter
active transport is not involved, as neither metabol- coloration from the scleral spur is evident and finally,
ic poisons nor temperature affect this system to any below the scleral spur, the very dark coloration given
significant degree.2,3 The remaining 10-20% of total by the pigment in the ciliary body stroma is seen. This
aqueous outflow has been reported to leave the normal lowest layer of the meshwork, seen from the gonioscopic
eye via the uveoscleral pathway,4,5 which has become perspective, is referred to as the ciliary body band
a primary target for medical intervention in glaucoma. (Fig. 3b). For comparison, these same structures are
However, this chapter will only focus on the conven- depicted in a goniophotograph of a normal open angle
tional trabecular outflow pathway. in Figure 3c and 3d. A series of alternating dark and light
bands is evident, corresponding to the areas shown in
Figure 4. The uppermost dark band is Schwalbe’s line,
2. Normal anatomy of the conventional which is commonly decorated with various amounts of
aqueous outflow pathway pigment, even in the normal eye. The lighter line below
that represents the anterior or nonfiltering meshwork.
2.1. Trabecular meshwork This portion of the meshwork is not adjacent to SC and
The TM is a triangular-shaped band of tissue encircling no aqueous humor drains out of this region. The amount
the anterior chamber angle (Fig. 1a). The apex of the of pigment phagocytosed by the trabecular cells in
triangle is attached to the terminal edge of Descemet’s this region is low and results in minimal pigmentation.
membrane of the cornea, which is termed Schwalbe’s Below this lighter line is a darker line corresponding
line. From this point of origin, the TM expands as it to the posterior or filtering meshwork. This portion of
bridges the iridocorneal angle, and ends posteriorly by the meshwork leads most directly to SC. Here, both
blending with the scleral spur, ciliary body, and stroma the flow and the amount of phagocytosed pigment is
of the iris. The scleral spur projects like a shelf onto the greater compared to the nonfiltering meshwork (Fig.
base of this triangle, and its posterior surface serves as 5), resulting in a darker appearance on gonioscopy (Fig.
a point of insertion for the longitudinal bundle of the 3c). Below this dark line is another lighter line corre-
ciliary muscle. The length of the TM from Schwalbe’s sponding to the scleral spur. Finally, just below this, the
line to the scleral spur is 694.9 ± 109 µm in men and lowest dark line corresponds to the ciliary body band.8,9
713.2 ± 107 µm in women by histological assessment.6
Using optical coherence tomography (OCT), the mean 2.1.1. The uveal and corneoscleral meshwork
length of the TM was found to be 466.9 ± 60.7 µm in The uveal and corneoscleral meshwork are composed
vivo.7 An imaginary line drawn from Schwalbe’s line to of a series of trabecular lamellae or beams that delimit
the tip of the scleral spur separates the TM into two a system of aqueous flow channels (Figs. 1 and 4). The
major parts; the portions of the TM closer to the sclera corneoscleral and outer uveal trabecular beams are
in relation to this imaginary line include the corneo- flattened, perforated sheets that are orientated circum-
scleral meshwork, the juxtacanalicular tissue, and SC. ferentially, parallel to the surface of the limbus. However,
The portion of the TM closer to the anterior chamber the inner one to two layers of uveal sheets closest to the
internal to this imaginary line is termed the uveal anterior chamber have a round, cord-like profile and
meshwork, because it extends from Schwalbe’s line are oriented in a radial, net-like fashion, enclosing large
to the stromata of the ciliary body and iris (Fig. 1). The open spaces for aqueous outflow. The spaces become
uveal meshwork is readily viewed gonioscopically. progressively smaller from the uveal to the corneo-
It is important to understand the relationship among scleral meshwork (Figs. 1 and 4). After surgical removal
the anterior chamber angle structures by comparing of uveal meshwork from the TM, outflow facility was
Anatomy of the conventional aqueous outflow pathway 3
Fig. 1. Normal trabecular outflow pathway. (a) A light micrograph of the anterior chamber angle is shown. Trabecular meshwork (TM),
Schlemm’s canal (SC), collector channel (CC), intrascleral plexus (ISP), episcleral vessels (ESV), scleral spur (SS), ciliary muscle (CM), and iris
are labeled. The white arrowhead demarcates the terminus of Descemet’s membrane, also known as Schwalbe’s line. Reproduced from
Gong et al.18 (b) The trabecular meshwork is shown at higher magnification. From proximal to distal, the uveal trabecular meshwork (U),
the corneoscleral trabecular meshwork (CS), and the juxtacanalicular tissue (JCT) are labeled. The anterior chamber (AC) and Schlemm’s
canal (SC) are also labeled. Adapted from Gong et al.148
Fig. 2. (a) Macroscopic photograph and (b) corresponding sketch identifying structures visible in a meridional section of the normal
anterior chamber angle of a monkey eye. The anterior chamber is artificially deepened because of posterior sagging of the iris following
removal of the crystalline lens. The heavily pigmented region corresponds to the posterior or filtering meshwork. Schwalbe’s line (SL),
Schlemm’s canal (SC), trabecular meshwork (TM), scleral spur (SS), and ciliary body band (CBB). Reproduced from Freddo.8
Fig. 3. The anterior chamber angle viewed with both microscopy and gonioscopy. (a) Macroscopic photograph of angle structures viewed
from the gonioscopic perspective. Schlemm’s canal is filled with blood in this specimen, demonstrating its relationship to the other angle
structures. An iris process (IP) is also shown. (b) A corresponding sketch of (a) (black box). (c) Goniophotograph of a normal open angle
and (d) corresponding sketch representing a view analogous to that in (c). Five alternating dark and light bands are evident in the angle.
The uppermost dark band corresponds to Schwalbe’s line (SL). The uppermost light band corresponds to the anterior or nonfiltering
meshwork. The next dark band corresponds to the posterior or filtering meshwork (TM). The next light band corresponds to the scleral
spur (SS). The final dark band, just above the peripheral iris, corresponds to the ciliary body band (CBB). Reproduced from Freddo.8
Fig. 4. Drawing of the aqueous outflow pathway and

adjacent tissue. (a) Schlemm’s canal; (b) an internal
collector channel opens into the posterior part
of Schlemm’s canal; (c) corneoscleral meshwork
beams; (d) scleral spur; (e) limbus; (f) uveal beams; (g)
Schwalbe’s line (peripheral terminus of Descemet’s
membrane); (h) an iris process extends from the root
of the iris to merge with the uveal meshwork; (i) the
longitudinal ciliary muscle is attached to the scleral
spur but has a portion which joins the corneoscleral
meshwork; and (j) the corneal endothelium becomes
continuous with the deep limbus. Double-headed
arrows represent a broad transition zone that begins
near the termination of Descemet’s membrane and
ends where the uveal meshwork joins the deep
limbus. CB: ciliary body. Adapted from Hogan et al.61
Fig. 5. Light micrograph of the trabecular meshwork

demonstrates phagocytosis of melanin by trabecular
endothelial cells in the posterior meshwork. Note
the abrupt reduction in the amount of pigmentation
in the anterior meshwork beyond the anterior edge
of Schlemm’s canal (SC) (black line). This difference
in pigmentation is evident clinically. Reproduced
from Freddo et al.149
Fig. 6. Transmission electron micrographs of normal trabecular meshwork. (a) The trabecular meshwork from a 61-year-old donor eye,
perfusion-fixed at 15 mmHg. Most beams are covered with a single layer of endothelial cells (arrowheads). Giant vacuoles (V) are seen
along the inner wall of Schlemm’s canal (SC). ITS: intertrabecular spaces. Reproduced from Gong et al.18 (b) Each trabecular beam is
covered by a single layer of trabecular endothelial cells (TEC) that rest on the basal lamina (BL), which surrounds a central connective
tissue core. Collagen (C), elastic fiber (EL), sheath material of elastic fiber (SM), and intertrabecular spaces (ITS). Reproduced from Gong
et al.150
Fig. 7. Transmission electron micrographs of the juxtacanalicular region (JCT). The JCT region is composed of the JCT cells and matrix.
The JCT cells are devoid of a basal lamina; their cell processes (arrowheads) connect to endothelial cells of the inner wall of Schlemm’s
canal (SC) and other JCT cells. The matrix is composed of collagen (C) and elastin (E). Reproduced from Gong et al.151
found not to be significantly influenced.10 Ultrastruc- tendons from the longitudinal bundle of the ciliary
turally, the uveal and corneoscleral beams consist of muscle extend into the meshwork, culminating in a
a central connective tissue core that is enveloped in system of elastic fibers that connect to the inner wall
a continuous wrapping of thin endothelial cells and a of SC, which has been termed the cribriform plexus
subcellular basal lamina (Fig. 6). Trabecular cells are (Fig. 8).19,20 The majority of the resistance to aqueous
phagocytic11 and capable of removing endogenous12,13 outflow is believed to reside in the JCT region near SC
and exogenous14,15 particles to keep the trabecular and is modulated by the inner wall of SC,10,21-27 but the
outflow channels free of potentially obstructive debris. actual source of this resistance has remained elusive.
A progressive, age-related loss of trabecular cells has The balance between ECM synthesis and degradation
been reported in normal eyes, and additional cell plays an important role in the regulation of aqueous
loss was reported in the TM of POAG eyes, compared outflow resistance and IOP.28 Abnormal accumula-
to normal subjects.14,16,17 Fusion of trabecular beams tions of ECM in the JCT region have been reported in
observed in POAG eyes may result from adhesions both primary and secondary open-angle glaucoma,29-32
between denuded portions of adjacent trabecular including POAG patients with no medical treatment.29
beams.18 Thus, this accumulation of ECM appears to be a primary
pathophysiologic event in POAG.
2.1.2. The juxtacanalicular region
The portion of the TM between the outermost corneo- 2.1.3. Schlemm’s canal
scleral beam and the inner wall of SC has a fundamen- SC is a continuous channel oriented circumferential-
tally different structure. Instead of connective tissue ly, deep within the internal scleral sulcus. Its lumen is
beams confined within endothelial wrappings, the JCT directly continuous with the venous system of the eye.
region is an open connective tissue matrix in which Despite this connection, blood is not usually seen in
fibroblast-like cells, lacking a basal lamina, are located. the canal unless IOP falls below the episcleral venous
The cells in the JCT form long processes by which they pressure or when the limbal vessels are compressed, as
attach to each other, to an extracellular matrix (ECM), occurs with the use of a flanged gonioscope. When cut
and to the inner wall endothelial cells of SC (Figs. 6a in cross-section, the canal has an elliptical appearance
and 7). In addition, studies have documented that with its major length varying from 264 ± 55 µm by his-
Fig. 8. (a) Anterior ciliary muscle tendons (T) and their connections with the trabecular meshwork (TR). Tendons from the longitudinal
bundle of the ciliary muscle (CM) extend to the scleral spur (SP), into the outermost corneoscleral trabeculae, and into the juxtacanalicu-
lar region contributing to the cribriform plexus. Connecting fibrils (CF) extend from the plexus toward the endothelial cells (E) lining the
inner wall of Schlemm’s canal (Sc). EL: elastin. Reproduced from Rohen.19 (b) Immunoelectron micrograph shows a single connecting fibril
(C) attaching to the endothelium (E) of the inner wall of Schlemm’s canal (SC). Scattered small black dots represent colloidal gold staining
for elastin, confirming that these connecting fibrils contain this protein. Reproduced from Gong et al.20
tological assessments33 to 347.2 ± 42.3 µm as measured than I-pores.42 Previous tracer studies showed an
with OCT.7 The mean height of SC (at the widest distance increased pore density with increased accumulation of
between the inner and outer wall of the canal) is 31 ± fluorescent tracers along the inner wall44 and near the
2 µm in normal human eyes by histology.34 pores on both basal and apical sides of the inner wall
The canal usually appears slit-like (Fig. 1a), and at endothelium of SC (Fig. 14).45 Although an earlier study
some points around the circumference of the eye it reported that pores were responsible for about 10%
can be divided into two parallel channels that rejoin of total outflow resistance in normal eyes,43 a hydro-
after a short distance. One side of the canal directly dynamic interaction between the pores of the inner
abuts the sclera, which is termed the outer wall of SC. wall of SC and the underlying JCT may greatly increase
The opposite side is connected to the JCT region of outflow resistance in this region through a funneling
the meshwork and is termed the inner wall of SC. The effect, by confining the flow to the JCT regions near the
endothelial lining of SC is composed of a single layer of inner wall pores, forcing a funneling pattern of aqueous
cells that rest on a discontinuous basal lamina (Figs. 6a outflow; thus, pores may modulate the resistance in
and 7). The endothelial lining cells are elongated, this region.26 Decreased pore density was found in
generally oriented parallel to the longitudinal axis of POAG eyes compared to normal eyes,25,46 suggesting
the canal (Fig. 9). The cells are 71.8-90.2 µm in length that loss of the ability to form pores may contribute to
and 9.7-13.3 µm in width in the central nuclear region, increased outflow resistance in eyes with POAG. A layer
and narrower (3.9-8.0 µm) in non-nuclear regions.35 of nonuniform glycocalyx lines the wall of SC and fills
Adjacent endothelial cells are overlapping and most of the pores through which aqueous humor flows
connected to each other by tight junctions (Fig. 10).36 into SC (Fig. 15).47 Glycocalyx in SC may play a role in
Decreased cell overlap and tight junction strands were transduction of shear stress and regulation of aqueous
found with increasing pressure experimentally.37 The outflow resistance, since a glycocalyx-filled pore has a
inner wall endothelial cells connect to the underlying far higher flow resistance than an empty pore.47
JCT cells and matrix through their cellular processes.35,38 Increasing IOP leads to progressive collapse of the
There are seven types of cellular connections between canal.39,48 As SC collapses, the outflow resistance
the inner wall cells and JCT cells and matrix based on increases and IOP rises further.49,50 Collapse of SC was
serial block-face scanning electron microscopy and 3D also associated with a shorter scleral spur (Fig. 16),
reconstructions (Fig. 11).35 A characteristic aspect of the which may compromise the ciliary muscle/scleral spur/
inner wall endothelium of SC is the formation of cellular TM network that maintains the patency of SC.34 The
outpouchings that are termed giant vacuoles (GVs; Figs. dimensions of SC in eyes with POAG were reported to
9 and 12). The GVs form when aqueous humor pushes be significantly smaller than in the normal eye.33,34 This
against the basal side of the inner wall endothelium.39 reduction in the dimensions of SC may account for
They appear to be pressure-dependent and are nearly half of the decrease in outflow facility observed
observed easily when the inner wall is fixed under in POAG eyes.33
conditions of active flow.40 There are often multiple GVs
within each inner wall cell, and usually one large GV near 2.2. The ciliary muscle and trabecular outflow
the cell nucleus accompanied by a few smaller GVs along Attached to the posterior surface of the scleral spur
the length of the cell (Fig. 9b).35 Aqueous humor enters are tendons of the longitudinal bundle of the ciliary
into SC from the JCT and is believed to exit through the muscle, which are continuous with the ECM of the TM
GVs and small openings or pores (Fig. 9).41 There are two (Figs. 8 and 16).51 Contraction of these longitudinal
types of pores that are termed intracellular and para- muscles pulls the scleral spur posteriorly and separates
cellular pores (Fig. 12).42 Intracellular pores (I-pores) are the layers of the corneoscleral meshwork attached to
often associated with GVs with a mean diameter around the anterior surface of this structure. This appears to
1 µm.43 Paracellular pores are located at the border facilitate aqueous drainage and is the basis for the use
between two adjacent endothelial cells (B-pores), where of miotics in increasing aqueous outflow to reduce IOP
overlap between two cells does not exist (Fig. 13).35 The in glaucoma. Surgical disinsertion of the ciliary muscle
mean diameter of B-pores is 1.64 µm, slightly larger has been shown to eliminate the outflow-enhancing
Fig. 9. The inner wall endothelial cells of Schlemm’s canal. (a) A scanning electron micrograph of the luminal surface of the inner wall of
Schlemm’s canal demonstrating numerous bulging giant vacuoles. Several pores are evident (arrowheads), shown at higher magnifica-
tion in the inset. Reproduced from Allingham et al.46 Inset reproduced from Gong et al.151 (b) 3D scene of an inner wall endothelial cell with
two giant vacuoles (GV) and a pore. An inner wall cell (blue) with an I-pore (circled) associated with one of two GVs (green) near the nucleus
(dark red) was 3D reconstructed based on serial, ultrathin scanning electron microscopy (EM) images. (c) A higher magnification snapshot
of the reconstructed I-pore encircled in (b). Reproduced from Lai et al.35
Fig. 10. Junctions between the adjacent inner wall cells of Schlemm’s canal (SC). Two adjacent endothelial cells are overlapping and
connected by tight junctions, which appear as fusion points between the plasma membranes of two adjacent cells (arrows).
Fig. 11. Types of connections between inner wall (IW) endothelium (red) of Schlemm’s canal (SC), underlying juxtacanalicular connective
tissue (JCT) cells (green), and extracellular matrix (ECM). Cell-to-cell (arrows) and cell-to-ECM (arrowheads) connections between the IW
endothelium and JCT cells or ECM were categorized into seven types based on serial block-face scanning electron microscopy images
and 3D reconstructions. Type 1 shows the IW cell extending a cytoplasmic process to underlying ECM (and not to any cell bodies of JCT);
Type 1: IW process-to-JCT ECM. Types 2-7 are between an IW and JCT cell; Type 2: IW process-to-JCT cell body, type 3: IW tongue-in-JCT
groove, type 4: IW process-to-JCT process, type 5: JCT process-to-IW body, type 6: JCT tongue-in-IW groove, and type 7: IW body-to-JCT
body. Reproduced from Lai et al.35
Fig. 12. Two types of pores: I- and B-pores. (a) Transmission electron micrograph of the juxtacanalicular tissue (JCT) region with elastic
fibers (EL) and inner wall endothelium of Schlemm’s canal (SC) showing giant vacuole (V) and an intracellular pore leading into SC
(arrowhead). Reproduced from Gong et al.150 (b) An opening from the juxtacanalicular tissue (JCT) to Schlemm’s canal (SC) (arrows)
between two inner-wall cells. Adapted from Ye et al.37
Fig. 13. B-pores and overlapping cell margins between two inner wall (IW) endothelial cells of Schlemm’s canal (SC). (a) 3D reconstructions
of two adjacent IW cells (green and orange) were made semi-transparent to show overlapping cell margins (dark green region indicated
by arrows) and a B-pore (encircled). GV: giant vacuole. (b) Higher magnification snapshot of reconstructed pore encircled in (a). (c) Three
serial block-face scanning electron micrographs from which the B-pore (arrow) was identified and reconstructed. Reproduced from Lai
et al.35
Fig. 14. Analysis of tracers crossing the inner wall. (a) Tracers (arrows) were observed across the inner wall of Schlemm’s canal (SC) at
various regions. (b) At a higher magnification, fluorescent tracers were observed on both the basal and apical side of a cell-cell junction in
the inner wall endothelium of SC. (c) Serial sections were cut in the same cell-cell junction region as shown in (b). A paracellular pore was
seen with tracers on both the basal and apical sides. Adapted from Yang et al.45
Fig. 15. Pores filled with glycocalyx. (a) A glycocalyx layer coats the luminal surface of Schlemm’s canal (SC) of a human eye. A pore in a
giant vacuole (GV) (arrow; insert at a higher magnification) is filled with glycocalyx, but the inner membrane of the GV is not coated with
glycocalyx; note the membranous material apparently in the passage through the GV. (b) Glycocalyx was seen filling a pore not associated
with the GV (arrow; insert at a higher magnification). Significant Alcian blue staining was also seen in the extracellular matrix of the basal
side of the inner wall endothelium (*). Adapted from Yang et al.47
Fig. 16. Shorter scleral spur in eyes with primary open-angle glaucoma (POAG). (a) A light micrograph from a normal eye, the red line
indicates the length of the scleral spur. (b) A light micrograph from a POAG eye; the scleral spur is shorter compared to that in the normal
eye (a). Schlemm’s canal (SC) is collapsed (arrows). TM: trabecular meshwork; CM: ciliary muscle. Adapted from Swain et al.34
effects of pilocarpine.52 In addition, the elastic fibers of side of the eye.54,55 This has been confirmed by studies
the scleral spur are continuous with the elastic fibers using three-dimensional microcomputed tomography
in the trabecular beams and the cribriform plexus in (3D micro-CT) (Fig. 17).56 There is great variability in
the JCT19 (Fig. 8) and extend to the basal lamina of the the orifice size of CCs, with a range between 5-50 µm
inner wall endothelial cells of SC.20 These tendons are to as high as 70 µm, depending on the study design.54-56
thought to put tension on the inner wall of SC, resisting Examined by scanning electron microscopy, two classes
the pressure-related collapse of SC when pressure is of CC orifices were identified. Simple, oval orifices (54 ±
elevated.53 4.6 µm diameter) often occurred in a planar region of
the outer wall of SC, and complex orifices (62.7 ± 3.4 µm
2.3. Aqueous outflow pathways distal to SC diameter) were usually associated with septal columns
and bridges.57 A previous study reported that smooth
2.3.1. Collector channels muscle actin was found near the CC ostia regions, 58 but
From SC, aqueous humor enters the CCs. Histologically, further study is needed to understand whether these
25-30 CCs are found randomly distributed circumferen- vessels are capable of contraction and thus contribute
tially around SC in the human eye, with a higher distri- to regulating aqueous outflow.
bution on the inferior-nasal side than on the temporal A light microscopic study has shown that CC ostia
Fig. 18. Diagrammatic representation of the distal portion of

the aqueous outflow pathways from Schlemm’s canal. External
collector channels (lower right), deep and intrascleral plexi (upper
right), aqueous veins (1 and 2; upper left), and arterial circle (lower
left). Reproduced from Hogan et al.61
into CCs in POAG compared to normal eyes.59,60

Fig. 17. Distribution of collector channels in a normal eye. (a)
Up to 30 collector channels (black arrows) were found unevenly 2.3.2. Scleral venous plexus
distributed around Schlemm’s canal (magenta). Asterisks denote From the CCs, aqueous humor passes through a tortuous
two adjacent collector channels. Reproduced from Hann et al.56 (b)
A light micrograph of the frontal section showing the trabecular
system of passages, including the deep, midlimbal, and
meshwork, Schlemm’s canal (SC) and collector channel (CC) ostia. superficial intrascleral venous plexuses that lead in turn
Reproduced from Gong et al.152 to the episcleral veins (Fig. 18).61 The intrascleral venous
plexus is composed of a series of small, interconnected
were significantly narrower in POAG compared to venules 10 to 50 µm in diameter with many interconnect-
normal eyes.59 A study examined the anatomy of CCs ing branch points forming a dense vascular network.
in enucleated normal and POAG eyes under normal The venous plexus is drained posteriorly by several
(10 mmHg) and high (20 mmHg) perfusion pressure larger veins forming a series of radial arcades. These
using 3D micro-CT.60 CC orifice area (8049.2 vs 6468.4 vessels are 50 to 100 µm in diameter and progressively
µm2) and CC diameter (36.2 ± 19.1 vs 29.0 ± 13.8 µm) converge into larger vessels moving posteriorly away
were found to be larger in 10 mmHg compared to 20 from SC. These vessels eventually converge with larger
mmHg perfusion pressure in POAG eyes. In normal episcleral veins. Visualization of these vessels has been
human eyes, CC orifice area was larger (9962.8 vs reported using OCT,62,63 fluorescent microsphere tracer
8825.2 µm2), but a similar CC diameter (34.3 ± 17.8 vs studies,63 and 3D micro-CT.56
32.7 ± 13.0 µm) was found at 10 mmHg compared to
20 mmHg, suggesting that compensatory mechanisms 2.3.3. Aqueous veins
for transient and short periods of increased pressure The human eye contains a small number of unique
are diminished in POAG eyes.60 Partial and total CC vessels termed AVs (of Ascher), which are of great
occlusions or partial and complete herniations into CC importance to normal aqueous outflow. AVs bypass
ostia were present in normal and POAG eyes, with an the deep and intrascleral venous plexus and directly
increase in total occlusions or complete herniations communicate from SC to episcleral veins that return
Fig. 19. Neoprene cast of Schlemm’s canal and limbal vessels

showing sector containing marked aqueous vein. The tantalum
wire loop is still to be seen in situ. Reproduced from Ashton.153
Fig. 20. Pulsatile flow changes in the normal eye. Illustration of characteristic pulsatile flow changes caused by increasing IOP or addition
of medications. Still frames and illustrations derived from video images of a 59-year-old male subject. (a) Baseline IOP: velocity (V) is low
and aqueous pulse-wave travel (D) with each stroke is small. A standing transverse interface of aqueous and blood oscillates, resulting
in systolic discharge of aqueous into a small venous tributary (ST). (b) Slightly increased IOP: The oscillatory aqueous fluid wave travels
an increased distance. (c) Highest IOP: increased velocity and travel of the aqueous fluid wave. At each systole a lamina of clear aqueous
discharges into an episcleral vein. (d) Decreasing IOP: velocity and travel of the fluid wave increase further. Continuous, oscillating laminar
flow is present in a more distal episcleral vein. Two hours after drinking water, IOP was again 10 mmHg and stroke volume returned to the
appearance seen in image (a). Reproduced from Johnstone et al.76
blood to the general circulation64-66 (Fig. 19). AVs of the TM. The TM must be deformable to dynamic
contain clear aqueous at their origins but anastomose pressure and volume changes in inflow and outflow
with episcleral vessels that contain blood. Transition- for normal aqueous outflow to occur from the anterior
al zones are often identified in AVs on the conjuncti- chamber to SC.76
val surface as a large vessel with a clear central lumen The major source of aqueous humor outflow
bordered on either side by dark blood. With changes in resistance is located in the JCT, within 7-14 µm of the
IOP, these transitional zones vary in their composition inner wall of SC by microcannula pressure measure-
of aqueous and blood. Direct observation of these ments,24 and is modified by the inner wall endothelium
changes is a reliable method to gauge the efficacy of of SC through its pores.10,21-23,25-27 Structures distal to SC,
medical and surgical treatments aimed at reducing IOP including the CCs, intrascleral venous plexuses, and AVs,
in glaucoma.67 are assumed to contribute less to outflow resistance.77,78
AVs vary in their position, size, and anatomical An early study reported that 75% of aqueous outflow
arrangements. On slit-lamp examination, two to three resistance was localized to the TM and SC with 25%
AVs are typically visible with up to a maximum of six occurring from the structures distal to SC21 when eyes
occasionally observed.68 AVs have unequal distributions were perfused at 25 mmHg. Following complete trabec-
and are present most abundantly in the inferior-nasal ulotomy, 49% of outflow resistance was eliminated at
quadrant, with the remainder in the inferior-temporal a perfusion pressure of 7 mmHg (corresponding to the
quadrant.68 Their size varies from 20-100 µm, with an normal IOP in enucleated human eyes with no episcleral
average of 50 µm.68-70 Histologically, AVs are indistin- venous pressure),79 and 71% of outflow resistance was
guishable from conjunctival and episcleral veins. eliminated at a perfusion pressure of 25 mmHg.10 This
A dynamic equilibrium exists in AVs based on the suggests that pressure-dependent changes in outflow
current understanding of pulsatile flow driving aqueous resistance are present in the TM and SC with additional
outflow (Fig. 20).71-73 Pulsatile flow occurs from an resistance distal to SC. Another study using excimer
oscillatory, compressive force provided by the cardiac laser to ablate one clock hour of tissue from the outer
pulse and blinking, inlet channels from the JCT and wall of SC and distal sclera eliminated 35% of outflow
the inner wall endothelium to SC, and outlet channels resistance at a perfusion pressure of 10 mmHg.80 These
via CCs and AVs. Glaucoma patients show a decrease studies indicate that one-third to half of the outflow
in pulsatile flow compared to normal subjects.74,75 The resistance lies distal to the inner wall of SC.
reduction of pulsatile flow in glaucoma patients can be
accounted for by physiologic changes in the elasticity
Fig. 21. Segmental aqueous flow pattern in normal human eyes. (a) Posterior view of the tracer distribution in the trabecular meshwork
(TM) in a global image. Segmental tracer distribution is seen. S: superior; N: nasal; I: inferior; T: temporal. (b) Segmental tracer distribution
is seen in the scleral veins in the anterior view of a global image. (c) A confocal microscopic image showing tracer distribution in the TM is
segmental, and more tracer (green) is near the collector channel (CC) ostia region, leading away from Schlemm’s canal (SC). (d) A confocal
microscopic image showing no tracer in this region of the TM, nor near a CC. Reproduced from Gong et al.152
Fig. 22. Pigmentation near the collector channel ostia region of the trabecular meshwork (TM). Light micrograph of the TM demonstrates
phagocytosis of melanin by trabecular endothelial cells. More pigmentation is observed in the TM near the collector channel (CC) ostia,
which is open to Schlemm’s canal (SC) obliquely. Reproduced from Gong et al.152
Fig. 23. Trabecular meshwork (TM) thickness in areas of active and inactive outflow. (a) In areas of active outflow, more fluorescent green
tracers were observed within the TM and along the inner wall of Schlemm’s canal (SC), and a thicker trabecular meshwork was noted (red
double arrows). CC: collector channel. (b) Inactive areas of outflow showed little to no green fluorescent tracers within the TM and along
SC inner wall, as well as a thinner TM (red double arrows). (c) TM thickness was significantly larger in areas of active outflow compared to
areas of inactive outflow (*P ≤ 0.01). Reproduced from Cha et al.82
3. Aqueous outflow patterns present and that pigment may serve as a useful internal
marker to identify the area with active flow. However,
3.1. Aqueous outflow is nonuniform (segmental) in active flow is not observed in some TM regions near CC
normal eyes ostia, especially in the superior and temporal regions
Aqueous humor outflow is nonuniform or segmental of the eye45,82 (Fig. 23b), suggesting higher outflow
circumferentially as observed from the distribution of resistance near these CC ostia. The factors that regulate
pigment in the TM81 and fluorescent tracer perfused regional outflow resistance remain unclear. A segmental
into the anterior chamber.48,82-84 At any given time, only nature of outflow is observed along the trabecular
a fraction of the outflow pathways is actively involved outflow pathway in the TM, near the inner wall of SC,
in aqueous humor drainage (Fig. 21a and 21b). This and in the episcleral veins (Fig. 21). Similar EFA was
active area is termed the effective filtration area (EFA). found in the inner wall of SC and episcleral veins. Pref-
Segmental outflow has been reported in n onhuman48,83-86 erential active outflow was observed in the nasal and
and human eyes.45,81,82 A greater concentration of tracer inferior quadrants of the eye, where a higher number
was observed in the TM adjacent to CC ostia where more of CCs was found.82 The TM and JCT in the active flow
pigment was also observed in human eyes (Figs. 21c, 22, region appear more expanded compared to inactive
and 23a), suggesting that preferential flow pathways are flow regions (Figs. 23 and 24).
Fig. 24. Juxtacanalicular connective tissue thickness in areas of active and inactive flow. (a) In areas of active outflow, the juxtacana-
licular region (JCT) is much more expanded with areas of empty space (double arrow). Tracers are abundantly observed in active flow
areas (small arrows). (b) In inactive areas of outflow, the JCT is much denser with less empty space (double arrow). Tracers are not readily
observed in this region.
3.2. Reduction of aqueous outflow area with in- and corresponding elevation of IOP.88 More continuous
creasing IOP and in POAG and thicker basement membranes observed along the
EFA, measured by the percent length of SC, i.e.: inner wall of SC and increased ECM in the JCT may
account for the reduction of active outflow areas and
% effective filtration length = outflow facility in POAG.89
(length of the inner wall exhibiting tracer labeling) 
  ____________________________________
        
(total length of inner wall of SC) 
 
 
× 100% 3.3.2. Collapse of SC and herniations of the TM into CC
ostia
In an acute IOP elevation study in bovine eyes,
was found to be reduced with acute elevation of morphological changes responsible for reduced
IOP in bovine eyes. Outflow patterns in the JCT and outflow area included a progressive collapse of the
inner wall near CCs transitioned from less segmental aqueous plexus (equivalent to SC in human eyes) and
(more uniform) patterns at normal IOP (7 mmHg in increasing numbers of herniations into CC ostia (Fig.
enucleated eyes) to increasingly segmental patterns 27).48 These morphological changes were associated
at higher IOP (15-45 mmHg; Fig. 25).48 This decrease in with decreases in effective outflow area and outflow
EFA is associated with decreased outflow facility and facility; however, they were reversible when IOP was
is reversible when pressure is reduced from a high to returned to a normal level.87 A progressive collapse
a normal level.87 A decrease in EFA was also reported of SC and an increasing number of tissue herniations
in chronic elevation of IOP in a laser-induced monkey into CC ostia following an acute elevation of IOP
glaucoma model.88 In this study, reduced tracer was were also found to be associated with a decrease in
found in areas of the TM that had received laser injury outflow facility in normal human eyes. These changes
even when CC ostia were present in the region. Active were reversible when IOP was decreased from high
outflow was found to be shifted away from areas to normal levels (Fig. 28).91 These data suggest that
with laser injury to areas without (Fig. 26). Significant collapse of SC and increasing numbers of herniations
reduction of EFA was also reported in POAG eyes into CC ostia may be important factors contributing
compared to normal eyes in a tracer study.89 Addition- to the decrease in outflow facility following acute IOP
ally, an inverse correlation between EFA and IOP was elevation.
documented in an ocular hypotensive and an ocular Examined by scanning electron microscopy, partial
hypertensive mouse model.85 Collectively, these results and total CC occlusions were present in normal and
suggest that the EFA is a valuable method of measuring POAG eyes, with an increase in total occlusions in
outflow resistance and the effects of changes in IOP in POAG compared to normal eyes.60 A study compared
human and nonhuman eyes. the light microscopic images from frontal sections
between normal autopsy eyes and those with POAG.
3.3. Morphological changes responsible for reduced The collapse of SC and the herniations into the CC
outflow area ostia were found to be common among eyes with
POAG, even when the eye was fixed at zero pressure
3.3.1. Increasing ECM in the JCT (Fig. 29).92 The longer the IOP remains high, the less
An increase in the amount of ECM or plaque material in pliable the changes in the TM tissue seem to become.
the JCT has been reported in the eyes of patients with The disturbing implication of these findings is that
POAG with and without medical treatment.29,31 This normally reversible morphological changes after an
increase is associated with increasing severity of optic acute elevation in IOP (Fig. 28) may become permanent
nerve damage in POAG.90 In laser-induced glaucoma in cases of POAG. Occluded CC ostia may explain the
monkey models, increased fibrosis and an accumula- variable success of surgical procedures intended to
tion of ECM was observed in the JCT in laser-damaged restore outflow into the episcleral venous system via
areas of the TM. This increased ECM has been shown the canal.
to result in a reduction in active outflow area. This
reduction contributes to a decrease in outflow facility
Fig. 25. Confocal microscopy of fluorescent microspheres perfused at four different IOPs. (a) At 7 mmHg, a uniform distribution of micro-
spheres (red) was found along the inner wall of the aqueous plexus (AP). In contrast, at pressures of (b) 15 mmHg, (c) 30 mmHg, and (d)
45 mmHg, there was a segmental pattern of microsphere distribution with a greater concentration of microspheres in the trabecular
meshwork near the collector channel (CC) ostia. This concentrated distribution was visually more dramatic at 45 mmHg than at 15 mmHg.
Reproduced from Battista et al.48
Fig. 26. Comparison of effective filtration length and width of Schlemm’s canal (SC) in control and laser-induced glaucomatous monkey
eyes. (a) In control eyes, SC was open and segmental distribution of microspheres (pink) was found with a greater concentration in the
trabecular meshwork (TM) near the collector channel (CC) ostium. (b) In the lasered region of laser-treated eyes, SC was collapsed and
fewer or no microspheres were found in most areas of the TM. (c) In the lasered region of laser-treated eyes, no microspheres were found
in the CC ostia region. (d) In the non-lasered region of laser-treated eyes, a large number of microspheres (pink) were seen near CC ostia.
(e) The average percent effective filtration length (PEFL = length of exhibiting tracer labeling [L] ÷ total length [TL]) in control eyes (47.47
± 10.79%) was six-fold larger than in laser-treated eyes (8.40 ± 4.81%, P = 0.013). (f) The mean distance between the IW and outer wall of
SC of control eyes (18.99 ± 6.03 µm) was five-fold greater than in laser-treated eyes (3.47 ± 0.33 µm, P = 0.01). Adapted from Zhang et al.88
Fig. 27. Light microscopy of the aqueous plexus (AP) and collector channels (CC) at four different pressures. (a) At 7 mmHg, the AP is more
open compared to the tissue perfused at higher pressures. (b) At 15 mmHg, the inner wall and JCT is partially herniated into the CC ostia.
(c) At 30 mmHg and (d) 45 mmHg, AP is collapsed adjacent to the CC ostia. There is a more dramatic herniation of the inner wall and JCT
into the CC ostia. Reproduced from Battista et al.48
Fig. 28. Light microscopy images of the collector channel (CC) ostia regions of normal human eyes after an acute elevation in IOP. (a) When
the eye was continually perfused at 45 mmHg, Schlemm’s canal (SC) was collapsed, and the trabecular meshwork was herniated into the
CC ostium. (b) When the eye was first perfused at 45 mmHg and then the IOP was reduced to 7 mmHg, the herniation into the CC ostia
seen at 45 mmHg (a) was reversed; deformation of the trabecular meshwork facing the CC ostium region was still seen. SC became wider
in this eye than in the eye perfused continually at 45 mmHg (a). (c) When the eye was continually perfused at 7 mmHg, SC was open and
no herniation was visible. Reproduced from Gong et al.152
Fig. 29. Light microscopic comparison between the POAG and normal collector channel (CC) ostia regions in immersion-fixed eyes (a) A
micrograph of a normal eye. Schlemm’s canal (SC) was open, and the herniation was not observed in the CC ostia region. (b) In comparison,
an eye with POAG demonstrated a collapse of SC adjacent to both sides of the CC ostium with focal adhesions between the inner wall and
outer wall. In addition, herniations of the inner wall and JCT into CC ostia were also observed. Scale bar: 25 µm. Reproduced from Gong
et al.152
Fig. 30. Evaluation of blockage of collector channels (CC) by blood reflux into Schlemm’s canal (SC) and fluorescein egress pattern in the
episcleral veins. (a-c) Gonioscopic view of blood in SC after preoperative paracentesis of the anterior chamber. (a) A good blood reflux
case shows that SC uniformly filled with blood indicating patent SC and CC. (b) Patchy or irregular filling indicates a partially collapsed
SC. Blood is only detectable near the CC ostia (arrows). (c) No refluxed blood indicating a collapsed SC or blocked CC. (d-f) Analysis of four
quadrants of each eye with episcleral veins exhibiting fluorescein egress. (d) No filling of the episcleral veins. (e) Filling of the episcleral
veins after injection of fluorescein dye into SC. (f) The average number of quadrants exhibiting fluorescein egress is consistent with blood
reflux patterns in (a-c). Reproduced from Gong et al.152
3.3.3. Blockage of CCs by clinical observation in POAG degree of blockage for blood reflux into the SC from
Blockages of CC ostia were reported clinically in black episcleral veins. In the good-reflux group, fluorescein
South African patients with POAG in both retrospec- egress into episcleral veins from SC was seen in more
tive93 and prospective studies.94 In a retrospective study than three quadrants (3.67 ± 0.50, mean ± SD) of the
with Dr. Robert Stegmann, clinical data was analyzed, eyes. In the patchy-reflux group, fluorescein egress into
including the video recordings of surgical procedures episcleral veins was seen in more than two quadrants
for 19 untreated black South African POAG patients (2.67 ± 1.21), while in the no-reflux group, fluorescein
(24 eyes) undergoing canaloplasty. Preoperative para- egress into episcleral veins was decreased to less than
centesis was followed by provocative gonioscopy to one quadrant or between one and two quadrants (0.89
elicit and grade patterns of inducible blood reflux into ± 0.93). This study suggests attenuated and interrupted
SC. After exposing SC, a flexible microcatheter was blood reflux into SC from CCs is consistent with
inserted into SC circumferentially, and fluorescein decreased numbers of quadrants exhibiting fluorescein
was injected into SC in each quadrant to evaluate the egress into episcleral veins via CCs, and that blockage
fluorescent outflow patterns from SC into the episcleral of CC ostia may exist in vivo.94 Whether the cause of
veins. Quadrants exhibiting fluorescein egress were these blockages is the irreversible herniations into CC
counted and analyzed. Three patterns of blood reflux ostia observed histologically warrants further study.
were observed (Fig. 30): good reflux (blood observed Since occluded CC ostia affect the success of surgical
along the entire circumference of SC, N = 9), patchy procedures intended to restore outflow into the
reflux (attenuated blood reflux observed, N = 6), and no episcleral venous system via SC, observing the reflux
reflux (no observable blood in SC, N = 9). Fifteen eyes of blood from the collector system into the canal could
(patchy + no blood reflux, 60.8%) demonstrated some serve as an indication of a patent system in that region.
3.4. Lowering IOP by increasing aqueous outflow chamber angle in patients in vivo. The technique
area requires a probe to be placed in a water bath held by
A new drug for the treatment of glaucoma, netarsudil an eye cup positioned in the palpebral fissure between
(Rhopressa®, Aerie Pharmaceuticals, Inc., Durham, the eyelids.99 UBM is useful to assess the iris position
NC, USA), is a Rho kinase/norepinephrine transporter and the patency of the anterior chamber angle. UBM
inhibitor, which increases outflow facility via multiple can provide measurements of depth of the anterior
mechanisms in human eyes. Experimental data showed and posterior chambers and thickness of the cornea,
that an increase in outflow facility induced by netarsudil iris, ciliary body, and sclera.100 Studies using UBM have
in enucleated human eyes is associated with TM and identified and measured SC and the TM. One study
JCT expansion and dilation of episcleral veins, resulting using iUltrasound (iScience Interventional, Inc., Menlo
in an increase in active filtration area in the TM near SC Park, CA, USA) examined the variation in diameter and
and in the episcleral veins.95 location of SC in vivo in 80 patients (40 normal and 40
A glaucoma device, trabecular microbypass (iStent, POAG) and found that the meridional diameter of SC
Glaukos, San Clemente, CA, USA) (also discussed in from anterior to posterior aspect was 233.0 ± 34.5 µm in
Chapter 9), increases outflow facility by directing normal and significantly decreased in POAG eyes (195.6
outflow into episcleral veins from SC, bypassing the TM. ± 31.1 µm).101 These values are much smaller compared
However, since the iStent is so small (1 mm length, 120 to histological measurements in immersion-fixed eyes
μm inlet), success of surgery is dependent on the cir- (316 ± 12 µm in normal eyes and 287 ± 10 µm in POAG).34
cumferential location (i.e., whether or not the implant is Clinically, UBM has been shown to be useful intra-
placed near the larger CC ostia). An increase in outflow operatively to guide maneuvering of microsurgical
facility is associated with implanting more than one instruments in ab interno procedures, including laser
iStent.96,97 Newer drainage devices would also benefit ablation trabeculotomy in ex vivo porcine eyes.102 Post
from preoperative knowledge of CC ostia location. A surgery, UBM has been used successfully to evaluate
recently approved device, Hydrus® Microstent (Ivantis, the function of filtering blebs after trabeculectomy
Inc., Irvine, CA, USA) (also discussed in Chapter 8), is a surgery.103,104 One study found a positive correlation
novel intracanalicular scaffold that increases outflow between UBM grade of bleb function (good, fair, poor —
facility by directing flow into more episcleral veins, based on scleral-flap visibility and internal reflectivity)
bypassing the TM and providing scaffolding to maintain and IOP control level (good: IOP < 15 mmHg; borderline:
patency of SC. In one study, the Hydrus Aqueous Implant IOP ≥ 15 and ≤ 18 mmHg; failure: IOP > 18 mmHg)
significantly increased outflow facility by increasing achieved in the patient.104 These studies demonstrated
the total episcleral vein active flow area. More scleral the usefulness of UBM in examining the anatomy of the
veins were accessed by the intracanalicular scaffold anterior chamber angle and determining the site and
via multiple CCs compared to controls or two iStent cause of failed trabeculectomy.
implants.98
4.2. Anterior segment OCT
4. In vivo assessment of structure 4.2.1. Introduction

and function of the aqueous outflow OCT is a noninvasive, noncontact method of imaging
ocular structures in vivo.105 OCT functions by analyzing
pathway
interference patterns. Light waves backscattered from
4.1. Ultrasound biomicroscopy optical structures interfere with a reference beam
Ultrasound biomicroscopy (UBM) is a noninvasive, and a depth and density profile is created.106,107 Spec-
two-dimensional imaging technique that utilizes tral-domain OCT (SD-OCT) devices use a single axial
ultrasound frequencies (35-100 MHz) to produce scan to acquire 3D information with high resolution
high-resolution images of the anterior chamber angle and increased signal-to-noise ratios, allowing for 3D
structures in vivo at microscopic resolution. UBM was reconstruction of structures of the outflow pathway,
one of the first tools available to assess the anterior including the iridocorneal angle, TM, SC, and scleral
venous plexus.63,107,108 The latest swept-source OCT 4.2.3. Potential surgical applications
(SS-OCT) devices utilize a longer wavelength (~1050 nm)
compared to previous OCT devices and are capable of 4.2.3.1. Preoperative applications
distinguishing deeper structures, including choroid The ability for OCT to visualize the aqueous outflow
and lamina cribrosa, and can further distinguish the anatomy in vivo may be useful in preoperative planning
scleral spur, Schwalbe’s line, and SC (Fig. 31).109-113 to optimize placement of microsurgical devices in
Previously, these structures could only be investi- areas near the CCs. This would increase therapeutic
gated with histological techniques, including light efficiency and contribute to better surgical outcomes.
and electron microscopy, and never in live patients. OCT devices provide baseline anatomical images
OCT technology is an innovative tool for research before a wide variety of surgeries, including trabe-
and clinical assessment of live patients through its culectomy bleb revision,124,125 trabeculotomy,126 and
noninvasive, noncontact imaging modality. canaloplasty.127-129 Advances in SS-OCT resolution have
been successful at visualizing CC anatomy,111,116,117 and
4.2.2. Identification of anatomical structures and these may soon offer better visualization than high
relationship between SC dimensions and IOP magnification with a gonioprism alone to guide surgical
Through precise identification of the structures of the placement of trabecular bypass microstents.
conventional outflow pathway, OCT technology has
the potential to guide and optimize surgical treatment 4.2.3.2. Intraoperative applications
of glaucoma. High-definition identification of the OCT has been used to monitor the procedure of
anterior chamber angle, the scleral spur, Schwalbe’s canaloplasty and evaluate suture tension within SC
line, and the anatomical boundaries of the TM has been through the Descemet window opened during deep
achieved with excellent reproducibility of angle mea- sclerectomy.130 This method reduced shadowing,
surements.7,113-115 While detailed evaluation of the TM, sometimes seen in OCT images, by utilizing the
SC, and CCs is more difficult due to the close association prepared window. Real-time, intraoperative feedback
of these different tissues at varying anatomical depths, on structural changes following anterior segment
many studies have successfully identified CCs and SC procedures may soon become standard of care with
dimensions with improvements in SS-OCT devices such new OCT technologies.131
as enhanced-depth imaging (Fig. 32).111,112,115-117 Other
SS-OCT studies have quantified the dimensions of the 4.2.3.3. Postoperative applications
TM and SC. Similar to studies with UBM, SS-OCT studies OCT has many clinical applications following surgery,
found that the anterior to posterior meridional SC including confirmation and evaluation of surgical
diameter decreased significantly in POAG eyes (190.91 outcomes. Many trabeculectomy studies have shown
± 46.67 µm; N = 68) compared to normal eyes (272.83 that anterior segment OCT (AS-OCT) is useful in
± 49.39 µm; N = 74).118 Collapse of SC has been found visualizing and monitoring the morphology of the
to be associated with acute IOP elevation48,119 and has filtering blebs created during surgery, by providing 3D
been observed in eyes with POAG.33,34 Using a commer- volumetric data over many years after s urgery.125,132-137
cially available OCT, a significant correlation was found After trabeculotomy surgery with Trabectome™
between increasing mean IOP and decreasing SC area (NeoMedix Corporation, Tustin, CA, USA), swept-
in normal and POAG patients.120,121 source AS-OCT has been effective in imaging the
Experimentally, pilocarpine-induced dilation of SC anterior angle postoperatively, to evaluate surgical
and prevention of SC collapse at elevated IOP in living outcomes and confirm removal of the TM (Fig. 33).126
mice can be visualized by SD-OCT.122 Additionally, using AS-OCT has been successful in visualizing the early and
OCT imaging and novel segmentation software, the persistent anatomical changes in SC after canaloplasty
effects of topical netarsudil on conventional outflow (Fig. 34).127-129,138 Studies also found that the height of SC
tissues in living mouse eyes can be visualized as widening increased from 15 µm to 41 µm three months postop-
of the TM and significant increases in cross-sectional eratively.128 In patients who received canaloplasty, the
area of SC following netarsudil treatment.123 increase in SC size correlated with decreased IOP.127-129
Fig. 31. Anterior segment swept-source optical coherence tomography (OCT) imaging of the anterior chamber angle. (a) Field (box) for OCT
imaging. (b) OCT image based on 96 B scans averaged for speckle noise reduction. Schlemm’s canal (arrowhead) was visible. Reproduced
from Uji et al.111
Fig. 32. Enhanced depth imaging optical coherence tomography scans can visualize variations of collector channel (CC) microstructure.
(a-d) CC (white arrows) originating from the lateral (posterior) portion of Schlemm’s canal (SC). (e-h) CC originating from the middle
portion of SC. (i-l) CC originating from the medial (anterior) portion of SC. AC: anterior chamber. Reproduced from Li et al.115
Fig. 33. Cross-sectional OCT image of nasal angle before and after combined trabeculotomy (Trabectome)-cataract surgery. (a) Baseline
scan before surgery. (b) After surgery, the image shows that the posterior trabecular meshwork has been removed leaving a wide
trabecular cleft (arrowhead). Adapted from Akil et al.126
4.3. Aqueous angiography fluorescein was used to see if the inactive outflow
Clinically, the segmental nature of aqueous humor became active after stent insertion.144 However, the
outflow around the circumference of the eye may correlation with aqueous outflow facility change has
play a role in patients’ surgical outcomes.82,139-141 A not yet been investigated.
new technique, aqueous angiography, was developed With further development of techniques for in vivo
to assess the functionality of the aqueous outflow assessment of outflow pathway anatomy, surgical
pathway in real time using fluorescent compounds, outcomes of trabeculectomy and placement of
including fluorescein and indocyanine green. This trabecular microbypass stents may improve from the
technique provides dynamic visualization of the active ability to localize areas of active and inactive outflow.
outflow regions through the episcleral veins and has The combination of AS-OCT and aqueous angiography
been successful in enucleated porcine,142 bovine,143 and provides real-time, in vivo visualization of the aqueous
human eyes (Fig. 35).142,144,145 Recently, the technique outflow pathway, which was not possible before with
has been applied in vivo to nonhuman primates146 and histological techniques. In vivo analysis may become
human patients.139,140,147 In live patients, a signal can standard of care with improved OCT technologies.131
be seen in the episcleral vessels rapidly after initial
injection into the anterior chamber (14.0 ± 3.0 seconds;
mean ± SE).140 This technique has the potential to 5. Summary
improve patient outcomes with trabecular microbypass
stents by guiding stent placement. Huang’s laboratory This chapter reviewed the basic anatomy of the conven-
recently performed aqueous angiography with two tional or trabecular outflow pathway and the structural
different color dyes in enucleated eyes.144 First, changes observed in experimentally induced elevation
indocyanine green was used to mark inactive outflow of IOP and in eyes with POAG. The structural changes
areas, and generation 2 stents (iStent inject®, Glaukos, in the outflow pathway that may be related to the
San Clemente, CA, USA) were inserted in the inactive reduction of active outflow area and thus increasing
flow areas. A second aqueous angiography with outflow resistance were also discussed. Using medical
Fig. 34. Cross-sectional OCT image of anterior angle before and after canaloplasty. (a) Baseline scan before surgery. (b) Scan taken
immediately after canaloplasty showing adequate trabecular distension (arrowhead). Reproduced from Mastropasqua et al.138
and surgical strategies to restore reduced active flow Acknowledgements

area in eyes with POAG to a normal level lowers IOP. With
further development of OCT and aqueous angiography The original work reported in this chapter was
it is possible that, in the future, some of the structural supported in part by EY022634, BrightFocus Foundation
and functional changes that currently are only able to be (Clarksburg, MD, USA), and The Massachusetts Lions
assessed histologically could be evaluated before and Eye Research Fund, Inc. (Belmont, MA, USA).
after medical or surgical treatments in POAG patients.
Fig. 35. Fluorescein aqueous angiography visualizes segmental pattern of aqueous humor outflow. Aqueous angiography performed with
2.5% fluorescein diluted in balanced salt solution, in post-mortem left eye of a 79-year-old female without any history of ophthalmic
disease, imaged with Heidelberg Spectralis HRA+OCT. The eye is oriented en face. Peri-limbal regions of the angiographic fluorescent
signal (arrowhead) were observed on the nasal (N) side, whereas no signal (arrow) was observed on the temporal (T) side. * denotes distal
signal. Reproduced from Huang et al.145
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2. Patents in an age of innovation
William Noonan
Klarquist Sparkman LLP, Portland, OR, USA
Abstract
Medicine is a research-intensive enterprise that relies Keywords: intellectual property, invention, medical
on patents to fund scientific development and promote technology, ophthalmology, patents
innovation. The essential requirements for patentabil-
ity in the United States are that an invention must be
patent-eligible subject matter that is new, nonobvious, 1. Introduction
useful, and described in sufficient detail to place the
invention in the possession of the public. The patent Ophthalmology is a technology-intensive specialty
system is emerging from a tumultuous period when that relies on patents to protect research investments
many of the basic rules have been changed. A new patent and fund scientific development. However, the alliance
law was introduced in 2013, and recent Supreme Court between patents and medicine has sometimes been
cases have upended the rules of patenting software uncomfortable.2 This discomfort is illustrated by a
inventions, natural products, and some diagnostic patent granted to Samuel Pallin (an ophthalmologist)
methods. However, patents on medical devices, in the 1990s on a chevron-shaped self-sealing incision
methods of treatment, and pharmaceuticals have been in the eye. When Dr. Pallin began to enforce his patent
relatively unscathed, and the rules of patenting these against eye surgeons who used the incision, there
and other inventions are reviewed. was a political outcry about the limits of patents in
medicine.3 Physicians from many specialties collabo-
1
The author is both a physician and a patent attorney. His 2
Noonan WD. Patenting Medical Technology, Journal of Legal
residency training was in ophthalmology, but he returned Medicine 1990;11(3):263-319. The discomfort has been felt on both
to practicing patent law. For many years he has represented sides. Physicians historically considered patents to be inappro-
companies, universities, and federal research laboratories to help priate intrusions into the doctor-patient relationship. The Patent
them protect medical inventions such as medical devices, phar- Office for its part was slow to protect medical inventions because
maceuticals, biologics, and DNA diagnostics. He was one of the the results of medical treatment were considered too speculative
first (and is still one of the few) physician patent attorneys. This and uncertain to deserve patent protection. Over the last 100
chapter should not be construed as legal advice or a legal opinion years both medicine and patent law have established a delicate
on any specific facts or circumstances. The contents are intended relationship that sometimes frays.
for general informational purposes, and an attorney should 3
U.S. Patent No. 5,080,111 issued to Dr. Pallin was asserted
be consulted about any specific legal questions. This chapter against medical doctors and eye clinics in the mid-1990s (Pallin
represents the views only of the author, and not of Klarquist v. Singer, 1996 WL 274407 (D. Vt., Mar. 28, 1996)). A more thorough
Sparkman, LLP or any clients of that firm. discussion of the Pallin patent controversy and the role of patents
in medicine may be found in Noonan WD. Patenting Medical and
Surgical Procedures, J Pat Trademark Off Soc. 1995;77(8):651-664.
Correspondence: William D. Noonan, MD, JD, Patent Attorney, Klarquist Sparkman, LLP, One World Trade Center, 121 S.W. Salmon Street
Suite 1600, Portland, OR 97204, USA.

40 W. Noonan
rated to change the patent law and protect clinicians to be challenged in the United States Patent and
from charges of patent infringement.4 Other con- Trademark Office (USPTO) instead of the courts. Over
troversies have arisen about patents in medicine, 90% of patents challenged in these proceedings have
such as the furor over patenting DNA molecules and been at least partially invalidated, although many of
diagnostic tests.5 The most famous case concerns the the invalidated patents have been on software and
Myriad Genetics patents for a cancer diagnostic test business method inventions.
that identified cancer-promoting mutations in BRCA The pendulum is always in motion, but it has swung
genes.6 When Myriad tried to enforce its patent on in a somewhat anti-patent direction in recent years.
the BRCA1 and BRCA2 genes against competitors, the These changes have come at a cost to the patent system
United States Supreme Court overturned a century of and American innovation. Without patent rights,
precedent and invalidated the patents because the there is less incentive to perform risky and expensive
inventions were “products of nature.” When medicine research because competitors can steal inventions
and American patent law have come into conflict, the with impunity.8 The United States patent system, which
result has usually been a retreat for patents.7 was once recognized as the best in the world, was in
The U.S. patent system was further altered in 2012 2018 ranked only 12th among global competitors (tied
when Congress replaced the then-existing patent law with Italy).9 By 2019, its ranking improved slightly into
with an entirely new patent law (the America Invents a tie for second place with ten other countries, but still
Act or AIA). Although the new law is mostly the same well below first-place Singapore.10 The United States
as the old law, several changes were introduced is reportedly losing its edge in innovation as global
that are harmful to innovators. For example, a new venture capital increasingly flows to other countries.11
Inter Partes Review (IPR) procedure permits patents However, there are still opportunities for protecting
4
35 USC § 287(c)(1) prevents entry of an injunction or an award 8
A similar decline in the strength of the American patent system
of damages against a medical practitioner performing a medical occurred in the 1970s, and it was blamed for a decline in U.S.
activity. Use of a patented device or composition is not a “medical research and development spending. Congress in the early 1980s
activity” hence the medical practitioner exception is narrow. See acted to strengthen the patent law and create a national patent
generally Noonan WD. Patenting Medical and Surgical Procedures, appeals court (the Federal Circuit), which for a time revived
J Pat Trademark Off Soc. 1995;77(8):651-664. The author testified the power of patents. Some economists believe these legal
before the House Judiciary Committee in 1995 about medical changes contributed to the economic boom of the 1980s and the
procedure patents and the proposed legislation to limit them. technological innovations in biotechnology and software that
Medical Procedures Innovation and Affordability Act and the transformed the American economy. For a spirited recent review
Inventor Protection Act of 1995. Subcommittee on Courts and of this perspective, see Solomon N. Correlation of U.S. Patent
Intellectual Property. October 19, 1995, (H.R. 1127 and H.R. 2419). System and Productivity Growth, IPWatchdog 2016. https://www.
5
The author testified before the Senate Judiciary Committee ipwatchdog.com/2016/09/29/correlation-us-patent-system-
in 1992 about patenting DNA. For a summary of those hearings productivity-growth/id=73254/ (accessed May 10, 2019).
see Kevles DJ, Berkowitz A. The Gene Patenting Controversy: 9
U.S. Innovation Economy Falls Even Further in Latest GIPC
A Convergence of Law, Economic Interests, and Ethics, Brook. Patent Rankings (Feb. 2018). https://cpip.gmu.edu/2018/02/08/u-
L. Rev. 2001;67(1):233-248, available at https://brooklynworks. s-innovation-economy-falls-even-further-in-latest-gipc-patent-
brooklaw.edu/cgi/viewcontent.cgi?article=1667&context=blr rankings/ (accessed May 10, 2019). Countries ahead of the
(accessed May 10, 2019). United States for patent protection are (in order from first place
6
Association for Molecular Pathology v. Myriad Genetics, Inc., 569 on the Chamber patent index): Singapore, France, Germany,
U.S. 576 (2013). Ireland, Japan, the Netherlands, South Korea, Spain, Sweden,
7
Another recent ophthalmology patent controversy concerned Switzerland, and the United Kingdom. See page 35 of the
Allergan’s Restasis® patents. Allergan transferred some of those Chamber report.
patents to a Native American Tribe to insulate the patents with 10
U.S. Patent System Jumps to Tie for Second Place in Interna-
“tribal immunity” that would prevent the patents from being tional IP Index. https://www.ipwatchdog.com/2019/02/07/u-s-
subjected to review and potential revocation in the United States patent-system-jumps-tie-second-place-us-international-ip-index/
Patent and Trademark Office (USPTO). That strategy was rejected id=106131/ (accessed May 10, 2019). The U.S. was tied with France,
by the courts in 2018 (Saint Regis Mohawk Tribe v. Mylan Pharma- Germany, Ireland, Japan, the Netherlands, South Korea, Spain,
ceuticals, Appeal No. 18-1638 (Fed. Cir. 2018)). Sweden, Switzerland, and the UK. According to the report, the
U.S. rankings increased due to reforms recently introduced by the
USPTO to counteract anti-patent policies previously in place.
11
Can the U.S. Keep Its High-Tech Edge? Wall Street Journal,
October 5, 2018, https://www.wsj.com/articles/can-the-u-s-keep-
its-high-tech-edge-1538754349 (accessed May 10, 2019).
Patents in an age of innovation 41
valuable inventions, particularly in the medical field, in the U.S. Patent Act (35 U.S.C.) and the laws of
and the object of this chapter is to chart the challenging other countries. The laws differ around the world, so
new terrain of a changing patent system. It explains the something that is patentable in one country may not
process for patenting an invention and the practical be patentable elsewhere. To simplify explanations,
impact of these many recent and controversial legal the laws of the United States will be applied, unless
changes. indicated otherwise.
There are also two patent laws currently in effect, The increasing importance of technology has made
depending on the filing date of the patent. The old patents more valuable than ever, even as the law has
(pre-AIA) law applies to patents that were filed before become increasingly hostile to patent protection.
March 16, 2013, while the new (AIA) law applies to Despite this hostility, the pace of patenting has increased
patents filed after that date. To simplify explanations, in recent years. It took 200 years for the total number
unless otherwise indicated, only the new (post-AIA) of U.S. patents to reach 5 million in 1991, and only 27
laws will be described because they are the laws years for that figure to double. Optics and vision-relat-
most pertinent to physicians and researchers who are ed patents have been well represented. For example,
currently interested in patenting their inventions. U.S. Patent No. 8,000,000 (2011) was issued on a visual
aid to electrically stimulate the retina, U.S. Patent No.
9,000,000 (2015) was on a system for enhancing visibility
2. Patent rights through windshields, and U.S. Patent No. 10,000,000
(2018) was on a laser system for medical imaging and
A patent grants the right to exclude others from making, guiding autonomous vehicles.
using, selling, or importing a patented invention. These
exclusive rights generally permit an invention to be
sold for a price premium during the life of the patent 3. Requirements for patentability
(currently 20 years).12 The American patent system,
which was set up by the United States Constitution to The essential requirements for patentability in the
“promote the progress of science and the useful arts,” United States are that an invention must be patent-
has been controversial from its birth. Thomas Jefferson eligible subject matter that is new, nonobvious, useful,
as Secretary of State reviewed all patent applications to and described in sufficient detail to place the invention
“draw a line between things that are worth to the public in the possession of the public. The goal is to reward
the embarrassment of an exclusive patent, and those patent owners for their investments of capital and
that are not.”13 But Jefferson later came to recognize creative efforts by granting a patent right commensu-
that patents had “given a spring to invention” beyond rate in scope with their scientific contributions, without
his conception. Abraham Lincoln, himself an inventor, taking away from the public anything that is already
praised patents for “adding the fuel of interest to the in the public domain. “Patent-eligible” inventions are
fire of genius.” But the question about “where to draw a process, machine, manufacture, or composition of
the line” persists to the present day and is embodied matter.14 “Novelty” demands that the invention be
12
The 20-year term is calculated from filing a non-provisional 14
35 U.S.C. § 101 lists these types of patent-eligible inventions.
patent application. Filing a provisional patent application does As discussed later in this chapter, the Supreme Court has created
not start the 20-year period. The 20-year term is started by additional non-statutory requirements for patent eligibility, such
filing a nonprovisional national application or an international as the invention relying on something more than a natural law.
application under the Patent Cooperation Treaty (PCT).
13
Stanford University v. Roche, 563 U.S. 776 (2011), Breyer dissent.
42 W. Noonan
somehow different from the “prior art” that has come invention occurs anywhere in the world. Disclosure
before it.15 An invention is “nonobvious” if an ordinary of the invention prior to filing the patent application
person working in the relevant field would find the is said to destroy novelty of the invention. The United
difference between the invention and the prior art to States and a few other countries21 have a more generous
be not obvious.16 “Usefulness” (or utility) allows patents deadline and allow the inventors to obtain patent
to be issued only on workable inventions that are protection in their countries within one year of the
practical and scientifically credible.17 The requirement public disclosure of their own invention. However, since
for adequate description of the invention18 assures that most medical inventions have an international market,
the public is informed of new scientific breakthroughs and non-USA patents have become more important in
that stimulate further research.19 The description recent years, it is wise to file a patent application before
requirement also assures that the scope of granted making any non-confidential disclosure of an invention,
patents is commensurate in scope with the inventors’ to protect all international patent rights. The types of
scientific contribution.20 disclosures that trigger the patent filing deadlines are
There are absolute deadlines for filing patent appli- discussed in further detail under the “prior art” heading
cations. In most countries, a patent application must of this chapter.
be filed before any non-confidential disclosure of the
15
The post-AIA § 102(a) states in pertinent part that a person 21
The United States, Canada, and Australia provide a one-year
is entitled to a patent unless “(1) the claimed invention was grace period for filing a patent application after the inventors have
patented, described in a printed publication, or in public use, publicly disclosed their invention. Japan grants a less generous
on sale, or otherwise available to the public before the effective six-month grace period. Most other major patent systems (such
filing date of the claimed invention; or (2) the claimed invention as those in Europe and China) require “absolute novelty,” so the
was described in a patent issued under section 151, or in an patent application must be filed before any non-confidential
application for patent published or deemed published under disclosure is made by the inventors.
section 122(b), in which the patent or application, as the case may
be, names another inventor and was effectively filed before the
effective filing date of the claimed invention.”
16
35 U.S.C. § 103
17
35 U.S.C. § 101 requires an invention to be “useful,” which has
been interpreted to require a practical, believable, and provable
use for the invention. For example, a perpetual motion machine
would lack patentable utility because it violates the first law
of thermodynamics (conservation of energy). A discovery such
as E = mc2 is also patent ineligible because it is only a natural
observation, not a practical application. A nuclear reactor that
produces energy by nuclear fission would be a patent-eligible,
useful application of the observation. The USPTO does not often
challenge the utility of medical devices and surgical inventions,
at least if a patent application explains how to use the inventions.
Drug patents are sometimes challenged as lacking utility if the
patent provides no evidence, such as in vitro or in vivo studies, that
would suggest a pharmaceutical use. For example, if a drug is said
to prevent Alzheimer’s disease then the USPTO would probably
request at least some proof that it does so. FDA-type clinical trials
are not generally required. Animal studies or in vitro data usually
suffice if human data is not available.
18
35 U.S.C. § 112
19
The alternative to a patent system is trade secrecy, in which
innovations are protected by maintaining them as secrets.
For example, Venetian glassmakers in the Middle Ages were
isolated on the island of Murano in part to protect the secrecy
of glassmaking techniques. Any glassmakers who disclosed
glass-making secrets were subject to execution by the Venetian
Republic. Patent systems offered a relatively more benign form of
protection for technical innovations.
20
Regents of the University of California v. Eli Lilly and Company,
119 F. 3d 1559 (1997).
4. Filing a patent application in the U.S. others) from becoming prior art against the invention.
and other countries The one-year delay between the provisional and
non-provisional filings also affords the inventors the
In the United States, a utility patent application opportunity to further develop the invention, obtain
is filed with the USPTO. The patent application data that may be needed to demonstrate patentabil-
must describe how to make and use the invention. ity, and further assess the commercial value of the
The patent application concludes with a series of technology before beginning the full patent process.
numbered paragraphs called claims that define the Foreign patent protection has become more
metes and bounds of patent protection sought for important to many patent owners, in view of the recent
the invention. The patent application is assigned to a decline in the strength of U.S. patent protection. The
patent examiner at the USPTO, who reviews the patent most common pathway to international protection is
application and the prior art and then issues “Office to file a Patent Cooperation Treaty (PCT) application
actions” that critique the patentability of the proposed within one year of the first-filed U.S. application
patent claims in view of the prior art. The language (generally within one year from filing a U.S. provisional
of the patent claims is often revised by the inventors’ application). Filing this single international patent
patent attorney during this review process (known application under the PCT is the first step in seeking
as patent prosecution) to arrive at a claim scope that protection in 152 countries around the world that
patentably distinguishes the claims from the prior art, have joined the PCT, and delays by 18-19 months the
and establishes a scope of patent protection that is need to file patent applications in those individual
commensurate in scope with the inventors’ scientific or foreign countries.22 The PCT application itself does
technical contribution. Claim language must be chosen not become a single international patent; it is only a
carefully because a patent only protects an invention placeholder application that acts as a bridge to foreign
that falls within the scope of the allowed patent claims. patent protection and delays patenting costs until the
Data in the patent application itself (or data submitted commercial value of an invention is better known. A
later to a patent examiner during patent examination) few months after the PCT application is filed, a single
is sometimes used to demonstrate patentability of the international patent search is performed by an Inter-
proposed patent claims. national Searching Authority, and a Written Opinion
In the United States, it is common to file a provisional is issued to help the applicant further assess the
patent application as the first step in the patent potential patentability of the invention before taking
process. The provisional application is not examined the more expensive step of seeking foreign patent
by the USPTO and does not start the 20-year patent protection in multiple countries. Armed with this prior
term running. The provisional application acts as a art information, the applicant can make an informed
place-holder to establish an early-priority date for decision about starting patent prosecution in the U.S.
the invention described in the patent application. and other countries.
The priority date is important because the patent Which countries to select for patent protection
application will be evaluated by the patent examiner depends on the type of invention, likely markets for
based on prior art that was available before the priority the product, the size of a country’s economy, the
date. A non-provisional application must be filed within presence of competitors in that country, the strength
one year of the provisional application filing date to and cost-effectiveness of patent protection there, and
retain the early-priority date. Although the provisional the available patent budget. One must also consider
application is not examined, an early-stage provisional whether an invention is even patentable in a country of
patent application can prevent subsequent inventor interest (because the patent laws are specific to each
disclosures (such as publications or other non-con- country). The European Patent Office, for example,
fidential information published by the inventors or forbids patents on some surgical and diagnostic
22
Different countries have different PCT national stage filing
deadlines. For example, the national stage application filing
deadline in the United States is a month earlier than in the
European Patent Office.
44 W. Noonan
methods practiced on the human body.23 The United 5. Prior art

States currently forbids patents on many types of
naturally occurring products, such as unmodified The “prior art” determines patentability, so it is
DNA or proteins, and diagnostic assays that rely on important to know what it is. The definition of prior
biological correlations (biomarkers).24 Medical patent art differs from country to country, but generally it is
applications are generally filed in countries such as anything that can be cited against a patent applicant or
the United States, Europe, China, Japan, Australia, and owner to defeat the patentability of a claimed invention.
Canada. Other countries of interest may be India, South The prior art is available as evidence of unpatentabil-
Korea, Mexico, and Brazil. Pharmaceutical inventions ity, and the date the evidence becomes available is
are typically filed in these and many other countries. sometimes referred to as a “bar date.” These bar dates
There are several regional patent systems that can drive the strategy for filing patent applications early
be used to reduce patent costs. For example, a single enough to establish a priority date before a bar date.
European Patent can be obtained and then validated in In the United States, the prior art is anything that
up to 38 European countries. Some of these countries has been previously “patented, described in a printed
(such as Spain and Italy) require a full translation of publication, or on public use, on sale, or otherwise
the patent into the official language of that country, available to the public” prior to filing the patent
but most European countries do not.25 It is generally application.27 Disclosures by the inventors of their
more cost-effective to validate the European patent in own work within one year before the filing date do not
countries that do not require full translations (such as qualify as prior art in the United States.28 Disclosures
Germany, France, the United Kingdom, Ireland, and the by others are prior art if the disclosures are available
Netherlands). The European Patent cannot be enforced any time before the patent application is filed, unless
in a European country where it was not validated. that disclosure was derived from the inventors. Similar
Although a single European Patent can be obtained, rules apply in Canada and Australia.29 However, in many
the individual validations must be enforced against foreign jurisdictions (such as Europe and China) the
infringers by litigation in each validation country. A prior art includes any non-confidential disclosure of the
new European Unified Patent Court, which is expected invention prior to filing the patent application, even if
to come into existence in 2020, could put an end to the the disclosure was made by the inventors themselves.
costly requirement of separately enforcing a European Most inventors file their patent applications before they
Patent in each country where infringement occurs.26 make any non-confidential disclosures to protect pat-
23
Article 53(c) of the European Patent Convention. See Guidelines 27
35 USC § 102(a).
for Examination 4.2, Surgery, therapy and diagnostic methods. 28
35 USC § 102(b).
https://www.epo.org/law-practice/legal-texts/html/guidelines/ 29
Japan grants a six-month grace period (instead of one year) to
e/g_ii_4_2.htm (accessed May 10, 2019). European Patents may be file the patent application following the inventors’ disclosure of
obtained for medical or surgical devices, or methods of treating a their own invention.
patient by administering a drug.
24
Association for Molecular Pathology v. Myriad Genetics, Inc., 569
U.S. 576 (2013) and Mayo Collaborative Servicers v. Prometheus
Laboratories, Inc. 566 U.S. 66 (2012). Legislation is currently
pending in the U.S. Congress that could make some of these
categories of inventions once again patentable.
25
The London Agreement in October 2000 dispensed with the
requirement for translating the entire patent application in
Austria, Belgium, France, Germany, Ireland, Luxembourg, Monaco,
Switzerland, and the United Kingdom. The claims must still be
translated into English, French, and German. See The London
Agreement: European patents and the cost of translations. Inter-
national Property Rights Experts Group (IPEG). https://www.ipeg.
com/_UPLOAD%20BLOG/london_agreement_en.pdf (accessed
May 10, 2019).
26
Unitary Patent and Unified Patent Court, EPO website, https://
www.epo.org/law-practice/unitary.html (accessed May 10, 2019).
entability of their inventions abroad. If inventors take standard of efficacy and safety.33 An invention can be
advantage of the one-year grace period in the United in public use and ready for patenting even if it is not yet
States, they will forfeit patent rights in many foreign ready for approval by the FDA.
countries. Offering an invention for sale may also create a prior
“Printed publications” (including published patents) art bar to patentability if the invention is ready for
are the most common type of prior art in the medical patenting, even if the invention lacks FDA approval,
field. For many physicians and medical researchers, cannot be sold to the public, and the sale was confi-
their own publications are the closest prior art. Most dential. In Helsinin Healthcare v. Teva Pharma USA, two
inventors recognize that scientific publications and years prior to filing its patent application and while
prior patents are part of the prior art, but even less the invention was still in FDA clinical trials, the patent
formal disclosures, such as abstracts, blog postings, owner agreed to supply the drug in its patented dosage
and conference presentations, qualify as printed publi- form to a distributor. This sale was sufficient to destroy
cations art if they are available to the public. Catalogs, patentable novelty of the invention in the U.S., even
manuals, brochures, poster board displays, industry though the details of the invention were not made
whitepapers, proposals circulated at working group public and the drug had not been approved for sale by
meetings, doctoral dissertations, and postings on the FDA. The Supreme Court recently reviewed this case
Internet discussion forums all constitute printed pub- and agreed that such a secret sale qualifies as prior art
lications that have been found to invalidate patents.30 under the new patent law (the AIA). It is therefore wise
“Public use” of an invention also creates prior art. This to file a patent application before (or soon after) any
type of prior art can be a problem in clinical practice if a sales negotiations are initiated.
physician or researcher wants to test an invention prior Informal discussions with colleagues or manu-
to patenting it. An invalidating public use or sale of the facturers can qualify as prior art in the absence of a
invention can only occur if the invention is “ready for confidentiality agreement. To avoid misunderstand-
patenting,” which is a difficult standard to define. For a ings that could invalidate a patent, it is best to always
mechanical device it generally means that the invention confirm in writing (for example with a confidentiality
has been made (“reduced to practice”) or that drawings agreement) the non-public nature of any disclosure
have been prepared that are sufficiently specific to of the invention prior to making the disclosure. A con-
enable a person skilled in the art to make the invention.31 fidentiality agreement is not as necessary once the
Clinical trials for medical devices, pharmaceuticals, and patent application is filed if one subsequently discloses
biologics can be “non-public” use under some circum- nothing more than is already in the patent application.
stances if they are experimental uses. Courts consider However, it is helpful to have a confidentiality agreement
the following factors when determining whether a use in place whenever discussing an invention in case new
is experimental: (1) length of the test period (short is ideas are proposed during the discussions.
better); (2) presence of confidentiality agreement (a Confidentiality agreements should also specify who
written agreement is better but not dispositive); (3) will own any patentable ideas that arise from confiden-
written records evidencing testing; (4) monitoring and tial discussions. Patent rights in the United States are
control of the test subject; (5) number of tests; and shared by all the inventors, and if someone becomes
(6) length of the test period for similar inventions.32 a co-inventor, he or she will become a co-owner of a
The ready for patenting standard is different than the U.S. patent on the joint invention, in the absence of an
more rigorous U.S. Food and Drug Administration (FDA) agreement to the contrary.34 Changes of inventorship
30
Yelderman S. Which Kinds of Printed Publications Invalidate 33
Helsinn Healthcare S.A. v. Teva Pharmaceuticals USA, Inc., 855
Patents in Court? PatentlyO. https://patentlyo.com/ F.3d 1356 (2017). The United States Supreme Court reviewed this
patent/2018/12/yelderman-publications-invalidate.html case in early 2019 and agreed that “secret sales” can be prior art.
(accessed May 10, 2019). Case No. 17-1229 (January 2019).
31
Pfaff v. Wells Electronics, 525 U.S. 55 at 67-68 (U.S. 1998). 34
Someone becomes a co-inventor if he or she makes an intellec-
32
Eli Lilly Co. v. Zenith Goldline Pharms., Inc, 471 F.3d 1369, 1381 tual contribution to even one claim of the issued patent.
(Fed. Cir. 2006).
46 W. Noonan
and ownership can also create prior art problems of purposes prior to the bar date. If the implantation of
their own.35 the lenses had been experimental it would not have
Many types of innocent disclosures and uses can barred patentability. In other cases, patents have been
become prior art and unintentionally destroy the barred by the inventor’s disclosure of the invention in a
patentability of an invention. This problem is best catalog38 or scientific publication prior to the bar date.
addressed by filing a patent application as soon as Novelty alone does not establish patentability; the
the invention is ready for patenting, to establish an invention must also be “nonobvious” in view of the prior
early “priority date” for the invention before any art. An invention is obvious if a person of ordinary skill
potential prior art disclosures occur. Even after a patent in the art would consider it obvious to make the claimed
application is filed, it is advisable to work with others invention in view of the prior art. For example, different
under the protection of a confidentiality agreement details of the invention may be found in different prior
and confirm in advance who will own any inventions art references, and obviousness depends on whether
arising from confidential discussions. there was a motivation to combine information from
these multiple prior art references, with a reasonable
expectation of success, to arrive at the invention. Even
6. Novelty and nonobviousness if there is a motivation to combine the references, an
invention is nonobvious if there is something unpredict-
If something qualifies as prior art, it can be used to defeat able or unexpectedly superior about the invention.39
the “novelty” of the invention or render the invention There are many ophthalmology patents that illustrate
unpatentably “obvious.” Novelty rejections often occur the concept of obviousness. For example, the topical
when an inventor tries to claim an invention so broadly ophthalmic antibiotic gatifloxicin with EDTA (Zymar®)40
that the patent claim encompasses the work of others was determined to be unpatentably obvious by courts
who have invented similar things in the past. When in the United States. A first prior art reference taught
trying to obtain a patent, a novelty rejection can often that gatifloxicin was a broad-spectrum antibiotic that
be overcome by more specifically claiming the invention could be used in the eye. A different reference suggested
to distinguish the prior art of others.36 For example, that adding EDTA to an ophthalmic preparation
if the prior art discloses treatment of the trabecular would increase corneal penetration of a drug. It was
meshwork with a laser of a certain wavelength to treat considered obvious to combine the teachings of these
glaucoma, a later method of treatment will be novel if it two separate references to make Zymar. Although the
uses a different wavelength of laser light or a different drug had improved corneal penetration, that effect was
treatment location. considered expected and predictable in view of the
An inventor’s own prior publications or actions prior art, and therefore unpatentably obvious.41
are a common source of novelty-destroying prior In contrast, topical azithromycin for the eye
art that cannot be overcome. For example, in Sinsky (Azasite®)42 was found to be nonobvious even though
v. Pharmacia37 a modified J-Loop intraocular lens azithromycin had previously been administered orally
was found to lack novelty because the inventor had for the treatment of bacterial infections in the eye. The
implanted eight of the lenses for non-experimental prior art taught that azithromycin would be a poor
35
Certain types of “obviousness-type double patenting” 38
Nobel Biocare Sevices AG v. Instradent USA, Inc., Case 17-2256
rejections of a patent application can be overcome if an earlier (Fed. Cir. 2018).
patent and later patent application have the same owner. If an 39
Evidence of unexpectedly superior results can be submitted
additional owner is added to a later-filed patent application on in the form of declarations from the inventor or submission of
an improvement of the invention, then it may not be possible to post-filing date publications.
patent the improvement. 40
Allergan, Inc., Irvine, CA, USA
36
Novelty and other prior art problems that arise during IPR 41
Senju Pharmacuetical v. Lupin Ltd., 780 F.3d 1337 (Fed. Cir.
or litigation of a patent cannot generally be overcome by 2015).
amendment. For that reason, it is important that the closest 42
Insite Vision Inc,, Alameda, CA, USA
prior art be taken into account during prosecution of a patent
application, and the claims written in a way that clearly distin-
guishes the prior art.
37
982 F.2d 494 (Fed. Cir. 1992).
choice to topically treat ocular infections, because it was was nonobvious.48

in a class of drugs that were bacteriostatic and required Many patents have also been issued on laser
multiple doses per day to penetrate tissue. There was treatments for glaucoma, which use various
no expectation that the drug could be successfully wavelengths, treatment locations, and modes of
used topically in the eye, and the topical formulation applying laser energy to the eye. As an example, Iridex’s
of the drug was therefore found to be nonobvious and MicroPulse G3 laser system was patentable in part
patentable.43 because its laser energy was applied from a probe in
In another example, Lumigan® 0.01% (bimatoprost)44 contact with the surface of the sclera instead of being
was found to be a nonobvious improvement over directed through a gonioscopic lens to the anterior
Lumigan® 0.03%, because Lumigan® 0.01% included chamber of the eye.49
four times as much benzalkonium chloride (BAK). The These and other possibilities for proving nonobvi-
prior art taught that the use of BAK in ophthalmic formu- ousness are as varied as the capacity for creation and
lations should be minimized to avoid safety problems, innovation. Whether an invention is obvious is a fact-de-
so it would not have been obvious to use higher concen- pendent inquiry that has changed relatively little in
trations of it. In addition, quadrupling the concentra- recent years. However, as discussed in the following
tion of BAK surprisingly increased corneal penetration sections of this chapter, other areas of patent law have
of bimatoprost. A lower concentration of bimatoprost undergone significant transformation.
(0.01% instead of 0.03%) could be used, which reduced
drug-induced hyperemia while improving control of
intraocular pressure. The new drug was nonobvious 7. Utility and written description
because the formulation was contrary to the teachings requirements
of the prior art and had unexpectedly superior results.45
New uses of old drugs can be patented if the new use An invention must be useful to be patentable; in patent
is nonobvious. A vivid example is the use of botulinum law this is known as the utility requirement.50 The
toxin to treat psychiatric disorders. Several patents utility of a patentable invention must be a specific
have been awarded on methods of treating depression and substantial utility that is credible.51 In the past the
and post-traumatic stress disorder by injecting utility requirement was used to screen inventions such
botulinum toxin at specific locations around the eyes.46 as perpetual motion machines that appeared to violate
The cosmetic uses of botulinum toxin would not have scientific laws (such as the Second Law of Thermody-
suggested a mechanism of action that would treat namics), or inventions that claimed to cure diseases that
these specific emotional disorders, and the methods were known to be incurable. The utility requirement
were patentably nonobvious. also prevented patenting drugs or medical devices
Methods of medical and surgical treatment can when an inventor only vaguely asserted that a drug
be patentably nonobvious even if they are similar to or method could be used to treat “disease,” without
prior art methods. For example, BlephEx patented a identifying a specific disease that would benefit from
method of treating blepharitis with a swab that spins the treatment. To avoid a utility rejection, it is helpful to
a small sponge along the edge of the eyelids to remove include data in the patent application that demonstrate
debris and exfoliate the eyelid.47 A similar method had the treatment has been or can be successfully used to
previously been used to remove rust rings from the treat disease in one or more patients. Clinical trials are
cornea, but there was no motivation in the prior art to not necessary, nor must one demonstrate clinical safety
use that technique on the eyelids and the new method as in an FDA-type trial. In vitro data, animal studies, or a
43
Insite Vision, Inc. v. Sandoz, 783 F.3d 853 (Fed. Cir. 2015). 48
Pain Point Medical Systems, Inc. v. Blephex, LLC (PTAB 2018)
44
Allergan, Inc., Irvine, CA, USA 49
U.S. Patent No. 8,945,103.
45
Allergan, Inc. v. Sandoz, Inc., 796 F.3d 1293 (Fed. Cir. 2015) 50
35 USC Section 101 defines patent-eligible subject matter as an
46
U.S. Patent No. 7,758,872 (treatment of depression) and invention or discovery that is “new and useful.”
European Patent 2919807 (treatment of social anxiety disorder), 51
Manual of Patent Examining Procedure (MPEP) 2107, II(B).
as well as U.S. Patent No. 9,254,431 (social anxiety or panic
disorder).
47
U.S. Patent No. 9,039,718.
48 W. Noonan
few case histories demonstrating successful treatment identified. Biological inventions are also supported
usually suffice for patent purposes. by examples of alternatives (such as variant DNA or
The utility requirement was one of the early bat- amino acid sequences) that illustrate the breadth of the
tlefields in the war over DNA patents that began in invention. Patent applications that contain only a single
the 1990s. Preliminary data from the Human Genome example of an invention are often undesirably limited in
Project had identified expressed sequence tags (ESTs) scope to that one specific example.
that had no readily identifiable biological significance. The written description requirement prohibits
The National Institutes of Health (NIH) filed patent adding any new matter to the patent application after
applications on cDNA molecules of unknown function it is filed. For that reason, the patent application as
that had been identified in Dr. Craig Venter’s laboratory. initially filed should thoroughly disclose the invention
Venter asserted the sequences would be useful as probes and all its expected variations.
or primers to detect or amplify genes of subsequent
interest, and perhaps determine the biological signifi-
cance of DNA sequences. Congressional Hearings were 8. Medical procedure patents
conducted in 1992 about these patents and whether
DNA molecules were even patentable at all.52 The Medical procedure patents galvanized political attention
USPTO ultimately decided that this vague assertion of in 1993 after Dr. Samuel Pallin sued fellow ophthalmol-
utility was inadequate; patentable utility required that ogist Dr. Jack Singer for infringing his cataract surgery
the patent identify specific targets of interest for the procedure patent on the use of a self-sealing chev-
probes in the genome. ron-shaped incision.55 This patent seemed to impose on
The written description requirement limits the a physician’s exercise of clinical judgement in treating
scope of a patent claim to the invention that has been patients, and raised the possibility of being sued for
described in the patent application. The invention patent infringement by performing surgery or any other
must be described in sufficient detail to enable others medical procedures.56 Procedure patents were also
skilled in the art to make and use the invention.53 contrary to the tradition in clinical medicine of publishing
The patent must also demonstrate possession of the discoveries and making them available to physicians
invention throughout its entire scope at the time the and patients as soon as possible. The American Medical
patent application is filed. A representative number Association (AMA) voted to “vigorously condemn the
of examples of the invention should be disclosed patenting of medical and surgical procedures and
to demonstrate the breadth of the invention.54 For work with Congress to outlaw this practice.”57 The AMA
a medical device this often means that multiple, joined with the American Academy of Ophthalmology
alternative embodiments of the device are shown in and two physician legislators (Senator Bill Frist and
the patent drawings and described in the text of the Congressman Greg Ganske) to exempt medical prac-
patent application. For pharmaceutical inventions, titioners and their affiliated health care entities from
multiple species within a patented chemical genus are infringement damages.58 Under 35 USC Section 287(c),
52
The author testified before the Senate Judiciary during the 55
Melvin E. The Ramifications of Physician Immunity from Medical
Congressional Hearings. https://pink.pharmaintelligence. Procedure Patent Infringement Liability, Minnesota Law Review
informa.com/PS021501/SENATE-HEARING-ON-GENE-PATENTING- 2007;91:1088-1112.
ETHICAL-ISSUES-CONVENES-SEPT-22 (accessed May 10, 2019). See 56
Noonan WD. Patenting Medical and Surgical Procedures, J Pat
also see Kevles DJ, Berkowitz A. The Gene Patenting Controversy: Trademark Off Soc. 1995;77:651-674. See also Mossinghoff G.
A Convergence of Law, Economic Interests, and Ethics, Brook. L. Remedies Under Patents on Medical and Surgical Procedures,
Rev. 2001;67(1):233-248, for an in-depth discussion of the Congres- Journal of the Patent and Trademark Office Society 1996;78:789-
sional Hearings and the DNA patent controversy. 801.
53
35 U.S.C. § 112. 57
Rundle J. The physician’s Immunity Statute: A Botched
54
LizardTech v. Earth Resource Mapping, Inc., 424 F.3d 1336 (Fed. Operation or a Model Procedure? Iowa J. Corp. Law 2009;34:943-
Cir. 2005). 966.
58
The author testified at the Congressional Hearings that led to
the enactment of this legislation. Medical Procedures Innovation
and Affordability Act: Hearings on HR. 1127 Before the Subcom-
mittee on Courts and Intellectual Property Committee of the
House Judiciary Committee, 104th Cong. (Oct. 19, 1995).
medical procedure patents could still be issued and 9.1. Diagnostic assays that rely on biological
even enforced, but no damages could be collected from correlations
most physicians. Medical procedure patents such as Dr. However, this approach began to change when the
Pallin’s became of little value. United States Supreme Court decided in Mayo Collab-
However, the medical procedure patent exemption is orative Services v. Prometheus Labs, Inc. (2012)60 that a
narrowly confined to procedures of the type patented medical patent which relied on a biological correlation
by Dr. Pallin that do not use patented devices or drugs. was not patent-eligible subject matter. The patent
Pallin’s invention was making a chevron-shaped incision claimed a method of optimizing dosages for treating
in the eye without relying on any special device to do so. If inflammatory bowel disease with thiopurine drugs by
one were to invent a patentable surgical instrument that measuring the blood levels of a 6-thioguanine drug
made the incision, then the patent would be enforceable metabolite of the thiopurine precursor. Although the
against individual physicians who used the device to thioguanine metabolites of thiopurine were known,
make the incision. However, a patent owner would only the effective blood levels of the metabolites were not.
rarely enforce such a patent directly against surgeons. It The inventors identified the therapeutic range of the
is far more cost-effective to sue the manufacturer of the 6-thioguanine metabolite that corresponded to the
device instead of many different surgeons who use it. therapeutic dosage of the precursor drug and patented
a method of determining the appropriate dosage of the
precursor drug depending on the measured level of the
9. Patent-eligible subject matter metabolite.61
The U.S. patent statute clearly authorizes patenting
The term “patent-eligible subject matter” refers to such methods if they are also new, nonobvious, and
categories of inventions for which patents may be useful. However, the Supreme Court ignored the
granted. patent statute and invalidated the patent based on a
Patent-eligible subject matter had been among vague new concept that the patented method claimed
the least controversial sections of the patent statute. a natural law instead of an application of such a law.
The relevant section of the patent law as written by Although the patented method applied the natural law
Congress clearly states that patent-eligible inventions by indicating how the dosage of the drug should be
include any invention or discovery of a “process, changed in response to the measured blood level, the
machine, manufacture, or composition of matter.”59 Supreme Court said such steps were well understood,
Even lawyers found it difficult to argue that the language conventional, or routine activity that did not transform
was ambiguous. The crux of patentability was whether an unpatentable law of nature into a patent-eligible
the invention was new and nonobvious, which was application of that law. This new legal concept conflated
a fact-dependent inquiry that protected noteworthy patent-eligible subject matter (a method) with the
inventions while precluding old or trivial inventions separate requirements that it be new (novel) and
from patent protection. nonobvious in view of the prior art. The Supreme Court
59
35 USC § 101. 60
Mayo Collaborative Servs. v. Prometheus Labs., Inc., 132 S.Ct
1289 (2012).
61
Claim 1 of the patent was: A method of optimizing therapeutic
efficacy for treatment of an immune-mediated gastrointestinal
disorder, comprising:
(a) administering a drug providing 6-thioguanine to a subject
having said immune-mediated gastrointestinal disorder; and
(b) determining the level of 6-thioguanine in said subject having
said immune-mediated gastrointestinal disorder, wherein the
level of 6-thioguanine less than about 230 pmol per 8x108 red
blood cells indicates a need to increase the amount of said drug
subsequently administered to said subject and wherein the level
of 6-thioguanine greater than about 400 pmol per 8x108 red blood
cells indicates a need to decrease the amount of said drug subse-
quently administered to said subject.
50 W. Noonan
also created an unclear and unworkable legal standard eligible if it detects a genetic mutation that impairs
that required a law of nature be applied in such a way metabolism of a drug and then on the basis of the test a
that was sufficiently unconventional to be patentable. low dosage of the drug is administered to slow metab-
It is often impossible to know when something is a suf- olizers.66 The method that includes the treatment step
ficiently unconventional application of a natural law to is patent eligible, even if the method of diagnosis by
be patent eligible.62 itself is not. Methods of treating disease are considered
The most immediate impact of this decision was patent eligible and have not been subjected to the same
that it effectively invalidated thousands of U.S. patents scrutiny as methods of diagnosing disease. However,
that had already been issued for methods of DNA diagnostic patents that require specific reagents or
diagnosis. Many of the DNA patents were for the use treatment steps provide a narrow scope of protection
of genetic markers in the diagnosis and treatment of that may not be as valuable as the method of diagnosis
eye disease.63 Some businesses that had been built itself. The patent may not be infringed if different
in reliance on DNA diagnostic assays were suddenly parties perform the diagnostic and treatment steps.
extinct. However, the most significant drawback of the The scope of patent protection for diagnostic patents
“unconventional use of a law of nature” standard was that rely on biological correlations has therefore been
that it destroyed the patentability of other ground- weakened but not eliminated.
breaking methods of medical diagnosis. For example, Methods of treatment using physical modalities or
Ariosa Diagnostics obtained a patent on a noninvasive, medical devices are patent eligible. For example, it is
prenatal diagnostic method that amplified cell-free possible to patent a method of treating glaucoma by
fetal DNA (cffDNA) found in maternal blood. It was not applying laser energy to the eye, or by applying laser
previously known that cffDNA circulated in maternal energy to the eye using a handheld probe.67 Methods
blood, but once it was discovered to be there it enabled of diagnosis are similarly patent eligible as long as they
prenatal diagnosis to be performed on maternal blood rely on a device or physical modality, such as laser
at reduced risk to both mother and fetus. However, or ultrasound. Examples include the use of optical
this patent was invalidated in view of the natural law tomography to diagnose specific eye diseases.68 To the
standard. Although the court admitted the invention extent that any medical device itself is patentable, it is
was a scientific breakthrough that revolutionized generally possible to patent the method of using the
prenatal care, the patent was nonetheless invalidated device for diagnosis or treatment.
as an application of a natural law (cffDNA was present However, many medical software inventions have
in maternal blood) that merely used conventional steps been found patent ineligible because they protect
(DNA amplification).64 “abstract principles.”69 For example, a method of
It is still possible to patent many types of medical detecting arrhythmias in ambulatory patients was
diagnostic methods, for example if they use a novel found patent ineligible because it relied on the abstract
device or reagent65 or if they also require a treatment idea of monitoring and analyzing heart-beat variability
step. For instance, a DNA diagnostic method is patent and interfering beats to alert the user of potentially
62
This case is a classic example of the Supreme Court deciding 66
Vanda Pharmaceuticals Inc. v. West-Ward Pharmaceuticals,
a case in a way that did more harm than good. The Court could 887 F.3d 1117 (Fed. Cir. 2018); see also USPTO Subject Matter
have decided the case using established law by finding that Eligibility Guidance regarding Recent Subject Matter Eligibility
the invention unpatentably obvious, but it decided instead to Decision (June 7, 2018) https://www.uspto.gov/sites/default/files/
mandate its confusing new “patent eligibility” standard. documents/memo-vanda-20180607.PDF (accessed May 10, 2019).
63
See Sahebjada S, Cantsileris S, Baird PN. Gene Patents Related 67
See the claims of Iridex’s U.S. Patent No. 8,945,103.
to Common Disease of the Eye, Recent Patents on DNA & Gene 68
U.S. Patent No. 10,134,143 (Method For Acquiring Retina
Sequences 2011;5(3):185-193, which reviews patent applications Structure from Optical Coherence Tomographic Image) and U.S.
and patents related to cataract, diabetic retinopathy, glaucoma, Patent No. 9,545,196 (Automated Assessment of Glaucoma from
and myopia. DNA diagnostic methods remain patentable in most Optical Coherence Tomography).
other major countries throughout the world, and development of 69
Alice Corp. v. CLS Bank International, 573 U.S. 208 (2014).
such assays is shifting to those countries.
64
Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371 (2015).
65
Examples of such a reagent are a specific new monoclonal
antibody or a specific DNA probe.
abnormal rhythms.70 This was considered an abstract on its patent for recombinant erythropoietin,75 and
idea that could be performed in the human mind. Genentech’s creation was based in part on its patent
In contrast, a related patent was found to be valid for recombinant insulin.76 Although the Supreme Court
because it was more narrowly limited to optimizing did not specifically state that genetically unmodified
the identification of R waves in the QRS complex by natural products could be patented, the “anything
selectively activating a T-wave filter to avoid false clas- under the sun made by man” standard signaled few
sification of a tall T wave as an R wave. This method was limits and encouraged the development of these and
a process that could not be performed in the human other companies that patented the DNA-encoding
mind and was therefore “tied to a machine.”71 Such therapeutic proteins. It was therefore a great surprise
machine-specific software techniques that cannot be when the United States Supreme Court decided in
duplicated by the unaided human mind are more likely 2013 that the Myriad Genetics patents on purified DNA
to be patent eligible. were patent-ineligible compositions of matter.77 Any
naturally occurring product found in nature could no
9.2. Natural products longer be patented unless the product was modified
Prior to 2013, purified vitamins, proteins, and even in an inventive way from the product of nature. For
DNA were considered patent eligible because they example, a chemical compound found in nature could
were compositions of matter that were protected be patented as a drug if it were chemically modified to
as patent-eligible subject matter by the patent improve its bioavailability, or a DNA molecule could be
statute.72 Purified natural products were considered modified to remove intronic (non-coding) sequences.78
novel because they did not exist in a purified form in The Supreme Court did not specifically address
nature, and they were nonobvious because it would patenting antibodies, but antibodies are still considered
not have been obvious to purify something that was patent eligible in the U.S. and in most other countries.
not previously known to exist.73 The Supreme Court Although antibodies do occur naturally, there is often
encouraged this belief in a 1980 case that confirmed no evidence that any particular antibody made in the
the patentability of genetically modified living micro- laboratory already existed in nature. Antibodies are
organisms that produced antibiotics.74 The Supreme very heterogeneous molecules that are the result of
Court found that Congress wrote the patent laws to random molecular combinations, and they are only
encompass a very broad interpretation of patent-el- rejected as products of nature if an antibody of the
igible subject matter and encourage innovation in same sequence is found in the prior art.
previously unknown areas. Patent protection was
considered to extend to “anything under the sun made
by man.” The living microorganism at issue in the case 10. Inter Partes Review — where
was a composition of matter that was protectable American patents go to die
under the patent law written by Congress.
This decision led to the founding of biotechnology Of all the patent changes in recent years, one of the
companies, the creation of a new American industry, most damaging to patent owners has been the intro-
and the development of biotechnology treatments for duction of a post-grant review procedure (IPR) for
many different diseases. For example, Amgen relied patents after the patent is issued. These patent reviews,
70
CardioNet, LLC v. InfoBionic, Inc. 2018 WL 5017913 (D. Mass. 75
Amgen’s first FDA-approved product was its recombinant eryth-
October 16, 2018). ropoietin.
71
CardioNet, LLC v. InfoBionic, Inc., 2017 WL 1788650 (D. Mass. May 76
Genentech’s Initial Public Offering of $35 million was issued
4, 2017). shortly after the Supreme Court’s encouraging decision in
72
35 U.S.C. § 101. Diamond v. Chakrabarty.
73
The newly discovered, purified products (such as vitamins and 77
Association for Molecular Pathology v. Myriad Genetics, Inc. 569
hormones) could be produced in pharmaceutical doses that for U.S. 576 (2013).
the first time allowed them to be used therapeutically. 78
The Supreme Court in Myriad specifically held that cDNA was
74
Diamond v. Chakrabarty, 447 U.S. 303 (1980). patent eligible because naturally occurring DNA molecules were
modified to remove non-coding nucleotide sequences.
52 W. Noonan
which were introduced by the new patent law (AIA) in and a presumption of validity was given to patents.84 IPR
2013, seemed like a good idea in theory because they proceedings offer no such protections to the patentee,
allowed the USPTO to take a second look at already-is- which is one reason the IPR system has been so harmful
sued patents that should not have been granted in the to the patent system. Since the introduction of IPRs in
first place. Opponents were able to cite new prior art 2013, the number of patent litigation lawsuits has fallen
that the USPTO may have missed in its original review by 45%.85 IPRs are fatal to so many patents that they do
and issuance of the patent without having to file a not survive to be enforced in a court proceeding. Patent
lawsuit in a federal court. However, the IPR system has owners have become reluctant to rely on their patents
been implemented in a way that is arguably unbalanced to protect their investments. This statistic is one of
and unfair to patentees. These proceedings have been the reasons the U.S. Patent System ranking has fallen
called a “Patent Apocalypse,”79 the “place where patents precipitously in recent years as compared to other
go to die”,80 or a “death squad” for American patents. countries.
Over 90% of patents challenged in these proceedings One of the reasons for this decline has been the harsh
have been at least partially invalidated.81 Legislative rhetoric of patent opponents in politics, academia, and
fixes have been proposed in Congress to “strengthen the media. Patents have been demonized as anticom-
the United States’ crippled patent system”,82 and the petitive86 and often directed to trivial inventions, such as
new Director of the Patent and Trademark Office is software programs for playing bingo on a computer87 or
attempting to restore balance. The situation is so swinging on a swing.88 Patents have also been justifiably
extreme that Allergan recently transferred its Restasis® blamed for contributing to the high price of some pre-
patents to the St. Regis Mohawk Tribe in an unsuccess- scription drugs, although some overpriced drugs (such
ful effort to use tribal immunity as a shield against its as doxycycline and the EpiPen) are no longer protected
patents being subjected to IPRs.83 by patents.89 But the most vocal opponents of the
Prior to 2013, patent validity was litigated in federal patent system have been the technology companies of
courts where a fair hearing was provided to both parties, Silicon Valley that rely on their size to dominate certain
the scope of patent claims was interpreted reasonably, software industries. Patents threaten monopolies
79
Maynard C. Minnesota Law Review 2017; 102, October 29, 2017. 84
The presumption of patent validity is codified in 35 USC § 282:
http://www.minnesotalawreview.org/2017/10/patent-apocalypse/ “A patent is presumed valid.” Congress enacted this presumption
(accessed May 10, 2019). because patents are examined by the USPTO prior to issuance.
80
Martone P. How the United States Patent Office Became the The presumption of validity also prevented judges who were
Place Where Patents Go To Die, June 2016 Who’s Who Legal http:// unfamiliar with technology or the patent law from relying on their
whoswholegal.com/news/features/article/33156/how-united- own biases to unfairly invalidate patents. The presumption has
states-patent-office-became-place-patents-go-die/ (accessed not been applied in IPR proceedings.
May 10, 2019). 85
Crouch D. District Court Litigation Way Down, Patentlyo, https://
81
Brachman S and Quinn G. Are More than 90 percent of patents patentlyo.com/patent/2018/12/district-patent-litigation.html
challenged at the PTAB defective? IP Watchdog, June 14, 2017, (accessed May 10, 2019).
http://www.ipwatchdog.com/2017/06/14/90-percent-patents- 86
The Economist. A question of utility 2015 (August 8).
challenged-ptab-defective/id=84343/ (accessed May 10, 2019). 87
Planet Bingo LLC v. VKGS LLC, No. 13-1663 (Fed. Cir. 2014). The
82
Brachman S. STRONGER Patents Act Introduced in House, underlying patents were U.S. Patent Nos. 6,398,646 and 6,656,045.
Seeks to Strengthen a Crippled Patent System; March 26, 2018 IP 88
U.S. Patent No. 6,368,227.
Watchdog. https://www.ipwatchdog.com/2018/03/26/stronger- 89
The basic patents on these products expired years ago. Some
patents-act-house/id=95188/ (accessed May 10, 2019). See critics assert that drug companies can extend their patents by
also, “Senators Appear Keen on Drafting New Patent Eligibility making trivial modifications to the underlying drug. Although
Law” IPLaw360, December 17, 2018, https://www.law360.com/ “trivial improvement patents” might be obtained, the argument
articles/1112205/sens-appear-keen-on-drafting-new-patent- is disingenuous because competitors could always make the
eligibility-law (accessed May 10, 2019). drug without the “trivial” modification and avoid infringing the
83
Saint Regis Mohawk Tribe v. Mylan Pharmaceuticals, Appeal No. patent. An important cause of high drug prices is that there is no
18-1638 (Fed. Cir. 2018). market check to help determine reasonable drug prices. https://
www.wsj.com/articles/drugmakers-raise-prices-on-hundreds-of-
-medicines-11546389293?mod=hp_lead_pos1 (accessed May 10,
2019).
because patents allow smaller companies to enter 11. Conclusion

the market and stop larger companies from using
inventions developed by start-up companies. This The patent system is emerging from a tumultuous
threat has made the technology companies some of the period when many of the basic rules have changed. A
fiercest opponents of patents; they have funded organi- new patent law was introduced in 2013, and Supreme
zations that exploit any defect in the patent system and Court cases have upended the rules of patenting
characterize patent owners who assert their rights as software inventions, natural products, and some
“patent trolls.” diagnostic methods. However, patents on medical
The new Director of the USPTO (Andrei Iancu) is devices, methods of treatment, and pharmaceuticals
attempting to reverse this trend. He has noted that “the have been relatively unscathed. In this challenging
rhetoric surrounding the patent system has focused environment it is more important than ever to be aware
relentlessly on certain faults in, or abuses of, the system of the rules of the patent system to avoid inadvertent
— instead of the incredible benefits the system brings loss of patent rights. A more promising era may be
to our nation.”90 He aims to create a more balanced opening for patents and the innovators who benefit
perspective that defines the patent system by the from them.
brilliance of its inventors, the excitement of invention, Congress is currently considering changes to the
and the benefits patents bring to society. He recognizes patent law that could restore this balance, and return
that if there is no way to protect an idea then everyone the U.S. patent system to its former position as an engine
is at the mercy of copyists. If there are defects in the of technological and economic progress. Prospects for
patent system, those defects should be specifically passage of the legislation appear to be good.
addressed instead of demonizing a system that has suc-
cessfully rewarded innovation and promoted scientific
progress for centuries.
90
Remarks by Director Andrei Iancu at U.S. Chamber of Commerce
Patent Policy Conference, April 11, 2018, as reported by the
USPTO at https://www.uspto.gov/about-us/news-updates/
remarks- director-andrei-iancu-us-chamber-commerce-patent-
policy-conference (accessed May 10, 2019).
3. Which MIGS procedure should one choose for a
specific patient?
Jithin Yohannan, E. Randy Craven
Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD, USA
Abstract
Today’s glaucoma surgeons are fortunate to have indicate technique of implantation for this this device
access to a wide array of procedures that can be tailored is critical.
to individual patients. As a general rule, procedures Subconjunctival minimally invasive glaucoma
with superior safety (e.g. trabecular outflow-enhanc- surgery can lead to enough IOP lowering to achieve a
ing procedures) may be less efficacious in lowering target in the low teens. In addition, for those with a low
intraocular pressure (IOP) than trans-scleral filtering likelihood of the conventional outflow system working,
surgery. such as those with raised episcleral venous pressure,
Schlemm’s canal (SC) outflow-enhancing procedures this option is appealing. The use of the XEN® Gel Stent
(e.g. trabecular bypass, goniotomy, and canaloplasty) (porcine gel stent; Allergan, Dublin, Ireland) decreases
are best considered for patients with an IOP target in tissue manipulation, often with improved visual recovery
the mid to high teens. In addition, those with medically compared to conventional procedures; the technique
controlled glaucoma and IOP targets in the low teens is evolving. The PRESERFLOTM MicroShunt (Santen,
may reach their IOP goals with trabecular bypass Osaka, Japan) and future smaller shunts currently in
procedures in conjunction with medications. When development require some tissue dissection, but less
choosing between different types of trabecular-bypass than the current tube shunts; these may produce more
implants, often the availability of the implant itself may consistent IOP reduction in patients with prior failed
play a role in what device is used; implant availability trabeculectomy, as well as in younger, non-white, and
may be limited by cost and/or insurance constraints. diabetic patients. More traditional therapy, such as
The mechanism causing the glaucoma (secondary trabeculectomy, can be employed to achieve very low
glaucoma vs primary open-angle glaucoma), the view targets (< 8 mmHg) and tube shunts are useful with
of the angle, and the approach to the angle also play a neovascular, uveitic, and complex anterior segment
role in procedure choice. issues causing glaucoma.
Suprachoroidal implants increase outflow through
an alternate route to the SC outflow pathway; they can Keywords: glaucoma outflow, minimally invasive
achieve IOP targets in the teens. The first supraciliary glaucoma surgery (MIGS), procedure selection, subcon-
stent approved (CyPassTM, Alcon, Fort Worth, TX, USA) junctival devices, trabecular bypass
was withdrawn from the market because of concerns
related to increased rates of endothelial cell loss in
some patients; the rate was higher with a longer length
of the implant in the anterior chamber, which would
Correspondence: E. Randy Craven, MD, Johns Hopkins Wilmer Eye Institute, 6430 Rockledge Drive Westmoreland Building, Suite 600
Bethesda, MD 20817, USA.

56 J. Yohannan and E.R. Craven
1. Introduction 2. First consideration: When considering

MIGS, which outflow pathway should
The goal of the glaucoma surgeon is to safely stop or
one choose?
reduce glaucoma progression by lowering a patient’s
intraocular pressure (IOP) to an appropriate level. Most likely, if a surgeon is considering a MIGS, safety
Hopefully, the targets set by the surgeon are low is a primary consideration. It may also be that patient
enough to achieve stability. Ideally, glaucoma surgery concerns, or a prior trabeculectomy or tube complica-
is done with no perioperative complications and rapid tion are factors. Either way, a MIGS is being considered.
visual recovery. Although surgeons have been able to
achieve low IOP targets for years with trabeculectomy 2.1. What is the mechanism of glaucoma?
and tube-shunt surgery,1,2 the rates of bleb-related com- Mild to moderate primary open-angle glaucoma (POAG)
plications are high enough to make minimally invasive responds reasonably well to most MIGS procedures.
glaucoma surgery (MIGS) procedures a consideration.3 POAG patients on multiple medications with IOP over
Starting in the 1990s, innovative surgeons attempted 30 may not be a candidate for trabecular or supracho-
to improve the safety of trabeculectomy by inventing roidal MIGS given their efficacy at the time of this
a variety of nonpenetrating glaucoma procedures, writing. If the angle is closed or the patient has a
including deep sclerectomy,4 viscocanalopasty,1 and secondary glaucoma, some MIGS may work but space
later ab externo canaloplasty.5 In addition to achieving and visualization to place the MIGS may be challenging.
target IOP, the goals of these procedures were three- Some surgeons have tried restoring outflow through
fold: Schlemm’s canal (SC) with the trabecular inject system
1. reduce the risk of early and late postoperative if the trabecular meshwork (TM) is visible in patients
hypotony, by avoiding a through-and-through with narrow-angle glaucoma.8
trans-scleral incision; It is important to target an outflow pathway that is
2. avoid or reduce the bleb size and associated most likely viable for the specific patient. For instance,
complications; and in patients with narrow or closed angles, the native lens
3. potentially restore physiologic outflow. should be removed before MIGS implantation to see if
However, we learned that such procedures only gave there is a good view of the TM before a bypass stent is
similar results to trabeculectomy if the procedures placed; this is because these patients are at much higher
were turned into trans-scleral filtration by YAG-gonio- risk for peripheral anterior synechiae (PAS) without lens
puncture and the use of mitomycin C (MMC).6 removal. Alternatively, patients with closed angles post
MIGS devices have evolved over the past two decades lens extraction may be good candidates for subconjunc-
to address the safety concerns associated with trabe- tival MIGS. Furthermore, certain secondary glaucomas
culectomy and tube-shunt surgery. In addition, they offer respond to TM extirpation procedures (see section 3.1).
better standardization of the surgical technique and
cause less fibrosis than prior surgical techniques. The 2.2. What is the mechanism of action for the MIGS?
MIGS procedures use multiple outflow pathways; they Based on the mechanism of glaucoma, targeting a
are not limited to trans-scleral filtration. The U.S. Food viable outflow pathway is the next consideration.
and Drug Administration (FDA) guidelines published in Current MIGS devices and procedures allow the surgeon
2015 define MIGS devices as “a type of [implant] used to achieve a lower IOP by targeting one of three outflow
to lower IOP using an outflow mechanism with either pathways:
an ab interno or ab externo approach and associated 1. the trabecular bypass/SC space;
with little or no scleral dissection and minimal or no 2. the suprachoroidal/supraciliary space; or
conjunctival manipulation.”7 In the sections below, 3. the subconjunctival space.
we will focus on describing the MIGS devices we have The choice of which outflow pathway to utilize hinges
experience with in detail and share pearls on how we on the considerations detailed below.
decide between the different MIGS devices.
Which MIGS procedure should one choose for a specific patient? 57
Fig. 2. A patient with a large, cystic, overhanging bleb after filtration

surgery. If this patient needs surgery in the other eye, an ab interno,
blebless surgery can be considered to prevent bleb-related issues.
revisions in the other eye, has a history of endophthal-

mitis from a bleb in the other eye, or has issues with
hypotony or dysesthesia, blebless internal MIGS may
be a reasonable option (Fig. 2).
Fig. 1. The cornea of this glaucoma patient has significant opacity.
Due to this, visualization of the angle and implantation of a 2.4. What is the baseline and current IOP?
canal-based MIGS device would be difficult. In such cases, an ab
externo MIGS approach or a traditional filtration surgery should be Baseline IOP is an important consideration when
the first line treatment. selecting the appropriate surgery. Patients with very
high baseline IOP (40 mmHg or higher) may best be
2.3. What about the ocular tissue? Can the surgeon served by an incisional surgery, since such procedures
achieve adequate visualization to implant the seem to have a lower risk of postoperative spikes
MIGS, and what is the status of the conjunctiva and compared to ab interno MIGS. Also, if the nerve cannot
sclera? tolerate significant IOP spikes (i.e. advanced glaucoma),
Patients with corneal opacity are not good candidates considering an incisional surgery is reasonable.9 Some
for an ab interno MIGS due to poor angle visualization have used MIGS in advanced cases but in conjunction
(Fig. 1). In such cases, converting to an ab externo with medications.10
approach may be better. In some patients, such as the
contact-lens-dependent patient with keratoconus, 2.5. What target IOP is the surgeon trying to
a bleb might need to be avoided; such patients are achieve?
sometimes appropriate to consider for an ab interno This is probably the most important consideration for
MIGS procedure. Patients with significantly scarred selecting a pathway to target (Fig. 3). Once a target
conjunctiva from multiple prior ophthalmic procedures IOP — or target IOP range — is set, a decision can be
and systemic conditions, such as ocular cicatricial made on the most reasonable pathway to target. Once
pemphigoid, may not do well with a bleb created by the pathway is selected, there is considerable leeway
a subconjunctival MIGS procedure. Patients who have to decide which device or procedure to employ within
had a history of scleral buckle may be a good candidate that pathway.
for ab interno MIGS due to conjunctival scarring, but The trabecular-bypass pathway is likely limited by
care should be taken to make sure that the IOP is not an IOP floor dictated by the episcleral venous pressure
elevated due to an overly tight buckle. Furthermore, (EVP), which is typically 8-10 mmHg.11 However, the
patients with significant proptosis, e.g. from Grave’s role of EVP on IOP is variable and a trabecular bypass
orbitopathy, and a risk for bleb exposure may be ab may only lower IOP to a level above the floor level set
interno MIGS candidates. If a patient has had bleb by the EVP.12 Secondary increases in EVP may also limit
Target
IOP
≤13 ≥13
Subconjuctival Canal-based
MIGS MIGS
Stenting Extirpation Expansion
PRESERFLO Ab externo Ab interno iStent/iStent Partial 360° Ab interno

Hydrus canaloplasty
MicroShunt XEN XEN Inject goniotomy Goniotomy
• Good for eyes • Good for eyes • Good for • Rapid • Slightly • Good when • Cost • Less heme
that have with high risk eyes with visual greater IOP logistical constraints than
failed prior of bleb fibrosis low risk of recovery lowering constraints prevent goniotomy
filtering (younger, dark bleb fibrosis • Can be effect than prevent stenting procedures
surgery and/or pigmentation) • Rapid used when iStent stenting • More • Lack of
have high risk procedure angle not • Angle must • Often more Heme than significant
of bleb fibrosis wide open be wide heme than partial evidence
(younger, dark open stenting. goniotomy
pigmentation) • Rapid • Good for • Good for
visual eyes with eyes with
recovery secondary secondary
glaucomas glaucomas
Fig. 3. How to select the appropriate MIGS device for a patient. IOP: intraocular pressure; MIGS: minimally invasive glaucoma surgery
accessing the episcleral venous network.13 Ironically, in

some patients with increased EVP (Fig. 4) we are very
keen to avoid the risks of traditional filtering surgery,
as overfiltration may lead to an increased risk for
suprachoroidal hemorrhage; some have suggested that
deep sclerectomy may be a better option here.14
Beyond the effects of EVP on the IOP floor, the
resistance at the TM, SC, and the collector channels play
an important role in reducing outflow and increasing
IOP,15,16 and it stands to reason that bypassing this
area of resistance may lower IOP. Indeed, trials of TM
stenting or TM removal (i.e. extirpation) showed final
IOPs ranging from low to high teens.17,18 However, using
travoprost in conjunction with a TM stent does allow
for even lower IOP.19 Therefore, the use of trabecular
bypass procedures lends itself to:
1. patients with uncontrolled glaucoma who have
Fig. 4. Engorged conjunctival vessels suggestive of an increase in
episcleral venous pressure. In such patients, a trabecular bypass targets of mid-teens or higher and need to
will be insufficient. achieve target IOPs; and
2. patients with well-controlled glaucoma on
the success of TM-bypass procedures, as these raise medications and with targets in the low teens
the IOP floor. In order to achieve the most effective IOP who desire a reduction in medication burden but
reduction, some have recommended identification of are not opposed to the use of medication to get
aqueous veins to locate the optimal procedure site for the IOP low enough.
Although the only FDA-approved suprachoroidal desired with the ab interno sclerostomy procedures in
device (CyPassTM; Alcon, Fort Worth, TX, USA) has been the early 1990s.26-28 The IOP these devices can achieve
voluntarily withdrawn from the market, we will discuss is determined by:
the suprachoroidal-pathway approach as it may be a 1. Hagen-Poiseuille’s equation (inner diameter and
viable option for the future (e.g. re-release of CyPassTM, length of the implant); and
approval of iStent SupraTM [Glaukos, San Clemente, 2. the resistance created by conjunctival wound
CA, USA], or MINIject; iSTAR Medical, Wavre, Belgium). healing/fibrosis.29
Suprachoroidal devices offer the theoretical advantage Without conjunctival resistance, these devices are
of being less influenced by the EVP. Therefore, such designed to achieve IOPs in the high single digits.
devices may allow one to achieve lower medication-free In our real-world experience, with correct patient
target IOPs. Indeed, some patients do achieve these selection, careful surgical technique, and periopera-
targets and even develop hypotony maculopathy after tive management, we are able to achieve IOPs in the
suprachoroidal stenting.20 However, on average, results low teens in the majority of patients undergoing XEN
from the COMPASS trial demonstrate that patients in Gel Stent30 (also discussed in Chapters 12 and 20) or
the phacoemulsification plus CyPassTM group achieved PRESERFLO MicroShunt31 (also discussed in Chapter 13)
a mean final IOP of 18 mmHg.21 Hypotony developed implantation with MMC. Therefore, we offer these sub-
in 7.2% of patients and some had IOP spikes > 10 conjunctival MIGS procedures for:
mmHg above baseline. Other trials involving patients 1. patients with IOP targets in the low teens or
with more advanced glaucoma reported a higher patients with progressive disease;
percentage of patients with IOP spikes and some spikes 2. patients where the TM is not visible or there is a
being sustained.22 Such variable responses may be due closed angle without enough room to implant a
to the variability in suprachoroidal wound healing or TM bypass or suprachoroidal device; or
outflow differences between patients. It may also be 3. patients needing filtering surgery who are at high
due to uveoscleral pathway outflow issues, such as risk for choroidal hemorrhage or effusion.32,33
saturation and scleral egress. Patients with myopia
may experience hypotony due to the position of the
CyPass in the eye and susceptibility of the sclera to fold 3. Second consideration: which device?
in myopic patients.23 There may also be a role for other
factors besides the size and patency of the cleft.24,25 If a surgeon thinks the trabecular outflow system is
Because of this variability, we tended to use CyPass viable, the following should be considered:
for patients with target pressures in the teens who
would be able to tolerate an IOP spike. Due to the risk 3.1. Which SC-based procedure should be used?
of hypotony, mostly reported with more than mildly SC-based procedures can be divided into three different
myopic patients, we are cautious to recommend the categories:
suprachoroidal option for the moderate to significant 1. stenting procedures;
myopes.20 Furthermore, we did consider CyPass for 2. extirpation (removal, cutting, or tearing) proce-
eyes with good visual potential and limited pliable con- dures; and
junctival tissue (i.e. multiple prior failed tube/trabe- 3. SC-expansion procedures.
culectomy surgeries). Choosing the correct procedure depends on a number
Subconjunctival, bleb-forming MIGS devices — such of factors, including the desired IOP-lowering effect, the
as those from Allergan (Dublin, Ireland) and possibly tolerance for side effects, the type of glaucoma being
Santen (Osaka, Japan), at the time of this writing — addressed, and the availability and cost constraints.
utilize the same pathways as trabeculectomy and tube Stenting procedures, such as the iStent, iStent Inject
shunts to achieve IOP control. However, these devices (both also discussed in Chapter 9), and Hydrus (also
aim to improve safety by standardizing the flow to discussed in Chapter 8), all three by Ivantis (Irvine, CA,
a rate that would — theoretically — reduce the risk USA), help promote flow through SC by promoting more
of hypotony. This is not too different from what was aqueous to enter the SC via the stent lumen. In addition,
angles in combination with phacoemulsification, when

they are at the risk of PAS formation occurring.
The Kahook Dual Blade (KDB, New World Medical,
Inc., Rancho Cucamonga, CA, USA), gonioscopy-assisted
transluminal trabeculoplasty (GATT), the Trabectome
(NeoMedix, Tustin, CA, USA), and the TRAB360 (Sight
Sciences, Menlo Park, CA, USA) are examples of ab
interno trabecular extirpation (i.e. goniotomy and tra-
beculotomy) procedures. When compared to trabecular
bypass stents, these devices may be more cost effective
and possibly lower the IOP more than TM stents. A retro-
spective study comparing the efficacy of a single iStent
to KDB surgery found that the KDB produced a 23.7%
IOP reduction compared to 16.4% for a single iStent.38
Fig. 5. A gonioscopic view of the Hydrus microstent, which both
stents — i.e. provides an inlet for aqueous flow into the canal — and However, the KDB group did have a slightly higher
provides expansion of the canal for 90º. baseline IOP, which may account for the difference. In
addition, in our experience patients undergoing KDB
some procedures (e.g. the Hydrus) provide scaffolding surgery have a slightly higher risk of hyphema and a
to support and expand a large area of SC (Fig. 5).34 slightly longer visual recovery period than patients
Clinical trials have demonstrated that such devices can undergoing trabecular stenting. There can be irido-
achieve modest IOP reductions with visual recovery dialysis.18 We have seen iridodialysis in some patients
and complications no different to standard phacoemul- with hypotony. Because of this, we tend to use stenting
sification.17,35 We tend to favor TM stenting procedures instead of KDB surgery in most patients with target
for target IOPs in the mid to high teens, or for patients IOPs in the mid-teens or higher undergoing phacoemul-
with lower targets who do not mind using a medication sification. However, goniotomy is a viable alternative
to achieve enough reduction. There is evidence that to TM stenting and can be preferred in congenital or
iStents combined with medications achieve low IOPs.36 juvenile glaucoma, pseudophakia, and possibly uveitic
In the USA, these procedures are only approved for use glaucoma.39 The Trabectome has been shown to be
in conjunction with cataract surgery and many payors effective in POAG, pseudoexfoliation glaucoma, and
will not reimburse for standalone stents. Therefore, secondary glaucoma.40 We have found it useful in pseu-
in our practice we tend to use these devices only in doexfoliation glaucoma and uveitic patients that may
patients with cataract and glaucoma who have open have steroid-response glaucoma.
angles and a good enough view for implantation. The GATT procedure (also discussed in Chapter 7) has
Which trabecular bypass stent lowers IOP most been used for many types of glaucoma, mostly refrac-
effectively? Using two iStents, or the iStent Injects, tory,41 which is distinctly different from the iStent pop-
may achieve lower pressures more often than only one ulation. GATT is cost effective when performed with a
first-generation iStent.19,37 The COMPARE trial suggests 5-0 prolene and can be done as a reimbursable, stand-
that the Hydrus microstent may have a slight advantage alone procedure in the USA. The TRAB360 and OMNI
in reducing medications and achieving a 20% IOP reduc- (Sight Sciences, Menlo Park, CA, USA) has a handpiece
tion compared to two first-generation iStents. Although to allow for two 180° SC passes (Fig. 6); the GATT and
the Hydrus may be slightly better at reducing IOP and the OMNI/TRAB360 allow for full 360° extirpation of the
medication burden, we reserve its use for patients with TM. On the other hand, the KDB and the Trabectome do
strictly wide-open angles — grade 2-3 or greater — as not easily allow for 360° extirpations. We see hyphema
even with open angles the incidence of PAS is as high occur with GATT surgery in as much as one-third of the
as 18.7%, due to the larger size of the implant.35 Due patients in the first week after surgery,42 even more than
to the smaller size of the iStent and iStent Inject, these with the Trabectome or the KDB. This results in slower
implants can be employed in patients with less open visual recovery and a more cumbersome postopera-
threading a catheter into SC and injecting viscoelastic

material through the lumen of the catheter to expand
the SC. Scleral incision is avoided. This procedure can
be done with a preloaded device (OMNI) or manually
using the iTrack catheter (Ellex iScience, Inc., Fremont,
CA, USA). Recent retrospective data suggests that
internal canaloplasty may be effective at reducing
IOP to the mid-teens in open-angle glaucoma patients
with minimal adverse events.44 Therefore, internal
canaloplasty may be beneficial over extirpation
procedures when bleeding is a significant concern,
e.g. patients on blood thinners, and potentially for
patients with increased TM resistance (secondary
glaucoma, such as steroid-induced and uveitic
glaucoma). To date we still lack an ability to image the
SC or collectors, but in time we may be able to use
imaging techniques and determine who would best be
Fig. 6. The TRAB360 handpiece. This photo demonstrates the served by a specific MIGS device.
flexible, blue trabeculotome entering SC, which can be used to
perform two 180° goniotomies. 3.2. Which subconjunctival MIGS should be used?
Once it is determined that the trabecular or supracho-
tive course compared to patients undergoing stenting roidal MIGS devices are not the best option for a given
procedures, Trabectome, or KDB surgery. One potential patient, due to inadequate IOP-lowering effects — i.e.
solution to this is to perform a hemi-GATT, where one- patient needs IOP in the low teens — or other con-
half of SC is opened for 180° instead of the full 360°. In siderations (e.g. elevated EVP), the patient will need
our experience, this substantially reduces the rate of bleb-forming surgery. Newer, subconjunctival MIGS
hyphema. For residual angle-closure patients — with devices, such as XEN and the PRESERFLO MicroShunt,
now open angles — that are pseudophakic, or second- can achieve the goal of bleb creation with the potential
ary open-angle glaucoma patients where a standalone benefits of increased safety and faster visual recovery
procedure is needed and the target is mid-teens or compared to traditional filtering surgeries.
higher, the Trabectome, the KDB, a hemi-TRAB360 or a XEN implantation techniques are evolving. Initial
hemi-GATT can be effective and result in less hyphema. studies evaluated both ab interno (Fig. 7) and ab externo
However, a 360° GATT tends to be particularly effective approaches (Fig. 8);45 currently, we are doing about
at reducing IOP in congenital, juvenile, and secondary half ab interno and half ab externo. The choice for ab
glaucoma with prior procedures.43 We do consider using interno vs ab externo depends on a number of factors,
360° extirpations as first-line therapy in advanced or including age, race, status of the conjunctiva, and
progressive secondary glaucoma (i.e. steroid-induced, desired quadrant of placement. For instance, in younger
pigmentary, and traumatic glaucoma) with target IOPs African Americans with a thicker Tenon’s capsule and a
in the low teens. GATT is particularly useful in younger higher chance of implant impingement, we open the
patients with secondary disease, where the conjunctiva conjunctiva to create a free path for placement of the
should be preserved as long as possible. implant’s external lumen above Tenon’s capsule, as
As for ab interno canaloplasty (also discussed in such patients are at high risk of the implant getting
Chapter 11), a SC-expansion procedure, there are few caught in Tenon’s capsule via a purely ab interno
studies evaluating this newer method of performing approach. When placed via an ab interno approach,
an older procedure (canaloplasty ab externo). There is XEN can be extremely fast to implant and has a more
some evidence that the ab externo procedure lowers rapid recovery period compared to the PRESERFLO
IOP. The newer ab interno canaloplasty requires MicroShunt, tube implantation, or trabeculectomy. Ab
Fig. 9. The PRESERFLO MicroShunt requires significant conjunc-

tival and sub-Tenon’s dissection for proper placement in the
sub-Tenon’s space.
Fig. 7. Ab interno XEN placement. Care must be taken to make

sure the device is injected in the subconjunctival space and not it in eyes which have failed prior filtering surgery. In
embedded in Tenon’s layer. our experience, a significant majority of patients with
failed prior filtering surgery achieve their target IOP
with the PRESERFLO MicroShunt.2 Because it has a
posteriorly displaced lumen and because we close
Tenon’s capsule over the PRESERFLO MicroShunt, we
find that PRESERFLO blebs tend to be more posterior
and diffuse compared to the blebs achieved with XEN.
Due to this favorable bleb morphology, we often favor
the PRESERFLO MicroShunt in patients who are con-
tact-lens wearers.
4. Third consideration: is traditional

filtering surgery or a valve a better
Fig. 8. Ab externo XEN placement. A small, conjunctival opening is option for this patient?
created to ensure that the XEN external lumen rests above Tenon’s
layer and fluid flows into the subconjunctival space. Emerging MIGS devices hold the promise of lowering
IOP effectively with a better safety profile than con-
interno placement of the XEN tends to lower IOP partic- ventional trabeculectomy and tube-shunt surgery. One
ularly well in nondiabetic, Caucasian patients.30 might ask whether there is still a place for trabeculecto-
For optimal results, PRESERFLO surgery involves my or a tube in today’s glaucoma armamentarium. We
more significant dissection of the conjunctiva and feel strongly that traditional procedures have a place
sub-Tenon’s space (Fig. 9), but we have found that the alongside the latest MIGS procedures.
PRESERFLO MicroShunt has more consistent IOP-low- Trabeculectomy (also discussed in Chapter 4) is the
ering effects across all ages and ethnicities compared to gold-standard technique for achieving a very low target
XEN. Because of this, we tend to employ the PRESERFLO (IOP < 12 mmHg). Clinical trial data demonstrates that
MicroShunt for advanced or progressive glaucoma in five years after surgery, the mean IOP of trabeculecto-
patients who are younger, diabetic, and non-white. my eyes was 12.6 mmHg.47 In order to get lower than
As the SIBS polymer in the PRESERFLO MicroShunt is this mean and achieve a single digit pressure, great care
designed to be resistant to fibrosis,46 we tend to use has to be taken to closely monitor IOP in the perioper-
63
Table 1. How MIGS procedures compare to less invasive options

Most likely Low IOP
mechanism of Angle status range Downside Upside Reference
action (mmHg)
Trabecular bypass Conventional Open to 15-19 Efficacy; placement to achieve Little bleeding; leaves TM Arriola-
(iStent; ab interno) outflow narrow IOP reduction intact Villalobos et al.49
Trabecular bypass with canal dilation Conventional Open 12-17 PAS Both a trabecular bypass and Samuelson et
(Hydrus; ab interno) outflow canal dilator al.35
Goniotomy-like trabecular extirpation Conventional Open 12-19 Hyphema Opens access to the canal Grover et al.42
(ab interno) outflow system
Canal dilation Conventional Open 12-19 Specialized catheter needed Little bleeding Okeke et al.40
(ab interno canaloplasty) outflow
Suprachoroidal bypass Uveoscleral Open 13-18 Varying IOP course May work if SLT or Vold et al.21
(ab interno; CyPass and iStent Supra) outflow medications fail; repeatable
Subconjunctival Trans-scleral Open or closed 12-15 Bleb, fibrosis, need for Achieves low IOP targets; Batlle et al.31,
(bleb-forming; XEN and PRESERFLO) bleb needling less hypotony; fast visual Heindinger et
recovery. al.50
Endoscopic cyclophotocoagulation Cyclodestructive Open or closed 17-28 Poor response with exfoliation; No bleeding; good when the Kaplowitz et
IOP spike; IOP control may be cornea is cloudy al.51, Francis et
limited; patient needs to be al.52
pseudophakic
Which MIGS procedure should one choose for a specific patient?
Phacoemulsification alone Conventional Open or closed 18-30 IOP spike, no effect on IOP for Low risk for most patients Brown et al.53
outflow some patients
(probably)
IOP: intraocular pressure; PAS: peripheral anterior synechiae; SLT: selective laser trabeculoplasty; TM: trabecular meshwork
ative period and perform postoperative suture lysis inflammatory cells may occlude the microlumen of
and/or needling before permanent bleb fibrosis sets in. the XEN or the PRESERFLO MicroShunt. Finally, in
Outside of its usefulness at achieving very low target eyes that require a low target IOP as well as a complex
IOPs, trabeculectomy is a particularly cost-effective segment procedure — e.g. pupilloplasty, complex
way to lower IOP, as no implant or other specialized cataract surgery, or intraocular-lens exchange — we
machinery is required, with the exception of the laser tend to favor tube shunts over XEN or the PRESERFLO
for suture lysis. Therefore, it may be the procedure of MicroShunt, as the increased inflammatory reaction
choice to achieve a low IOP target in a cost-constrained after such a procedure risks microlumen occlusion.
setting. In addition, tubes may be placed in the sulcus or pars
Tube shunts have a much larger lumen (300 microns) plana in eyes with corneal issues that may not tolerate
than the microlumens of the PRESERFLO MicroShunt anterior chamber placement of XEN, the PRESERFLO
(75 microns) or XEN (45 microns). Therefore, we tend MicroShunt, or even trabeculectomy.48
to use tube shunts in eyes that need a low target IOP With so many options, clinical trials comparing MIGS
and are at risk of microluminal occlusion, or for those to each other and traditional surgery will be invaluable.
who require a more posterior bleb. We tend to perform There is a significant amount of overlap, and time will
tube-shunt surgery in eyes with neovascular glaucoma help us to sort out which MIGS to employ at which point
that are at high risk of bleeding or occlusion of stoma over the lifetime of a glaucoma patient. For now, we
with a trabeculectomy or the microlumen of a MIGS. have not given up on traditional surgery but are doing
We also tend to utilize tube shunts in eyes with uncon- fewer of these than in the past.
trolled glaucoma from granulomatous uveitis, in which
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using a collagen glaucoma stent. J Cataract Refract Surg. canal for the reduction of IOP via an ab-interno approach. Clin
2014;40(8):1301-1306. Ophthalmol. 2018;12:2149-2155.
30. Schlenker MB, Gulamhusein H, Conrad-Hengerer I, et al. 45. Grover DS, Flynn WJ, Bashford KP, et al. Performance and safety
Efficacy, safety, and risk factors for failure of standalone ab of a new ab interno gelatin stent in refractory glaucoma at 12
interno gelatin microstent implantation versus standalone tra- months. Am J Ophthalmol. 2017;183:25-36.
beculectomy. Ophthalmology. 2017;124(11):1579-1588. 46. Pinchuk L, Riss I, Batlle JF, et al. The use of poly(sty-
31. Batlle JF, Fantes F, Riss I, et al. Three-year follow-up of a novel rene-block-isobutylene-block-styrene) as a microshunt to treat
aqueous humor microshunt. J Glaucoma. 2016;25(2):e58-65. glaucoma. Regen Biomater. 2016;3(2):137-142.
32. Morgan WH, Yu DY. XEN-45 gelatin microfistula for uveitic 47. Gedde SJ, Schiffman JC, Feuer WJ, et al. Treatment outcomes in
glaucoma. Clin Exp Ophthalmol. 2018;46(4):323-324. the Tube Versus Trabeculectomy (TVT) study after five years of
follow-up. Am J Ophthalmol. 2012;153(5):789-803.
48. Rososinski A, Wechsler D, Grigg J. Retrospective review of 51. Kaplowitz K, Kuei A, Klenofsky B, Abazari A, Honkanen R. The
pars plana versus anterior chamber placement of Baerveldt use of endoscopic cyclophotocoagulation for moderate to
glaucoma drainage device. J Glaucoma. 2015;24(2):95-99. advanced glaucoma. Acta Ophthalmol. 2015;93(5):395-401.
49. Arriola-Villalobos P, Martinez-de-la-Casa JM, Diaz-Valle D, Mo- 52. Francis BA, Kawji AS, Vo NT, Dustin L, Chopra V. Endoscopic
rales-Fernandez L, Fernandez-Perez C, Garcia-Feijoo J. Glaukos cyclophotocoagulation (ECP) in the management of uncon-
iStent inject trabecular micro-bypass implantation associated trolled glaucoma with prior aqueous tube shunt. J Glaucoma.
with cataract surgery in patients with coexisting cataract and 2011;20(8):523-527.
open-angle glaucoma or ocular hypertension: a long-term 53. Brown RH, Zhong L, Lynch MG. Lens-based glaucoma surgery:
study. J Ophthalmol. 2016;2016:1056573. using cataract surgery to reduce intraocular pressure. J
50. Heidinger A, Schwab C, Lindner E, Riedl R, Mossbock G. A ret- Cataract Refract Surg. 2014;40(8):1255-1262.
rospective study of 199 xen45 stent implantations from 2014 to
2016. J Glaucoma. 2019;28(1):75-79.
4. In defense of the trabeculectomy
Ryan Machiele1, Makena Parker2, Leon W. Herndon3
Campbell University School of Osteopathic Medicine, Buies Creek, NC, USA; 2North Carolina State University, Raleigh,
1
NC, USA; 3Department of Ophthalmology, Duke University, Durham, NC, USA
Abstract
The trabeculectomy has long been the gold-standard involving the use of devices to increase fluid flow and
treatment for lowering intraocular pressure. In the thereby decrease IOP.
21st century, it has decreased in popularity despite The trabeculectomy has long been considered the
inconsistent evidence in favor of surgical alternatives. gold standard for the lowering of IOP.1 Over time, the
We reviewed the current literature on the important addition of mitomycin C (MMC) during the surgical
place of the trabeculectomy in the current treatment procedure has increased the effectiveness and longevity
paradigm and examined evidence for other surgeries of that result.2 Many novel procedures attempt to lower
in defense of the long-standing treatment of choice. We IOP even further with more favorable safety profiles.
conclude that while complications of the trabeculec- Risk factors for failure for trabeculectomies include
tomy can be substantial, its foundation of high-quality age, previous ocular surgery, and long-term exposure
evidence combined with continued refinements make to topical medications.3 Although the preference
it a viable treatment option for refractory glaucoma. has shifted from trabeculectomies to these novel
procedures, trabeculectomies are still more effective
Keywords: filtration surgery, glaucoma surgery, trabe- at lowering the IOP, but with a slightly less favorable
culectomy safety profile.4 Trabeculectomies are more effective at
dramatically lowering IOP in cases such as normal-ten-
sion glaucoma, for example.5
1. Introduction
Glaucoma is a dynamic disease in which patients 2. The case for trabeculectomy

undergo many fluctuations in symptoms and increases
in intraocular pressure (IOP) requiring adjustments to Lowering IOP has long been the primary target in
their treatment plan. There are a variety of minimally the treatment of glaucoma. Surgical interventions
invasive options, including topical medications and have been designed to either increase the outflow or
laser treatments. As the condition becomes more decrease the inflow of aqueous. The trabeculectomy
advanced, a variety of surgical interventions are was developed in 1968 as a means of increasing aqueous
available to assist in lowering the IOP over the long term. outflow in open-angle glaucoma. It was described by
The variety of treatments allows for a combination of Cairns as a pressure-lowering surgical alternative to
therapies to be tailored to each patient, dependent the full-thickness anterior sclerotomy and iridencleisis
upon their disease progression. Once surgical inter- that had previously been the mainstays of surgical
vention is required, there are a number of options intervention.6 The trabeculectomy was intended to
including trabeculectomies and more novel techniques utilize a novel mechanism of drainage of the anterior
Correspondence: Leon W. Herndon, MD, Box 3802 Med Ctr, Durham, NC 27710, USA.

68 R. Machiele, M. Parker and L. W. Herndon
chamber: in theory, extracting a segment of Schlemm’s elevated IOP. This is commonly due to healing of the
canal would open its cut ends to freely receive aqueous. subconjunctival bleb. Use of steroids in modulating
In reality, the primary mechanism of filtration proved subconjunctival healing proved effective early on.9 The
to be subconjunctival, just as with full-thickness use of the antimetabolite MMC has added significant
procedures that preceded it. Its lasting advantage, benefit in combating untoward bleb healing, allowing
however, has been the level of control the procedure for achievement of lower IOP. Numerous randomized
affords with regards to filtration. controlled studies support its effectiveness in
Since the 1960s, the trabeculectomy has been sustaining lower IOPs than trabeculectomy alone.10-12
the gold-standard procedure for lowering IOP.1 As a Numerous variations in the method of MMC application
guarded filtration surgery, it achieves the powerful have been proposed, which have proven efficacy in
IOP-lowering effect afforded by prior full-thickness further minimizing complications.13,14
procedures while greatly diminishing the side effects The primary goal of the trabeculectomy is achieving
of these antiquated interventions. Within the current a significant decrease in IOP in order to prevent visual
glaucoma treatment paradigm, trabeculectomy may be field loss. The efficacy of the trabeculectomy in reducing
employed when medications and laser trabeculoplas- IOP is undisputed, but quantifying its efficacy, partic-
ty fail to adequately control IOP. The trabeculectomy ularly important in the face of newer surgical options,
has proven particularly advantageous in the treatment remains a challenge for multiple reasons. Measures
of normal-tension glaucoma, where medications and of the overall effectiveness of trabeculectomy in
laser trabeculoplasty are unable to attain an IOP below reducing IOP vary widely due to inconsistent measures
episcleral venous pressure. of success and variability of populations studied.15 A
Numerous sustaining developments have allowed study examining measures of success in trabeculec-
the trabeculectomy to remain relevant despite the tomy treatment across 100 publications reported 92
emergence of competing surgical options. Alternative different definitions of success with regard to IOP, with
interventions have sought to achieve similar IOP associated success rates ranging from 36% to 98%.15
lowering while avoiding the complications of trabe- Accurate assessment of the effectiveness of trabe-
culectomy. Significant early and late postoperative culectomy in lowering IOP is deceptively complicated.
complications are intrinsic to the trabeculectomy, While definitions of treatment success vary widely, the
but refinements of the procedure have done much to trabeculectomy has been practiced long enough that
mitigate these complications. prospective studies have been able to chart outcomes
The greatest risk to the eye in the early postopera- over many years. Generally accepted success rates of
tive period following trabeculectomy is inadequate- trabeculectomy describe a 96% rate of achieving IOP of
ly controlled aqueous outflow, resulting in hypotony 21 mmHg or less at 1 year, 86% at 10 years, and 79% at
with secondary hypotonous maculopathy. This can 20 years.16
be incited during surgery by unidentified conjunctival The concept of the use of a tube to divert aqueous
trauma, but may also be due to inadequate scleral flap from the anterior chamber was first described by
closure or an unusually large bleb. In order to achieve Molteno in 1969.17 This concept has evolved as the
better control of scleral flap closure, primary use of glaucoma drainage device (GDD) or tube shunt, and
tight permanent sutures, with subsequent laser cutting has since had consistent success in lowering IOP when
of sutures to modulate IOP has been standard practice trabeculectomy is not an appropriate treatment. Tra-
for many years.7 Beyond refinements in flap suture ditionally, this has included patients with iridocorneal
technique, experimental variations in conjunctival flap endothelial syndrome and rubeosis iridis, as well as
architecture have been frequent, with oscillating trends patients with complicated glaucomas due to chronic
in favor of a limbus-based vs fornix-based incision. The uveitis and aphakia.18 In recent years, concern about
best evidence, however, shows no significant difference bleb-related complications in the setting of trabe-
in efficacy between incision techniques.8 culectomy has contributed to an expanded use of GDDs
The greatest risk to the eye in the late postoper- and a decline in the popularity of the trabeculectomy.
ative period is failure of the bleb with consequently The TVT study, a multicenter randomized clinical trial,
In defense of the trabeculectomy 69
sought to compare the efficacy of trabeculectomy with remain, but compared with the current state of efficacy
MMC to that of GDD surgery in patients with medically and safety data on MIGS, trabeculectomy possesses
uncontrolled glaucoma who had previous cataract proven and consistent benefit.
and/or glaucoma surgery.19 The study demonstrated As the main short-term risk of the trabeculectomy
at five years of follow-up that within this population, is uncontrolled hypotony, developments have sought
tube-shunt surgery had a higher rate of success to improve control of aqueous outflow through shunt
than trabeculectomy and achieved comparable IOP implantation. The EX-PRESS shunt (Alcon, Fort Worth,
reduction, concluding that both surgical interventions TX, USA) has undergone significant trials and has
are viable options in the treatment of medically uncon- proven efficacy. Early implementation of these devices
trolled glaucoma in patients with a previous cataract involved subconjunctival installation through full-thick-
and/or glaucoma surgery.20 ness sclera, which resulted in failure-inducing fibrosis
Despite the success of the trabeculectomy as the and conjunctival erosion.23 Subsequent refinement of
gold-standard hypotensive treatment for glaucoma, its the procedure resulted in a treatment that mirrors the
serious complications have stimulated development trabeculectomy but dispenses with the sclerotomy in
of less invasive techniques, known collectively as favor of shunt installation beneath the partial-thick-
minimally invasive glaucoma surgeries (MIGS). These ness scleral flap. Consequently, while the shunt was
techniques are broadly defined as surgical procedures developed as a disruptive device, it now occupies
with an ab interno approach, minimal trauma with very the somewhat ambiguous place of a trabeculectomy
little or no scleral dissection, minimal or no conjunc- variant. A randomized, prospective, comparative trial
tival manipulation, a good safety profile, and rapid of the EX-PRESS shunt has shown efficacy in short-term
recovery.21 While these procedures are typically lower and long-term control of IOP to be similar between
in overall efficacy than the trabeculectomy, they are shunt implementation and standard trabeculecto-
designed to have an extremely low risk profile, making my, and has noted no significant difference in visual
them a potentially useful intermediate treatment for acuity beyond three months postoperatively.24 The key
the cadre of patients with open-angle glaucoma whose advantage of EX-PRESS shunt surgery lies in minimizing
IOP is not adequately controlled by medication and early postoperative fluctuations in IOP and a decrease
laser trabeculoplasty. in postoperative complications.24
While MIGS shows great promise as a low-risk surgical
intervention, long-term safety and efficacy data
continues to be lacking, complicating standardized 3. Conclusion
implementation. Additionally, the plethora of new and
emerging techniques presents a steep learning curve All of the surgical options discussed in this chapter seek
for surgeons, further hindering widespread adoption. to lower IOP by creating a path for aqueous diversion
Most significantly though, the evidence regarding from the anterior chamber. With increasing IOP-low-
implementation of MIGS is not adequate. The bulk of the ering efficacy comes an increase in adverse effects.
data on MIGS are derived from noncomparative studies This cost/benefit dilemma can be traced as far back
that have a demonstrable risk of confounding bias due as the anterior sclerotomy and continues to govern
to lack of baseline IOP and medication adjustment treatment development and clinical decision-making
between groups.22 Randomized controlled trials, up to the present day. The trabeculectomy occupies
where they do exist, uniformly raise concerns for lack a unique position in the treatment of uncontrolled
of masking among patients, surgeons, and outcome glaucoma in that its complications are substantial
assessors with frequent allocation concealment.22 In but its efficacy in reducing IOP is difficult to match.
general, while the complications of the trabeculec- Significant technical and pharmacological refinements
tomy are not insignificant, its long-term efficacy has have over time increased its efficacy, and development
been proven. Refinements in suture technique and of adjuncts such as the EX-PRESS shunt continues to
modulation of bleb healing have further amplified its push the cost/benefit scale in favor of higher efficacy
impact. Varying definitions of success in lowering IOP and reduced complications. Most importantly, as the
70 R. Machiele, M. Parker and L. W. Herndon
gold-standard IOP-lowering surgery for more than the current treatment landscape, high-quality evidence
half a century, the trabeculectomy has an unparal- continues to be sparse. The trabeculectomy, therefore,
leled catalog of evidence to guide its implementation. offers continued promise in the proper setting as an
Despite the myriad of novel ab interno treatments in evidence-based high-impact treatment.
References
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2. Rajendrababu S, Shroff S, Patil S, et al. Surgical outcomes of tomycin-C on the outcomes of trabeculectomy with Ex-PRESS
repeat trabeculectomy augmented with high dose mitomycin glaucoma filtration device: a randomized trial. J Glaucoma.
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5. Koike KJ, Chang PT. Trabeculectomy: a brief history and review 17. Molteno AC. New implant for drainage in glaucoma. Clinical
of current trends. Int Ophthalmol Clin. 2018;58(3):117-133. trial. Br J Ophthalmol. 1969;53(9):606-615.
6. Cairns JE. Trabeculectomy. Preliminary report of a new 18. Morgan WH, Yu DY. Surgical management of glaucoma: a
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7. Hoskins HD, Jr., Migliazzo C. Management of failing filtering 19. Gedde SJ. Results from the tube versus trabeculectomy study.
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8. Wang W, He M, Zhou M, et al. Fornix-based versus limbus-based the Tube Versus Trabeculectomy (TVT) study after five years of
conjunctival flap in trabeculectomy: a quantitative evaluation follow-up. Am J Ophthalmol. 2012;153(5):789-803.e782.
of the evidence. PloS One. 2013;8(12):e83656-e83656. 21. Saheb H, Ahmed, II. Micro-invasive glaucoma surgery: current
9. Sugar HS. Clinical effect of corticosteroids on conjunctival fil- perspectives and future directions. Curr Opin Ophthalmol.
tering blebs; a case report. Am J Ophthalmol. 1965;59:854-860. 2012;23(2):96-104.
10. Skuta GL, Beeson CC, Higginbotham EJ, et al. Intraoperative 22. Lavia C, Dallorto L, Maule M, et al. Minimally-invasive glaucoma
mitomycin versus postoperative 5-fluorouracil in high-risk surgeries (MIGS) for open angle glaucoma: A systematic review
glaucoma filtering surgery. Ophthalmology. 1992;99(3):438- and meta-analysis. PLoS One. 2017;12(8):e0183142.
444. 23. Stewart RM, Diamond JG, Ashmore ED, et al. Complications fol-
11. Kitazawa Y, Kawase K, Matsushita H, et al. Trabeculectomy with lowing ex-press glaucoma shunt implantation. Am J Ophthal-
mitomycin. a comparative study with fluorouracil. Arch Oph- mol. 2005;140(2):340-341.
thalmol. (Chicago, Ill: 1960). 1991;109(12):1693-1698. 24. Netland PA, Sarkisian SR, Jr., Moster MR, et al. Randomized,
12. Chen CW, Huang HT, Bair JS, et al. Trabeculectomy with si- prospective, comparative trial of EX-PRESS glaucoma filtration
multaneous topical application of mitomycin-C in refractory device versus trabeculectomy (XVT study). Am J Ophthalmol.
glaucoma. J Ocul Pharmacol. 1990;6(3):175-182. 2014;157(2):433-440 e433.
13. Zhang M, Li B, Wang J, et al. Subconjunctival versus intrascleral
application of mitomycin C during trabeculectomy. Invest Oph-
thalmol Vis Sci. 2014; pii: IOVS-14-14159. doi: 10.1167/iovs.14-
14159. [Epub ahead of print]
5. On the use of curcumin as a multimodal
antifibrotic agent for glaucoma surgery
Nicholas M. Pfahler1, Michael C. Giovingo2,3, Paul A. Knepper1,3
Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA; 2Department of
1
Ophthalmology, John H. Stroger Cook County Hospital, Chicago, IL, USA; 3Department of Ophthalmology, Northwestern
University Medical School, Chicago, IL, USA
Abstract
Purpose: Excessive wound healing is a primary cause of intraocular surgery, and use of topical glaucoma
of surgical failure following glaucoma filtration medications. Surgical failure remains common in tra-
surgery. This chapter reviews the success of current beculectomy surgeries performed using metabolites
management strategies for postoperative wound as intraoperative antifibrotics. Despite this, no
healing, examines several alternative therapies in alternative or adjunctive therapy has consistently
development, and proposes the use of curcumin as outperformed the use of metabolites alone in human
a novel and multimodal therapy to reduce excessive trials. In vitro, animal, and human studies show that
postoperative scarring following glaucoma filtration curcumin, a polyphenol derived from turmeric, targets
surgery. all four phases of the wound healing process and may
Methods: To determine risk factors associated with be a safe and viable anti-inflammatory and antifibrotic
surgical failure in glaucoma filtration surgery, a review agent used to reduce postoperative scarring following
was conducted of large clinical studies reporting glaucoma filtration surgery.
significant hazard ratios for factors associated with Conclusions: The use of intraoperative antifibrotics
surgical failure. To determine rates of surgical failure in to control wound healing is not always effective and
trabeculectomy surgery using metabolites as intraop- carries additional risks. Alternative or adjunctive anti-
erative antifibrotics, a review was conducted of clinical fibrotic therapies, however, have not proven any more
studies in which trabeculectomy was performed in effective. It is proposed that the diverse mechanisms
patients without previous intraocular surgery and of curcumin make it a viable alternative or adjunctive
surgical success was defined as intraocular pressure therapy to target excessive wound healing, reduce
≤ 21 mmHG or a reduction ≥ 20-30% from baseline. postoperative scarring, and improve outcomes
A further review was conducted to explore the following glaucoma filtration surgery.
mechanisms of wound healing and assess potential
alternative antifibrotic agents. A search was performed Keywords: curcumin, glaucoma, glaucoma filtration
of in vitro, animal, and human studies testing the surgery, toll-like receptor 4 (TLR4), wound healing
effects of curcumin in wound healing.
Results: Preoperative clinical and demographic risk
factors associated with complications and surgical
failure following glaucoma filtration surgery include
age, race, diabetes, secondary glaucoma, history
Correspondence: Paul A. Knepper MD, PhD.150 East Huron, Suite 1000, Chicago IL 60611, USA.

72 N.M. Pfahler, M.C. Giovingo and P.A. Knepper
1. Introduction after and tested. Growth factors such as vascular

endothelial growth factor (VEGF) and transforming
Filtration surgery is often required to control intraocular growth factor-β (TGF-β), for example, have increasing-
pressure (IOP) in glaucoma patients who are refractory ly been viewed as targets to modulate wound healing
to topical medication and/or laser treatment. Trab- following filtration surgery. No adjunctive or alternative
eculectomy is the most common filtration surgery, therapy, however, has consistently been shown to be
although tube-shunt implantation is utilized in more effective than MMC or 5-FU alone. In vitro, animal,
high-risk patients. The principle of these procedures, and human studies have shown that curcumin, the
however, is the same: to create a new pathway for the polyphenol derived from the root of turmeric (Curcuma
drainage of aqueous humor to decrease IOP. In trabe- longa), targets all four phases of the wound healing
culectomy surgery, an opening is created between the process (Fig. 1) and may therefore modulate wound
anterior chamber and subconjunctival space, which healing during and after filtration surgery. This chapter
allows aqueous to bypass the trabecular meshwork reviews strategies currently used for managing wound
(TM) and flow directly into a newly formed reservoir, healing following filtration surgery, examines several
called the filtration bleb, where it can be absorbed. In alternative or adjunctive therapies in the developmen-
tube-shunt surgery, a silicon tube is implanted, creating tal stage, and proposes the use of curcumin as a novel
a permanent sclerostomy allowing aqueous to drain and multimodal agent to reduce excessive postopera-
into an external reservoir. Some tube shunts feature a tive scarring of the conjunctiva and Tenon’s capsule.
control valve to reduce the risk of hypotony. Regardless
of the procedure, filtration surgery comes with a risk of
postsurgical complications typically associated with 2. Wound healing in glaucoma surgery
inflammation and hypertrophic scarring of Tenon’s
capsule and the conjunctiva. In trabeculectomy, a Wound healing is a synchronized process that comprises
balance must be achieved between adequate wound four characteristic and overlapping phases: hemostasis,
healing and excessive scarring to create a drainage inflammation, proliferation, and remodeling (Fig. 1).
pathway with optimal resistance. In tube-shunt surgery, Wound healing begins immediately after tissue injury
the risk of scarring-related complications is reduced by and continues for several months to several years,
the implantation of an artificial barrier. Nevertheless, depending on the tissue type. The initial hemostatic
excessive scarring is associated with poor outcomes phase begins immediately as platelets and red and
in tube-shunt surgery due to encapsulation of the white blood cells form blood clots to patch the damaged
drainage reservoir, which restricts flow of aqueous and vessel and prevent leakage. This process results in the
increases IOP.1 Consequently, excessive wound healing release of various growth factors, cytokines, hormones,
is the primary cause of failure in glaucoma filtration and damage-associated molecular patterns (DAMPs)
surgery. that signal the migration of immune cells and initiate
Currently, mitomycin C (MMC) and 5-fluoroura- inflammation through mediators such as toll-like
cil (5-FU) are the standard intraoperative antifibrot- receptor 4 (TLR4) and TGF-β receptors.2 The hemostatic
ics used to prevent hypertrophic scarring following and inflammatory phases may overlap as a single, early
filtration surgery. MMC and 5-FU, however, are not phase of wound healing occurring over the first 0-7
always effective and carry additional risks related days. Subsequently, fibroblasts and endothelial cells
to their potent cytotoxicity, which can render a bleb migrate to the wound site and trigger an intermediate
vulnerable to failure or even result in loss of vision. proliferative phase characterized by fibroblast prolifer-
Additional postoperative management procedures ation, collagen synthesis, reorganization of the extra-
such as bleb needling are commonly employed to cellular matrix (ECM), granulation tissue formation, and
control IOP, but are not always effective and further angiogenesis.3 Migration and proliferation of fibroblasts
increase the risk of failure going forward. For these begins around 3-5 days postsurgery and occurs for 2-3
reasons, alternative strategies to manage hypertrophic weeks thereafter.3 The final remodeling phase overlaps
scarring in glaucoma surgery continue to be sought with the end of the proliferative phase as the balance
On the use of curcumin as a multimodal antifibrotic agent for glaucoma surgery 73
Fig. 1. (Top) Overview of the effects of curcumin on the four phases of wound healing. (Bottom) The structure of curcumin.
between ECM production and degradation. In this late ratio for previous intracapsular cataract extraction was
stage of wound healing, the tensile strength of the tissue found to be 49.0 (95% confidence interval 11.5-209.3,
is increased as ECM/collagen is reorganized and aligned P < 0.0001).7 Other reported risk factors include a
in the wound bed. Remodeling can last for several Humphrey visual field mean deviation (MD) score of
months to several years —depending on the severity of -15.00 or less, high IOP, diabetes, the use of two or
the wound and type of tissue(s) involved — and results more topical medications, and the use of glaucoma
in the formation of mature scar tissue. Excessive wound medication for three or more years.7-9 In addition,
healing can result in obstructive scar tissue formation. patients with secondary glaucoma experience higher
In the case of trabeculectomy and tube-shunt surgery, rates of surgical failure compared to those with primary
failure is typically associated with hypertrophic scar open-angle glaucoma (POAG) or chronic angle-closure
tissue formation, which limits the flow of aqueous into glaucoma (CACG).5,7,8 Secondary uveitic, exfoliative,
the bleb.4 and pigmentary glaucoma are among the strongest risk
There are numerous preoperative risk factors factors for surgical complications and poor outcomes.
associated with an increased risk of scarring after Preoperative patient characteristics are strong
glaucoma surgery (Table 1). Namely, young age (< 40 indicators of surgical success and may explain the
years) and black race/African descent are risk factors for wide degree of variability in reported data concerning
surgical failure due to an increased fibrotic response.5,6 surgical outcomes in glaucoma filtration surgery.
Another prominent risk factor for scarring-related For example, Issa de Fendi et al.8 stratified patients
surgical failure is a history of previous intraocular into low, medium, and high risk-groups according to
surgery, such as trabeculectomy or cataract extraction. the prevalence of preoperative risk factors including
In one study of 330 eyes over 33 months, the hazard secondary glaucoma, previous trabeculectomy, use
Table 1. Risk factors for filtration surgery
Hazard ratio
Study N Risk factor P-value
(95% CI)
Previous IC cataract extraction 49.0 (11.5-209.3) < 0.0001
Age < 40 years 14.3 (4.1-40.8) < 0.0001
Uveitic glaucoma (vs POAG) 12.1 (3.7-39.7) < 0.0001
Previous EC cataract extraction 10.4 (3.1-35.1) < 0.0001
Landers et al. (2012) 7
330 Secondary glaucoma (vs POAG) 8.6 (2.9-25.2) < 0.0001
Topical medications ≥ 2 4.2 (1.9-9.3) < 0.0001
HVF MD ≤ -15.00 dB 4.1 (1.9-8.9) < 0.0001
Previous trabeculectomy 6.8 (1.9-23.6) < 0.01
Previous other ophthalmic surgery 6.8 (1.5-30.3) < 0.01
CAT-152 Trabeculectomy Study Group (2007)6 726 Black race (vs Caucasian) 3.6 (1.7-7.9) 0.002
Secondary glaucoma (vs POAG) 7.5 (1.7-33.5) 0.008

Glaucoma medication # ≥ 4 4.8 (1.2-28.0) 0.04
Issa de Fendi et al. (2016)8 120
Previous ophthalmic surgery 3.6 (1.1-21.0) 0.04
Glaucoma medications for ≥ 3 years 2.8 (1.8-9.6) 0.01
Diabetes 2.9 (1.9-4.4) < 0.001
Postoperative complication (≥ 1) 2.0 (1.4-2.9) < 0.001
AGIS investigators (2002)9 513
IOP (increase of 1 mmHg) 1.04 (1.01-1.06) 0.002
Age (increase of 1 year) 0.97 (0.95-0.99) 0.005
African descent (vs European) 2.1 (1.5-2.8) <.001
Nguyen et al. (2001) 5
227 Other glaucomas (vs POAG) 1.9 (1.3-2.6) <.001
Male sex 1.5 (1.1-2.1) 0.007
AGIS: Advanced Glaucoma Intervention Study; CI: confidence interval; EC: extracapsular; HVF MD: Humphrey visual field mean devia-
tion; IC: intracapsular; IOP: intraocular pressure; POAG: primary open-angle glaucoma
of four or more glaucoma medications, and use of 5-FU modulate postoperative conjunctival scarring
glaucoma medications for three or more years. In this by inducing apoptosis in Tenon’s capsule fibroblasts
study, the probability of surgical failure after three and therefore reduce the amount of fibroblast-de-
years was 7% for the low-risk group (0 risk factors), 17% rived ECM proteins, such as collagen.10 MMC is both
for the intermediate-risk group (1-2 risk factors), and safer and more efficacious than 5-FU and, as a result,
62% (P = 0.003) for the high-risk group (3-4 risk factors). is more commonly used where available. Successful
These risk factors and others may help to inform presurgical outcomes in filtration surgeries are enhanced
and postoperative management decisions on a case- using intraoperative MMC and 5-FU, but not without
by-case basis according to an assessment of risk. an increased prevalence of postsurgical complica-
tions. Complications arising from these agents include
punctate epithelial keratopathy, filamentary keratitis,
3. Antifibrotics and surgical success in hypotony, bleb leaks, endophthalmitis, subconjunc-
trabeculectomy tival hemorrhage, and formation of avascular blebs.
Success rates in glaucoma surgery, however, are difficult
Filtration surgery is almost always performed using to analyze due to the inconsistency of both procedural
a topical intraoperative antifibrotic agent, of which and analytic techniques. Parameters that commonly
the antimetabolites MMC and 5-FU are the most and differ between studies include surgical technique (e.g.
second most commonly used, respectively. MMC and fornix- vs limbus-based corneal flap); the type, con-
centration, and duration of antifibrotic agent; patient further surgical intervention despite the use of anti-
population; follow-up time(s); definitions of complete metabolites. Table 2 features a review of studies that
and qualified success; and the thoroughness of data reported surgical outcome data using a similar, con-
reported including the disclosure of medications. servative definition of success, i.e. IOP ≤ 21 mmHG
Consistently, however, a subset of patients requires or a reduction in IOP ≥ 20% from baseline with or
postoperative management, medication, and/or without medication. In general, about 30-50% of trab-
Table 2. Failure rates of trabeculectomy in patients without previous intraocular surgery
Complete Qualified
Follow-up
Study Design Antifibrotic N failure rate* failure rate† Success criteria
(Mo)
(N, %) (N, %)
Prospective,
Lachkar et al. (1997)77 None 18 16 6 (37.5) 7 (43.8) IOP < 21 mmHg
randomized
Prospective,
Mwanza et al. (2001)78 None 20 11 4 (36.4) NR IOP < 21 mmHg
randomized
Prospective,
Oh et al. (1994)79 5-FU 6 26 6 (23.1) NR IOP < 21 mmHg
randomized
Prospective, IOP < 21 mmHg or ≥
Singh et al. (2000)80 5-FU 10 54 4 (7.4) 31 (57.4)
randomized 20% from baseline
WuDunn et al. (2002)81 5-FU 12 48 3 (6.3) 4 (8.3)
randomized 30%↓ from baseline
Prospective,
Lachkar et al. (1997)77 5-FU 18 18 6 (33.3) 8 (44.4) IOP < 21 mmHg
randomized
Prospective,
Oh et al. (1994)79 MMC 6 29 3 (10.3) NR IOP < 21 mmHg
randomized
Singh et al. (2000)80 MMC 11 54 1 (1.9) 25 (46.3)
WuDunn et al. (2002)81 MMC 12 54 6 (11.1) 11 (20.4)
randomized 30%↓ from baseline
Retrospective,
Alwitry et al. (2009)82 MMC 12 59 4 (6.8) 10 (16.9) IOP < 21 mmHg
consecutive
Gedde et al. (2018)83 MMC 12 109 9 (8.3) 45 (41.3)
Retrospective,
Cackett et al. (2007)84 MMC 12 304 19 (6.3) 105 (34.5) IOP < 21 mmHg
consecutive
Prospective,
Mwanza et al. (2001)78 MMC 20 11 2 (18.2) NR IOP < 21 mmHg
randomized
Prospective,
Cillino et al. (2011)85 MMC 24 20 3 (15.0) 9 (45.0) IOP < 21 mmHg
randomized
Retrospective, IOP < 21 mmHg or ≥
Panarelli et al. (2016)86 MMC 24 45 11 (24.4) 14 (31.1)
consecutive 20% from baseline
Retrospective, IOP < 21 mmHg or ≥
Perkins et al. (1998)87 MMC 24 68 17 (25.0) 28 (41.1)
consecutive 20% from baseline
Retrospective,
Takihara et al. (2011)88 MMC 38 175 13 (7.4) 72 (41.1) IOP < 21 mmHg
consecutive
Retrospective, IOP < 21 mmHg or ≥ 30%↓
Shigeeda et al. (2006)89 MMC 60 123 32 (26.0) 41 (33.3)
consecutive from baseline
*Complete failure rate was defined as patients who failed to meet success criteria regardless of medication or surgical intervention.
†
Qualified failure rate was defined as patients who either failed outright or required surgical intervention to meet success criteria,
regardless of medication. 5-FU: 5-fluorouracil; IOP: intraocular pressure; MMC: mitomycin C; Mo: months; NR: not reported
eculectomy surgeries failed or required postoperative MMC and MMC alone.15-17 A meta-analysis of nine tra-
surgical intervention to succeed (i.e. qualified failure) beculectomy studies using antiVEGF agents to control
and approximately 7-25% failed despite postopera- scarring found that successful outcomes were more
tive surgical intervention (i.e. complete failure). This than twice as likely to occur with antimetabolites than
review includes a diverse group of patient populations, with antiVEGF agents when each was used alone.18
including studies performed in Nigeria, the Caribbean, When antiVEGF agents were used adjunctively with
Italy, England, and the United States, in order to MMC, outcomes were no different than when MMC was
emphasize regional variation in failure rates. used alone. Nevertheless, VEGF may represent a useful
secondary target for antifibrotic agents.
4. Growth factors as modulators of scar 4.2. TGF-β

tissue TGF-β is a profibrotic and proinflammatory growth
factor that induces the migration and proliferation
A growing understanding of the pathways involved of conjunctival and Tenon’s capsule fibroblasts, the
in wound healing could lead to the identification and synthesis and deposition of ECM proteins, and the
development of alternative or adjunctive antifibrot- formation of scar tissue.19 When applied exogenously
ic agents with increased safety and efficacy. Growth to the subconjunctiva, TGF-β isoforms -β1, -β2, and -β3
factors such as platelet-derived growth factor (PDGF), are each capable of inducing hypertrophic scarring.20
fibroblast growth factor (FGF), VEGF, and TGF-β, for Some evidence suggests that outcomes in filtration
example, have long been known to be important surgery are directly associated with preoperative levels
players in the early and intermediate wound healing of TGF-β2. One study, for example, found that increased
process, but are now recognized as specific mediators preoperative TGF-β2 levels were associated with an
of late scar tissue formation. For this reason, a number 11-fold increased risk of poor outcome.21 Consequent-
of clinical trials have been conducted testing antiVEGF ly, several antiTGF-β agents have been examined for
and antiTGF-β agents as antifibrotics to control their ability to mitigate hypertrophic scarring including
excessive scarring following filtration surgery. CAT-152 (lerdelimumab),22 a TGF-β2 monoclonal neu-
tralizing antibody, and SB-431542, an inhibitor of
4.1. VEGF TGF-β/SMAD signaling.23 Several prospective clinical
VEGF is a well-known pro-angiogenic growth factor trials have been conducted using CAT-152 with mixed
that plays a significant role in the process of wound results. While an early pilot trial24 reported significant-
healing and contributes directly to the development of ly lower IOP in the treatment group over 12 months, a
scar tissue. In wound healing, angiogenesis supports larger Phase-III clinical trial25 featuring 388 glaucoma
the proliferation of tissue by providing oxygen and patients found no effect on surgical outcomes between
nutrients.12 VEGF also participates in the formation of MMC with concurrent CAT-152 or MMC alone. The lack
granulation tissue and directly stimulates the prolifera- of efficacy was attributed to the brief exposure time
tion of Tenon’s capsule fibroblasts, thereby promoting and large variation in preoperative TGF-β2 levels,
the deposition of scar tissue in the wound.13 Following indicating a possible need for individual dosing.
the success of antiVEGF therapy in animal models of SB-431542 is an inhibitor of the SMAD pathway directly
acute wound healing,13 several clinical trials have tested downstream of TGF-βRI/II and has shown promise in
the efficacy of subconjunctival injections of VEGF-neu- vitro and in animal models,26 but has yet to be tested
tralizing antibodies to control scarring in filtration in humans. The increased focus on TGF-β2 as a target
surgery. Although one study found that subconjunc- to control wound healing highlights the importance of
tival bevacizumab injections improved outcomes inflammatory mediators in the pathological fibrotic
compared with MMC,14 several more studies have found response and may point toward related and more
no differences in outcomes between bevacizumab plus efficacious targets.
5. TLR4 in wound healing The MyD88-independent pathway is largely antiviral

and results in the transcription of IRF3-inducible
Among the prominent inflammatory mediators active genes. In addition to binding pathogenic bacterial lipo-
in wound healing, innate immune receptor TLR4 polysaccharide (LPS), TLR4 binds sterile endogenous
stands out as a highly relevant potential target. TLR4 DAMPs such as fibronectin extra domain A (FN-EDA),
is a dynamic receptor known to function in innate low molecular weight hyaluronic acid (LMW-HA), high
immunity, inflammation, and thrombosis. TLR4 signals mobility group box 1 (HMGB1), and several heat shock
through two independent pathways, often referred to proteins, which are released during tissue injury and can
as the MyD88-dependent and -independent pathways. be found at increased levels in the trabecular meshwork
The MyD88-dependent pathway results in the trans- and aqueous humor of POAG patients (Table 3).27-36
location of two primary transcription factors, nuclear The interaction of TLR4 and DAMPs produced by tissue
factor kappa-light-chain-enhancer of activated B cells injury can trigger a chronic inflammatory feedback
(NFĸB) and AP-1, which together transcribe an array of loop, resulting in excessive tissue damage and hyper-
proinflammatory cytokines and chemokines (Fig. 2). trophic scarring.
Fig. 2. Diagram showing the multiple mechanisms of action of curcumin in TLR4- and TGF-β-mediated inflammation and fibroblast prolif-
eration. The canonical TGF-β pathway is shown in green and the non-canonical TGF-β pathway is shown in orange.
Table 3. Endogenous TLR4-binding DAMPs increased in POAG
Outflow
DAMP Description Tissue/Model
pathway
HMGB1 Nuclear protein NR Acute glaucoma mouse model28
β-amyloid Peptide (oligomer) TM/CB Human donor vitreous29
SAA Peptide TM Human donor TM cells30
cFN-EDA Glycoprotein TM Human donor TM cells31
LMW-HA Glycosaminoglycan TM Human donor aqueous32
Versican Proteoglycan TM Human donor TM cells33
CD44* Proteoglycan CB Human donor aqueous34
αB-crystallin Heat shock protein TM Human donor TM35
HSP27 Heat shock protein TM Human donor TM35/retina, ONH36
HSP60 Heat shock protein TM Human donor retina36
*TLR4 co-receptor involved in the binding of DAMPs. CB: ciliary body; CD44: cluster of differentiation 44; cFN-EDA: cellular fibronectin
extra-domain A; DAMPs: damage-associated molecular patterns; HMGB1: high-mobility group box 1; HSP: heat shock protein; LMW-
HA: low-molecular weight hyaluronic acid; ONH: optic nerve head; SAA: serum amyloid A; TLR4: toll-like receptor 4; TM: trabecular
meshwork; NR: not reported
In addition to its role in inflammation, TLR4 6. Curcumin

functions in the proliferative phase of wound healing
and modulates TGF-β2 signaling. It was recently Curcumin is a phyto-polyphenol pigment and the major
found that FN-EDA-induced activation of TLR4 in the curcuminoid found in the rhizome of turmeric (Curcuma
presence of TGF-β2 significantly increased collagen longa).39 Daily consumption levels of curcumin are
and fibronectin expression in human TM cells, an estimated to be between 2.7 and 14.8 mg, and vary by
effect that was abolished by inhibition of TLR4.37 This geographic region.40 Chemically, curcumin ((1E,6E)-1,7-
suggests that TLR4 signaling may represent a novel bis(4-Hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-
target for improved modulation of fibroblast-de- dione) is a symmetric linear diarylheptanoid consisting
rived ECM production, proliferation, and migration. of two aromatic ring systems containing o-methoxy
Supporting this hypothesis is the finding that key phenolic groups connected by a seven carbon linker
TLR4-induced inflammatory markers such as tumor with an α,β-unsaturated β-diketone moiety. Extensive
necrosis factor-α (TNF-α) and interleukin 6 (IL-6) are in vitro, animal, and human research has found that
not only elevated in post-trabeculectomy aqueous curcumin has antioxidative, anti-inflammatory, anti-
humor of POAG patients, but are predictive of surgical platelet, and antiproliferative mechanisms, making it
failure.38 TLR4 amplifies TGF-β signaling through an intriguing candidate for clinical trials in a variety
NFĸB-mediated inhibition of BMP and Activin mem- of diseases including cancer, Alzheimer’s disease,41,42
brane-bound inhibitor (BAMBI), the negative regulator glaucoma,42 cardiovascular disease,43 and arthritis.44
of canonical TGF-β/SMAD signaling. The dual role of
TLR4 in both the inflammatory and proliferative phases 6.1. Curcumin in hemostasis and inflammation
of wound healing suggest that the receptor may be a Inflammation is a key consequence of tissue injury
viable and efficacious approach to reducing excessive following filtration surgery and greatly increases the
conjunctival scarring. risk of postoperative complications and surgical failure.
In postoperative days 1-7, the management of inflam-
mation and oxidation is critical. Anti-inflammatory
steroids are sometimes used to temporarily control
inflammation; however, an estimated 90% of glaucoma also inhibits IKKb phosphorylation, which is required
patients experience steroid-induced increases in for the nuclear translocation of NFĸB. The result is
IOP,45 and thus the long-term use of steroids following complete inhibition of the three legs of TLR4 signaling:
filtration surgery is limited. Curcumin, a non-steroi- the MyD88-dependent MAPK-AP-1 pathway, the
dal anti-inflammatory agent (NSAID) and antioxidant, MyD88-dependent IKKα/b/γ-NFĸB pathway, and the
offers multimodal mechanisms of action to control MyD88-independent IKKε/IRF3 signaling pathways.47-
inflammation and oxidative stress following filtration 49
The involvement of TLR4 in acute injury-related
surgery without the risk of increasing IOP. inflammation was proven using TLR4 knockout mice in
During surgical tissue injury, damaged blood vessels a model of acute brain injury; curcumin administered
require platelets and other blood cells to plug the immediately following acute brain injury decreased
subendothelial surface to control leakage of proteins microglia/macrophage activation, inflammatory factor
and cells into the surrounding tissue. Released release, neurological deficit, and neuronal apoptosis
coagulation factors and ECM-derived DAMPs trigger after 24 hours. In humans, evidence suggests that a
platelet activation and adhesion to the subendo- reduction of TLR4-induced proinflammatory cytokines
thelial surface to form temporary fibrin blood clots. such as TNF-α and IL-6 could increase surgical success
Platelet activation and degranulation causes the rates in trabeculectomy and tube-shunt surgery.38
release of cytokines, growth factors, and stress-relat- Additionally, the antiNFĸB mechanisms of curcumin
ed DAMPs into the surrounding environment, triggering may be useful in reducing the risk of cataract-asso-
an inflammatory response. POAG patients exhibit ciated surgical failure, as NFĸB levels are elevated in
increased levels of thrombin/collagen-induced pro-
coagulant (superactivated) platelets in the peripheral
vasculature,42 and may therefore exhibit a patholog-
ical hemostatic response during surgery resulting in
excessive clotting and inflammation. Unlike other anti-
fibrotic agents, curcumin inhibits platelet activation,
platelet aggregation, and the formation of superacti-
vated platelets through the inhibition of NFĸB, COX-2,
and 5-LOX. As an anticoagulant, curcumin inherently
increases the risk of bleeding, but is considered safer
than common NSAIDs and COX-2 inhibitors. The
antiplatelet activity of curcumin represents a novel
mechanism by which to reduce excessive coagulation
and acute inflammation during the initial hemostatic
phase of wound healing without substantially elevating
the risk of bleeding.46
During the inflammatory phase of wound healing,
inflammation and oxidative stress can cause collateral
damage to the surrounding tissue, resulting in the
accumulation of DAMPs, activation of TLR4, and Fig. 3. Mechanisms of curcumin in filtration surgery. Curcumin
initiation of a chronic inflammatory feedback loop. The inhibits the binding of DAMPs released during surgery to innate
anti-inflammatory mechanisms of curcumin involve immune receptor TLR4, preventing the proinflammatory and
profibrotic effects of TLR4 activation. Curcumin also prevents
inhibition of the TLR4-NFĸB-mediated production of TGF-β-induced signaling directly, resulting in dual inhibition of
proinflammatory cytokines, chemokines, and growth the TLR4-TGF-β interactive pathways. A vicious feedback loop can
factors (Fig. 3). Curcumin blocks the binding of DAMPs occur between tissue injury, DAMPs, and inflammation as a result
to TLR4 by obstructing the formation of the TLR4 of chronic TLR4 activation, resulting in chronic inflammation and
excessive deposition of scar tissue during recovery. POAG patients
homodimer receptor complex47 through occupation are at heightened risk for chronic TLR4 activation due to increased
of adaptor protein MD-2.48 Independently, curcumin preoperative levels of ocular DAMPs.
epithelial cells of lenses with cataracts as compared to within both the TLR4- and TGF-β-induced signaling
those without.50 pathways. With respect to TLR4, curcumin interferes
Curcumin is also a potent antioxidant, acting as with the binding of DAMPs and independently inhibits
both a free radical scavenger/electron donator and downstream phosphorylation of IKKb, resulting in
inhibitor of intracellular nitric oxide synthase (iNOS) inhibition of both the IKKα/b/γ-NFĸB and MAPK-AP-1
induction.51-53 In vitro, curcumin has been found to MyD88-dependent pathways as well as the IKKε-IRF3
inhibit H2O2-induced intracellular reactive oxygen MyD88-independent pathway. With respect to
species (iROS) production and protein carbonylation — TGF-β, curcumin inhibits Smad2/3, p38 MAPK, and
markers of oxidative stress — in TM cells.54 Several ERK phosphorylation, resulting in inhibition of both
studies have confirmed these effects in animal models the canonical and non-canonical TGF-β signaling
of neurodegenerative disease, including transgenic pathways. Furthermore, by inhibiting TLR4-mediat-
mouse models of Alzheimer’s disease55 and Parkinson’s ed activation of NFĸB, curcumin prevents the ampli-
disease.56 Numerous studies have also suggested fication of TGF-β signaling caused by NFĸB-mediated
that the antioxidant mechanisms of curcumin may be inhibition of BAMBI, the constitutive negative regulator
useful for reducing the risk of cataract formation.57-59 of the TGF-β receptor. These mechanisms suggest that
For example, it was shown that dietary curcumin sup- curcumin is a potent antifibrotic. Therefore, curcumin
plemented with vitamin-E inhibits galactose-induced should exhibit increased efficacy compared with
cataract formation in rats by inhibiting lipid peroxida- the existing unimodal antiTGFβ agents, which fail to
tion and reducing glutathione content.60 Curcumin may incorporate TLR4-mediated inflammation and ampli-
also reduce oxidative damage by means of crystallin fication of TGF-β-induced fibroblast proliferation and
redistribution and protein solubization.61 ECM deposition.
6.2. Curcumin in proliferation and remodeling 6.3. Routes of administration

In addition to operating on the initial hemostatic The efficacy of curcumin in different contexts is largely
and inflammatory stages of wound repair (0–7 days), dependent on its formulation and route of adminis-
curcumin exhibits therapeutic effects in the interme- tration. Oral administration is constrained by a lack of
diate proliferative (4–14 days) and late remodeling bioavailability caused by poor absorption and rapid
(14 days–6 months) stages (Fig. 1). Numerous in vitro metabolism. Increasingly, however, formulations are
and animal model studies have shown the efficacy of being developed to improve availability. The addition
curcumin in preventing fibroblast proliferation and of piperine from black pepper extract, for example,
ECM deposition in subcutaneous, lung, cardiac, and inhibits hepatic and intestinal glucuronidation to
renal tissue through the inhibition of the canonical increase availability. For use in filtration surgery,
NFĸB/Smad signaling.62-67 Curcumin also modulates curcumin can be administered topically, by eye drop,
fibroblast proliferation through the non-canonical or by subconjunctival injection. The hydrophobicity
TGF-β-induced phosphorylation of mitogen-acti- and poor solubility of curcumin can be overcome using
vated protein kinases (MAPK) ERK, JNK, p38 MAPK, delivery systems such as polymeric, solid-lipid, or
and AKT, which results in transcription of AP-1 liposome-encapsulated curcumin nanoparticles with
controlled genes.68-70 This pathway overlaps with sustained release.73 Eye drops containing a mixture
the TLR4-MyD88-dependent signaling cascade and of curcumin (1.3% w/v) and several other herbal
includes the MAPK-ERK-mediated transcription of the compounds have been successfully tested in clinical
angiogenic factor VEGF.71 In the context of filtration trials for conjunctivitis, dry eye, and pterygium.74 Other
surgery, curcumin inhibits TGF-β-induced prolifera- possibilities include the use of biodegradable intra-
tion of conjunctival and Tenon’s fibroblasts and the cameral injection-implanted drug carriers such as
synthesis of collagen-1 and -3 through the inhibition the poly(ethylene glycol)-poly(ε-caprolactone)-poly
of both the canonical Smad2/3 and the non-canonical (ethylene glycol) (PEG-PCL-PEG, PECE) hydrogel system,
MAPK signaling cascades induced by TGF-β1 and -2.72 which has been used to safely deliver bevacizumab
Curcumin therefore targets multiple points to rabbit eyes following filtration surgery.75 Hydrogel
systems containing curcumin have already been ranibizumab and bevacizumab, and antiTGF-β agents,
proposed for use in cutaneous wound healing and may such as SB-431542 and CAT-152. None of these agents,
make ideal systems for curcumin delivery following however, have proven effective in the setting of a
filtration surgery without the need for repeated sub- controlled, prospective clinical trial, leaving MMC and
conjunctival injections.76 5-FU as the standard antifibrotics in use today. The
diverse and multimodal mechanisms of curcumin
make it a superior alternative to agents that target only
7. Conclusion and future perspectives specific proteins or pathways such as VEGF or TGF-β.
Curcumin exhibits inhibitory effects during each phase
Filtration surgery remains the most frequently of wound healing including hemostasis, inflammation,
employed surgical procedure to control IOP in proliferation, and remodeling. In addition to inhibiting
glaucoma. Postoperative complications and surgical platelet procoagulant activity and DAMP/TLR4-induced
failure associated with hypertrophic scarring, inflammation and oxidation, curcumin has specific
however, continue to be problematic for ophthalmol- antiVEGF, antiTGF-β, and antiPDGF mechanisms that
ogists worldwide. The use of intraoperative antifibrot- reduce angiogenesis, fibroblast proliferation, and ECM
ics such as MMC and 5-FU to control wound healing deposition/remodeling. For these reasons, we propose
is not always effective and carries additional risks, that the TLR4 inhibitor curcumin may be a viable and
including loss of vision. Assortments of alternative safe antifibrotic agent for the reduction of hypertro-
or adjunctive antifibrotic therapies have been tested phic scarring following filtration surgery.
in humans, including antiVEGF antibodies, such as
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6. The future of MIGS
Department of Ophthalmology and Visual Sciences, Washington University in St. Louis, St. Louis, MO, USA
Abstract
Microinvasive glaucoma surgery (MIGS) is maturing. With an implant as well as reports on the development of
several devices being developed in the past few years, promising new instruments. The future of the field is
and some more in the pipeline, we expect some consol- exciting, but with so many innovations it is crucial for
idation in the near future, as well as novel ways to use the anterior segment surgeon to stay updated and
the current products. Surgeons should expect seeing well-prepared to best determine their position in this
more MIGS being used without concomitant cataract evolving new glaucoma treatment paradigm. Table 1
surgery, as well as in combination with other MIGS. A provides an overview of current MIGS procedures,
full spectrum of therapeutic options will develop to fill basing the reader for further discussion.
the need of patients in different disease stages. Further
expanding the practice of the anterior segment surgeon
are implantable drug-delivery and IOP-sensing devices. 2. Competition
The future holds promise for the field.
With an increasing number of MIGS devices being
Keywords: future, implant, intraocular, glaucoma, marketed and the inevitable competition between
microinvasive glaucoma surgery (MIGS) these procedures, we expect some consolidation to
ensue in the future, especially inside the same category
(trabecular bypass, subconjunctival shunts, etc).
1. Current scenario Currently, research has been focused on only a few
of these devices, mostly implants. We suspect this is
Glaucoma is the leading cause of irreversible blindness due to pre-market authorization (PMA) study require-
in the world.1 Treatment of mild to moderate disease ments by the FDA for implants. Given that devices that
usually involved instillation of multiple eye drops, do not produce solid evidence of their utility will likely
several times a day. The inconvenience of such therapy fall out of favor, we suspect that the short-term future
coupled with developments in material sciences of the field will be one of much research, with devices
enabled a true revolution with the development trying to prove themselves against their competitors.
of several microinvasive glaucoma surgery (MIGS) The publication of the American National Standards
procedures. Given the value of safe and effective Institute (ANSI) Z80.27 for glaucoma implantable
glaucoma treatment, the MIGS scenario is constantly devices in 2015 is a welcome addition, as it should help
evolving, with an increasing number of companies researchers design studies appropriately and also allow
hoping to develop the blockbuster MIGS. In 2018 alone for better reproducibility and comparison of results
we saw the publication of two pivotal trials resulting among different studies.
in FDA approval of two devices, the withdrawal of An illustration of how competition will be in this field
Correspondence: Arsham Sheybani, MD, Department of Ophthalmology & Visual Sciences, Washington University School of Medicine in
St. Louis, 517 South Euclid Avenue, St. Louis, MO, USA.

86 T.A. Moulin and A. Sheybani
Table 1. Current MIGS procedures
Device Manufacturer Materials/Description Procedure FDA approval
Increasing trabecular outflow

8.0 mm, crescent-shaped
Ivantis Inc. Implanted ab interno into
Hydrus™ Microstent stent made of nitinol (alloy 2018
(Irvine, CA, USA) Schlemm’s canal
of nickel and titanium)
Heparin-coated
nonferromagnetic grade
iStent® Trabecular Glaukos Corporation  Implanted ab interno into
5 titanium stent; 60 2012
Micro-Bypass Stent (Laguna Hills, CA, USA) Schlemm’s canal
µg weight, 1.0 x 0.33
mm; L-shaped
Heparin-coated
nonferromagnetic grade 5
Glaukos Corporation  titanium stent; 230 × 360 Implanted ab interno into
iStent® inject 2018
(Laguna Hills, CA, USA) μm bullet-shaped stents; Schlemm’s canal
Inserter comes pre-loaded
with 2 stents
Flexible microcatheter
Ellex with illuminated tip and
iTrack® Surgical System Ab interno canaloplasty 2008
(Adelaide, Australia) viscoelastic injection
system
Sight Sciences with illuminated tip and
OMNI® Surgical System Ab interno canaloplasty 2018
(Menlo Park, CA, USA) viscoelastic injection
system
Trabecular meshwork removal
NeoMedix
Trabectome® Bipolar, 550Hz electrode Ab interno trabeculectomy 2006
(Tustin, CA, USA)
New World Medical,
Kahook Dual Blade® (Rancho Cucamonga, Dual-blade device Ab interno trabeculectomy 2015
CA, USA)
Gonioscopy-assisted
Ellex Flexible microcatheter with
iTrack® Surgical System transluminal trabeculotomy 2008
(Adelaide, Australia) illuminated tip
(GATT)
Gonioscopy-assisted
Sight Sciences with illuminated tip and
OMNI® Surgical System transluminal trabeculotomy 2018
(Menlo Park, CA, USA) viscoelastic injection
(GATT)
system
Ab interno endoscopic
Excimer laser TUI-Laser AG 80 ns 308-nm AIDA XeCl
trabeculotomy by
trabeculotomy (Germering, Germany) excimer laser
photoablation
Increasing uveoscleral outflow
Fenestrated polyamide
Implanted ab interno
Alcon Laboratories, Inc. tube; 6.35 mm length; 510 2016; withdrawn
CyPass® Micro-Stent between the ciliary body and
(Fort Worth, TX, USA) μm external diameter; 300 in 2018
sclera
μm internal diameter
Glaukos Corporation  Polyethersulfone and Investigational
iStent Supra® between the ciliary body and
(Laguna Hills, CA, USA) titanium; 4.0 mm tube use only in USA
sclera
24-karat gold, flat,
SOLX Corp. Implanted ab externo with a Investigational
SOLX® Gold Micro Shunt nonvalved plate; 5.2 mm
(Waltham, MA, USA) trans-scleral approach use only in USA
length, 3.2 mm width
The future of MIGS 87
Device Manufacturer Materials/Description Procedure FDA approval
Silicone microporous Implanted ab externo

iSTAR Medical SA Investigational
STARflo™ material; 11 × 5 mm, anvil- into suprachoroidal space via
(Isnes, Belgium) use only in USA
shaped shunt a scleral flap
Decreasing aqueous production
Endoscopic Endo Optiks 810-nm Nd: YAG laser diode Probe is advanced through
cyclophotocoagulation (Little Silver, NJ, USA) attached to a 19, 20, or 23-g a 2 mm clear corneal
(ECP) endoscopy probe incision and laser ablates
ciliary processes
Targeting the subconjunctival space

Polystyrene-block-
isobutylene-block-
Implanted ab externo to
Santen Pharmaceutical styrene biostable
facilitate subconjunctival Investigational
PRESERFLOTM MicroShunt Co. thermoplastic elastomer;
filtration; use only in USA
(Osaka, Japan) 8.5 mm cylindrical tube
mimics trabeculectomy
with 70 μm of internal
diameter
Collagen-derived
gelatin crosslinked with
XEN® 45 Glaucoma Gel Allergan allowing drainage between
glutaraldehyde; 6.0 mm 2016
Stent (Irvine, CA, USA) the anterior chamber and
cylindrical tube with 45 μm
the subconjunctival space
of internal diameter
FDA: US Food and Drug Administration; TM: trabecular meshwork
is the current one between Glaukos and Ivantis. Glaukos 2018 systematic literature review that there was just
is a pioneer in this field, bringing us the iStent® (Glaukos one economic study of the iStent but without cost-ef-
Corporation, Laguna Hills, CA, USA) (also discussed in fectiveness evidence.3 No other studies in this area
Chapter 9) back in 2012. In 2018, the FDA announced were found for other MIGS procedures, according to
the approval of their second-generation device, the the authors. The future of MIGS, especially in a scenario
iStent inject® (Glaukos Corporation) (also discussed of heightened sensitivity of medical expenditures by
in Chapter 9), and also of a direct competitor, the healthcare stakeholders,4 will certainly hinge on the
Hydrus® (Ivantis, Inc, Irvine, CA, USA) (also discussed in ability of a procedure being not just effective, but cost
Chapter 8). A head-to-head comparative effectiveness effective.
trial between the Hydrus vs two first-generation iStent Finally, what determines the viability of any of these
was recently published, the COMPARE study.2 The options and their survival against the competition is,
authors concluded that the Hydrus has superior efficacy ultimately, their safety profile. The CyPass (Alcon, Fort
and similar safety profile to the iStent. However, we are Worth, TX, USA), FDA-approved in 2016, was voluntarily
not aware of any comparisons between the Hydrus withdrawn by the manufacturer in 2018 after analysis
and the iStent inject, which would better determine a of five-year follow-up data revealed a statistical-
winner in the trabecular bypass category. ly significant decrease in corneal endothelial cells in
Practitioners and patients should benefit from patients that had the device implanted vs those that
this competition, as it should keep companies keen had cataract surgery (CS) alone.5 This loss is apparently
on developing better products and also make these related to the length of the device that is left inside the
procedures more economically accessible. As a matter anterior chamber. Alcon hopes to work with regulatory
of fact, we suspect that, following the rich effective- agencies and on labeling in order to appropriately
ness-focused research we already mentioned, cost- market their product. With the CyPass under revision,
effectiveness research will also be a hot topic in this the proposed iStent Supra (Glaukos) (Fig. 1) will not face
field. Currently, this is somewhat of a neglected subject direct competition in the USA if it clears FDA’s scrutiny.
of study, with Agrawal and Bradshaw affirming in their The device is already approved for marketing in Europe
and other countries, but according to a 2018 review6 mmHg), but the 0.68 unit decrease in medication use
and our own research, there have not been any studies was smaller than that of the control group (1.06). Also
reporting on the iStent Supra alone (a study on its use in 2017, Chen and Kim reported their successful experi-
combined with other therapies is described below). ence in combining iStent and CyPass in a case.10 Recent-
ly, Myers et al. published their report on the combined
use of two iStent inject, one iStent Supra, and topical
3. Combined and standalone use travoprost in a nonrandomized, open label study.11
Results show that 97% of the eyes had IOP below 15
While we predict consolidation of some procedures in mmHg at year 4. More research is bound to come in this
the future, we also expect more interactions between area, allowing surgeons to “mix and match”, tailoring
the different devices to happen. To date, the combination treatment to their patient’s needs. The use of multi-
of iStent, cataract surgery, and endoscopic cyclophoto- ple pathways for aqueous outflow has been explored
coagulation — the “ICE procedure” — has been studied for decades in glaucoma therapy; therefore, it is only
the longest, with results of a case series presented at logical that this same approach is investigated when
conventions back in 20147,8 and published in a peer- employing MIGS.
reviewed journal in 2017.9 According to the authors, the If there is interest in combining different MIGS
ICE procedure (vs iStent + CS without ECP) decreased devices, there is also increasing interest in using
mean intraocular pressure (IOP) by 7.14 mmHg (vs 4.48 implants as a standalone procedure (not combined
Fig. 1. The iStent Supra. Image courtesy of Glaukos Corporation.

with cataract surgery). This might be useful when a 4. Advanced cases

glaucoma patient is pseudophakic already or does not
have a significant cataract to justify its removal. Out of Most MIGS devices have been developed with the
all the available MIGS implants, only the XEN Gel Stent mild to moderate glaucoma patient in mind, leaving
(Allergan, Irvine, CA, USA) (also discussed in Chapters the advanced cases for the more surgically complex
12 and 20) is FDA-approved to be used without trabeculectomy or tube-implant procedures. This is
concomitant cataract surgery, with the PRESERFLO expected to change in the near in the future, with many
MicroShunt (Santen Pharmaceutical Co., Osaka, Japan), MIGS claiming the space once exclusive to more invasive
depicted in Figure 2, also expected to become a viable, procedures. Joining the ranks of the XEN Gel Stent in
FDA-approved, competitor in the near future.12 While the treatment of refractory glaucoma, the PRESERFLO
these devices promise superior IOP-lowering effect MicroShunt is expected to soon report on their FDA PMA
than other MIGS,12,13 they require the formation of a pivotal trial, a first comparing a MIGS to trabeculecto-
bleb which might then require subsequent needling or my.11 The device is already marketed in Europe and
maintenance. To offer a more titrated set of therapies, other countries, where clinical trials are also underway.
there is ongoing research on the use of the iStent, iStent A prospective case series reports a lasting effect of the
Supra and Hydrus as standalone procedures.11,14,15 device on lowering IOP and number of medications
as well as company-sponsored efforts to obtain FDA from 23.8 to 10.7 mmHg and 2.4 to 0.7, respectively, at
approval for such use.16,17 the 3-year follow-up visit.19,20 Glaukos is also seeking
An important side note to American practitioners the agency’s approval for their iStent infinite® system,
when combining procedures or using some implants a standalone procedure for refractory glaucoma
without concomitant cataract surgery (falling outside consisting of three stents preloaded into an inserter.21
of their FDA-approved use), is reimbursement.18 We They are joined by Ivantis, testing the safety/efficacy of
hope that with more research proving the safety and the Hydrus also in refractory glaucoma as a standalone
(cost-)effectiveness of these novel uses of MIGS, along device.16 In the future, we might also expect studies on
with FDA approval of standalone use, payers will adapt the use of more than one implant in one eye requiring
their reimbursement rules. greater IOP reduction, such as multiple Hydrus or XEN
Fig. 2. The PRESERFLO MicroShunt, under FDA scrutiny but approved elsewhere. Image courtesy of Santen Pharmaceutical Co.
Gel Stent, or, as already discussed, mixing and matching substance called DE-117. For that they developed a
different MIGS approaches in one eye. polycaprolactone implant that achieved controlled-re-
Nonimplantable devices do not require specific FDA lease kinetics of the drug over six months in vitro.33 A
approval for different marketing purposes. Therefore, it rabbit model also supported a consistent delivery of
is possible to treat (and get reimbursed for) advanced the drug up to 24 weeks as well as a decrease in IOP.31
and/or refractory glaucoma using the Kahook Dual Research will now move on to larger animals before it
Blade (New World Medical, Rancho Cucamonga, CA, can be tested in humans.
USA), the Trabectome (NeoMedix, Tustin, CA, USA), or Replenish’s MicroPump is another device the anterior
a GATT procedure (also discussed in Chapter 7) with segment surgeon should be aware of.29 This MEMs —
or without the assistance of a device such as the OMNI basically a very small machine — can be customized
(Sight Sciences, Menlo Park, CA, USA) or the iTrack (Ellex, to deliver different drugs with precise schedules and
Adelaide, Australia). Results from recent studies show dosage. It is composed of a drug reservoir that holds
that these procedures, considered more destructive up to 12 months of medication (and can then be
than device implantation, are effective in refractory refilled with a 31-g needle), a wirelessly rechargeable
and advanced cases.22–24 It is possible that, with more battery, electronics, and an electrolysis chamber that
research in this area, coupled with a dissemination of is responsible for the precise delivery of medication.
these techniques among surgeons, MIGS will gain more This is done by breaking down water into H2 and
traction in these advanced cases in the future. O2 gases, thus generating pressure that is relieved
with drug expulsion. The gases are then recombined
back into water. This implant can be inserted so as to
5. Novel therapies deliver medication to either the anterior or posterior
chamber. Implantation requires peritomy, followed by
At the very edge of the MIGS horizon lie medication a 2-mm-wide scleral tunnel into the desired chamber.
implants and IOP sensors. When it comes to medicating The device is placed so that it is completely covered
the eye, several novel strategies in ocular drug by conjunctiva. Such a device is promising and would
delivery are currently under development, including open MIGS treatment to all types of glaucoma and
microneedles,25,26 nanocarriers,27 medicated contact beyond. Expertise in its insertion would also mean
lenses,28 microelectromechanical systems (MEMs),29 that the anterior segment surgeon could be involved in
and implants.30,31 Many of these devices do not require treatment of other ocular pathologies, such as diabetic
surgical insertion and thus do not qualify as MIGS. We retinopathy. Research with diabetic macular edema
point out three devices that one day might integrate patients has shown a first-generation device to be safe,
this category: the iDose, from Glaukos, a polycaprolac- but more research is still needed.34 The authors state
tone DE-117 intracameral implant (Santen Pharmaceu- that a second-generation version was already under
tical, Osaka, Japan), and the Ophthalmic MicroPump® development and the company’s website disclaims that
System, from Replenish, Inc. (Pasadena, CA, USA). the device is still for investigational use only.35
The iDose, shown in Figure 3, is a travoprost-elut- The MIGS category may also one day incorporate
ing implant with size, shape, and insertion procedure the insertion of IOP sensors. These devices can be
similar to that of the iStent inject. The medicated integrated into contact lenses, intraocular lenses, or
implant finished its Phase II clinical trial, with results standalone implants. They can also be categorized by
showing a 30% IOP reduction at the 12-month time their underlying sensing technology: either MEMs or
point, which is also the expected duration of the microfluidics. In the first case, we have a miniaturized
implant.32 Glaukos is pursuing regulatory approval for machine capable of sensing IOP through capacitive,
this device in Europe, Japan, and the United States, resistive, or optical technologies. Microfluidics-based
where investigational new drug (IND) Phase III trials devices, on the other hand, use minimal amount of fluids
were expected to commence in 2018. processed into microchannels to provide a reading,
Santen is studying the long-term release of their much like a manometer or a mercury thermometer.
proprietary, novel medication for glaucoma, a So far, clinical use of sensors is limited to two devices:
Fig. 3. The iDose, a drug-eluting 1.8 x 0.5 mm titanium stent. Image courtesy of Glaukos Corporation.
Fig. 4. Schematic representation of the Opthalmic Micropump System implanted into the subconjunctival space between the superior
and lateral rectus muscles. The blue arrow indicates the intraocular cannula at the pars plana location. The red arrow indicates the
refill port. The black arrow indicates the body of the micropump containing the hermetic sealing package with all electronics, the drug
reservoir, and the check valve. Image reproduced from Humayun et al.34
the Triggerfish (Sensimed AG, Lausanne, Switzerland), 6. Conclusion

approved for use in the USA, Europe, and other
countries,36 and the Eyemate (Implandata Ophthalmic MIGS, once in its infancy, are maturing and expanding
Products GmbH, Hanover, Germany), which obtained its as more techniques are developed aiming at high
CE mark in mid-2017 but is not currently FDA-approved.37 efficacy and safety with low invasiveness. With more
The Triggerfish is an enhanced contact lens capable competitors, those that do not provide solid proof of
of 24-hour IOP monitoring in order to suggest the their worth will likely fall out of favor from surgeons.
best time to have a traditional tonometric evaluation, Devices should also gain further acceptance among
given that the validity of its own IOP measurement is practitioners and regulators alike, with several implants
still under study.36 The Eyemate, on the other hand, is becoming available to be used without concurrent CS. If
an intraocular implant that can be inserted through a future research confirms current expectations, patients
clear corneal incision, allowing it to be placed together with more advanced disease will likely be treated more
with CS. It is a flat ring with outer diameter of 11.3 mm often with MIGS procedures (either standalone or in
and inner diameter of 7 mm. Powered by an external combination with other devices and procedures) vs
proprietary reader, it does not require a battery.38 A more invasive therapies, such as filtration surgery. Once
clinical trial evaluating the efficacy and safety of the futuristic therapies such as automated drug delivery
device is currently underway, the ARGOS-02 study.39 implants and IOP sensors are on the horizon, and the
With several other devices under early development, anterior segment surgeon is the best positioned profes-
the future for anterior segment surgeons and their sional to soon put these instruments to use.
patients is very promising.40
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7. Gonioscopy-assisted transluminal
trabeculotomy (GATT)
Ronald L. Fellman, Davinder S. Grover
Glaucoma Associates of Texas, Dallas, TX, USA; North Texas Eye Research Institute, University of North Texas Health
Science Center, Fort Worth, TX, USA; Department of Ophthalmology, University of Texas Southwestern Medical Center,
Dallas, TX, USA
Abstract
Purpose: To describe the evolution of trabeculotomy appeal. Circumferential trabeculotomy reduces IOP
from ab externo to ab interno techniques culminating in by cleaving open a diseased outflow tract without
modern-day gonioscopy-assisted transluminal trabec- bleb formation and it continues to have a valuable
ulotomy (GATT), including indication, technique, and role in IOP reduction. The next step in the evolution
outcomes. of all canal-based surgeries should be in the direction
Methods: Review the indications, techniques, and of wound healing in order to maintain adequate flow
literature regarding GATT including surgical pearls from through the newly created area of decreased outflow
the authors. resistance.
Results: GATT is effective in reducing intraocular
pressure (IOP) in different types of glaucoma as a Keywords: circumferential trabeculotomy, collector
standalone or combination procedure and is typically channels, episcleral venous fluid wave, gonioscopy-as-
reserved for mild to moderate glaucomatous disease. sisted transluminal trabeculotomy (GATT), Schlemm’s
Patients with advanced glaucoma may require canal, trabecular shelf
subnormal IOPs, which may be difficult to achieve
with circumferential canal surgery. GATT typically
lowers IOP on average to a mid-teen level, which 1. Introduction
usually corresponds to a 40% reduction in IOP along
with a significant reduction in topical medications. The over half-century old objective to selectively
Congenital and especially juvenile glaucoma cleave open a diseased outflow system at its site of
patients respond extremely well to GATT, with a greatest resistance remains a milestone in the history
significant reduction in IOP oftentimes requiring no of glaucoma surgery. The methodology to accomplish
long-term topical postoperative medications. Sur- this has dramatically improved, decade-by-decade,
prisingly, patients post-failed conventional outflow culminating in a conjunctival sparing, circumferential,
procedures are still excellent candidates for circum- minimally invasive, ab interno gonioscopy-assisted
ferential canal-based surgery. transluminal trabeculotomy1 or GATT (also discussed
Conclusion: GATT is a stepping-stone in the evolutionary in Chapters 3 and 6). The authors prefer GATT for
pathway of trabeculotomy. The role of GATT continues congenital and juvenile glaucomas,2 refractory primary
to be defined, especially in light of suture GATT, a much open-angle glaucoma, various secondary open-angle
less expensive technique that has outstanding global glaucomas, and following failed conventional
Correspondence: Ronald L. Fellman, MD, Glaucoma Associates of Texas, 10740 N Central Expressway, Suite 300, Dallas, TX 75231, USA.

96 R.L. Fellman and D.S. Grover
Fig. 1. Ab interno canal-based glaucoma surgeries may be divided into segmented or circumferential procedures. These procedures vary
depending on the device used to either stent, ablate, dilate, or cleave open the angle. Segmental procedures include opening the canal by
either electrosurgical vaporization with the Trabectome (NeoMedix Corp., Tustin, CA, USA) or by excising the TM/IWSC with the Kahook
Dual Blade (New World Medical, Rancho Cucamonga, CA, USA), bypassing the TM/IWSC with one or two iStents (Glaukos, San Clemente,
CA, USA), or stenting open three clock hours of the canal with the Hydrus (Ivantis, Irvine, CA, USA). Circumferential canal surgery may be
accomplished with 360° viscodilation of the canal with either the Visco360 procedure (Sight Sciences, Menlo Park, CA, USA) or the ABiC
procedure (Ellex iTrack, Fremont, CA, USA). The canal may be cleaved open for 360° or 180° (hemi) with concomitant viscodilation, if
preferred, with either the GATT procedure or the TRAB360 from Sight Sciences (Menlo Park, CA, USA). The OMNI360 technique from Sight
Sciences allows for viscodilation and circumferential trabeculotomy, as does the GATT.
glaucoma surgeries.3 Additionally, GATT occupies a of trabeculotomy that led to the development of GATT
strong presence globally, especially the 5-0-prolene and discuss why trabeculotomy remains a viable pres-
suture GATT, in the management of many open-angle sure-lowering procedure. In addition, the authors cover
glaucomas as it is a very cost-effective minimally invasive the indications, complications, and technique of GATT
glaucoma surgery (MIGS). In the life of a glaucoma along with a general discussion of its efficacy.
patient requiring surgical intraocular pressure (IOP)
reduction, GATT is advantageous because it lowers IOP
by improving outflow into the patient’s native drainage 2. Evolution of trabeculotomy
system while preserving conjunctiva and sclera for
future filtration surgery, when necessary. From a global The majority of the pathologic resistance to aqueous
perspective where device costs may be critical, suture outflow is thought to occur at the level of the inner
GATT has the economic advantage of the cost of a 5-0 wall of Schlemm’s canal (IWSC), juxtacanalicular tissue
prolene suture (roughly 4 USD) to cleave open 360° of (JCT), and trabecular meshwork (TM). Trabeculoto-
the angle. my cleaves open these highly resistant dysfunctional
GATT is a member (Fig. 1) of an emerging diverse outflow structures (IWSC-JCT-TM) thereby increasing
group of ab interno canal-based procedures that the flow of aqueous through them (Fig. 2). Improving
include stenting, ablating, viscodilating, and cleaving the return of aqueous back into the general circulation
open diseased or malformed outflow structures. These thereby lowers IOP. Cleaving open the obstructed
blebless surgeries largely constitute the family of MIGS. proximal outflow structures improves the flow of
The purpose of this chapter is to review the evolution aqueous into the nearby distal collector channels,
Gonioscopy-assisted transluminal trabeculotomy (GATT) 97
Fig. 2. Circumferential trabeculotomy landmarks during GATT. The nasal canal is cleaved open during the GATT, exposing its posterior wall,
white stripe (black arrow). The resultant segment of cleaved tissue hangs over the iris, tethered at the scleral spur, forming a trabecular
shelf (blue arrow).
although distal resistance to flow remains at approxi- of their procedure, a more invasive surgery was used
mately 50% 4 and is likely worse in advanced disease.5 to cleave open the peripheral angle, producing a
The episcleral venous fluid wave or episcleral blanch, combined cyclodialysis and trabecular type cleft.
seen intraoperatively, reflects flow of aqueous or This procedure was deemed too invasive for their
balanced salt solution (BSS) into the distal collector young patient with glaucoma secondary to Marfan’s
channels during circumferential trabeculotomy,6 and syndrome. This patient inspired them to develop a
correlates with outcome7 and need for postoperative rigid metal trabeculotome device to be inserted solely
medications.8 The opening in the angle after trabecu- in Schlemm’s canal to cleave it open, leaving out
lotomy is very different than stenting, viscodilating, or the more destructive cyclodialysis part. Around the
ablating the outflow tissues. Each procedure leaves same time, across the Atlantic in England, Redmond
its own particular distinctive angle footprint with Smith10 developed a similar concept to solely open the
unique wound-healing characteristics. Over a 54-year canal and TM, but with a suture, of which he termed
period, trabeculotomy has improved from an invasive filamentary trabeculotomy. Both of these original tra-
segmental ab externo approach to a less invasive ab beculotomy procedures were ab externo and accessed
interno circumferential method that allows for opening the canal through a radial scleral scratch incision. One
360° if desired. major drawback to the radial ab externo approach is
the difficulty in finding the canal and verifying its exact
2.1. Origin of trabeculotomy location. Various improvements to the methodology
In 1960, Burian and Allen9 in Iowa City (IA, USA) of trabeculotomy ab externo were made in the 1960s,
codeveloped the concept of trabeculotomy, a technique including verifying the location of the canal under a
for a less invasive angle procedure, which they termed scleral flap,11,12 improved trabeculotome devices,13 and
trabeculotomy ab externo. Prior to the development extent of angle cleaved open in the 1980s.
2.2. Efficacy of trabeculotomy ab externo in adults beculotomy with one flap.16 The 360° trabeculotomy ab
The 1960 original trabeculotomy consisted of opening externo remains a standard for pediatric and juvenile
only a segment of the canal, roughly 1/3 of its circum- glaucomas by cleaving open a maldeveloped conven-
ference through an external approach with a metal tional outflow system and lowers IOP better than a
canalicular probe. Segmented or partial trabeculot- segmented approach.17 The advent of the illuminated
omy ab externo was a popular glaucoma procedure microcatheter for circumnavigating the canal was a
during the 1960-1980 period, especially when the major breakthrough for canal surgery in the pediatric
initial work of Grant in the late 1950s to early 1960s glaucomas,18,19 for the surgeon is constantly aware of
identified the TM/SC as the site of greatest resistance the position of the catheter at all times. Today, surgeons
to aqueous outflow, of approximately 75%. Improve- experienced in ab externo circumferential canal surgery
ments in laboratory outflow experiments and outflow oftentimes will open the canal with a less invasive
physiology later reduced this figure to approximately ab interno approach, typically seen with the GATT
50% of outflow resistance, as defined by Rosenquist procedure, using a 5-0 prolene suture.
and colleagues.4 Thus, half of all trabecular outflow
resistance is normally located distal to the outer wall of 2.4. Development of ab interno circumferential tra-
SC. In addition, surgeons were able to largely avoid bleb beculotomy or GATT
formation through their scleral incisions. However, the A confluence of improvements in instruments and
popularity of trabeculectomy in the late 1970s, along new devices, along with the determination of two
with the later development of mitomycin C (MMC) to experienced ab externo canal surgeons combined with
inhibit fibrosis created lower IOPs than trabeculotomy. the hope of lower IOP in a juvenile glaucoma patient led
Thus, segmental trabeculotomy was slowly abandoned to the first GATT procedure at Glaucoma Associates of
in the USA except for cases of congenital glaucoma, Texas (GAT) in 2011. Several factors were instrumental
which continued to show excellent IOP-lowering results. in the success of the first GATT procedure:
However, Japan and Germany remained hotbeds for 1. careful planning of the procedure and over three
the continued development of trabeculotomy in adults decades of combined experience with circumfer-
and children, with the intent and hope of lowering IOP ential canal surgery under a scleral flap with a
without the issues of bleb formation. suture and illuminated microcatheter;
2. the availability of microsurgical instruments for
2.3. Efficacy of trabeculotomy ab externo in pediat- working in the anterior chamber (AC) of the eye
ric glaucomas along with the illuminated microcatheter;
The work of Maumenee14 and others encouraged 3. the desire to avoid trauma to the conjunctiva
surgeons to continue to develop trabeculotomy for and sclera in order to preserve tissue for future
infantile glaucoma, where it was commonly thought filtering surgery; and
the angle was maldeveloped and cleaving it back open 4. the right timing with the right patient and, of
mimicked normal physiologic outflow. In addition, course, a lot of luck.
encouragement came from the excellent IOP lowering
following trabeculotomy in the pediatric age group.
In the mid 1980s, Lynn and Fellman progressed from 3. Technique of GATT
the segmented trabeculotomy to extend the work of
England’s Redmond Smith by developing a 360° tra- 3.1. Preoperative considerations
beculotomy ab externo in congenital glaucoma15 by Since SC is considered not just a canal but also a
creating two 180° opposing scleral flaps. This allowed vessel, bleeding during surgery and afterwards is a
for a 360° trabeculotomy for congenital glaucoma at major concern for patients who are unable to stop their
one sitting, a major improvement over the degree of anticoagulants. We therefore do not perform GATT in
angle treated along with assuredness of being in the patients who are unable to temporarily stop their anti-
canal. This was later improved upon and reported by coagulants. Preoperative gonioscopy is essential in
Beck and Lynch in the 1990s by creating the 360° tra- order to identify the scleral spur, the most important
angle landmark that separates conventional from gical Technology, Redmond, WA, USA) instruments
uveoscleral outflow. The cornea must be clear enough (Fig. 3b).
to see the vital angle structures. Pseudophacodonesis
is a major red flag that likely indicates zonulopathy that 3.2.3. Preparing and positioning the suture/catheter
may lead to dislocation of the intraocular lens (IOL) with and patient’s head.
vitreous prolapse during AC manipulations and possibly GATT may be combined with viscodilation of the canal.
the hyphema spilling over into the vitreous. Thus, With this technique, the iTrack catheter is primed
significant IOL laxity is a deterrent to GATT. We prefer with viscoelastic prior to insertion in the AC. The dial
not to do angle surgery in patients with advanced visual is turned on the microcatheter handpiece until visco-
field loss worse than -16 dB, for these patients need elastic is seen exiting the tip. The iTrack is brought into
lower IOPs to preserve vision than is typically achieved the field and tethered to the drape near its proximal
post-angle procedures. We also avoid GATT in patients portion, allowing a circumferential arc approach to
with broad or extensive peripheral anterior synechiae. the eye, and then inserted at its distal tip through the
nasal paracentesis and visualized in the AC. If properly
3.2. GATT surgical technique positioned through the preplaced paracentesis,
the distal tip of the iTrack approaches the canal in a
3.2.1. Anesthesia and positioning somewhat tangential position. If a 5-0 prolene suture
Following adequate peribulbar or topical anesthesia, is utilized instead of the microcatheter, it is thermally
the patient is placed in a reverse Trendelenberg blunted at its tip, creating a small bulb, and inserted
position (5-10°, head higher than heart) in order to into the AC (Fig. 3c-e). The patient’s head is then tilted
decrease intraocular bleeding by reducing episcleral approximately 35° away from the surgeon and the
venous pressure. operating microscope is tilted towards the surgeon
for approximately 45°. The surgeon repositions as
3.2.2. Paracenteses necessary in order to adequately view the angle through
Either an inferonasal or superonasal tangential (not a Swan-Jacob goniolens while sitting comfortably prior
radial) corneal paracentesis is made with a 23-g needle to intraocular maneuvers. It is critical to barely touch
or 15° super sharp (Fig. 3a) for insertion of the suture or the cornea with the nondominant hand that holds the
iTrack illuminated microcatheter (Ellex, Fremont, CA, goniolens in order to prevent corneal striae, which sig-
USA). Some surgeons believe GATT is initially easier nificantly decreases the view of the angle structures.
to learn when using the illuminated microcatheter,
however, several other surgeons are able to safely 3.2.4. Insertion and circumnavigation of canal
and comfortably learn and master GATT with the 5-0 While focusing on the nasal angle, the 25-g MVR blade
prolene suture with a thermally blunted tip or one is juxtaposed directly below Schwalbe’s line, which is
marked with dye, depending on suture preference.20 the anterior extent of the TM. Create a one to two-clock
Most right-handed surgeons prefer to use their hour goniotomy by lightly advancing the MVR blade
dominant hand to thread the suture or catheter into parallel and slightly below Schwalbe’s line (Fig. 3f).
the canal with a forehand maneuver, thus requiring an Then depress and expose the TM leaflet created by
inferonasal paracentesis for a right and superonasal the goniotomy to adequate create a space or pocket
paracentesis for a left eye. Some surgeons prefer a for insertion of the microcatheter or suture (Fig. 3g).
back-handed threading into the canal. A miotic is Commonly, at this juncture, additional viscoelastic is
injected into the AC, followed by a significant viscoelas- used to tamponade blood, elevate IOP, and thereby
tic fill (Healon GV, Johnson & Johnson, New Brunswick, improve the view. The MST micro-grasper is then
NJ, USA). The chamber deepens significantly, which is inserted through the temporal paracentesis, and when
a good sign that enough viscoelastic has been inserted mid-pupil, the Swan-Jacob goniolens is placed on the
to raise IOP and reduce intraocular bleeding. A second cornea. Grasp the distal portion of the iTrack catheter
paracentesis is made temporally for insertion of the or suture approximately 2 mm from its tip, orient it
MVR (microvitreal retinal) blade and MST (MicroSur- parallel to the exposed canal goniotomy site, and insert
a b
c d
e f
Fig. 3. GATT procedure on the left eye. (a) Infero-nasal paracentesis for insertion of either 5-0 prolene suture or iTrack. (b) Temporal
paracentesis. (c) Approximation of 5-0 prolene suture near hand held cautery tip. (d) Thermally blunt tip of prolene suture. (e) Placement
of suture through paracentesis site. (f) Position of MVR blade immediately before goniotomy.
g h
i j
k l
Fig. 3. GATT procedure on the left eye. (g) A small one clock-hour goniotomy is created. (h) Insertion of tip of suture into the canal (black
arrow). (i) Retrieval of tip of suture after advancing for 360°. (j) Positioning suture towards the pupil prior to trabeculotomy. (k) Proximal
portion of the suture is pulled creating the trabeculotomy while the distal tip is held constant in the AC. (l) Trabeculotomy extends from
the 8 o’clock to 3:30 clock hour.
m n
Fig. 3. GATT procedure on the left eye. (m) Two port irrigation and aspiration to remove viscoelastic. (n) Appearance of limbus immediately
prior to infusion of BSS. (o) Perilimbal blanching of tissues demonstrates the episcleral venous fluid wave.
the tip while making sure the exteriorized portion of the use of a viscoelastic partial fill is always useful in
the suture/catheter is free to advance (Fig. 3h). The suppressing bleeding from the initial goniotomy site.
black arrow in Figure 3h designates the blunted tip of Bleeding is not typically seen as the suture or catheter
the suture. With deliberate, slow pressure, and not too is traversing the canal. Most of the bleeding occurs
far from the canal entry site to avoid kinking, advance immediately after opening the canal, when the eye
the device around the canal for 360°. The suture is is transiently hypotonus. This is cleared out during
slightly more rigid and less likely to kink as compared the two-handed irrigation and aspiration phase.
to the catheter. The illuminated blinking tip easily Depending on the degree of bleeding and wave seen,
notes the progress of the catheter. When the catheter viscoelastic is reinserted at the end of the procedure,
or suture has progressed all the way around back to the approximately a 15-40% fill, to tamponade bleeding
goniotomy site, grasp the suture tip from the exposed along with reinstilling BSS to keep the eye firm at the
goniotomy site and bring it towards the pupil (Fig. 3i end of the procedure.
and 3j), while ensuring your MST instrument is anterior
to the proximal portion of the suture in the AC. In order 3.3.2. Failure to circumnavigate the globe
to create the trabeculotomy, pull the proximal portion Besides intraocular bleeding, the most common
of the suture away from the limbus while firmly holding problem encountered during GATT is inability to
onto the distal tip in the AC (Fig. 3k and 3l). After the completely circumnavigate the globe (relatively rare,
360° trabeculotomy, release the distal tip while pulling occurring perhaps 5% of times with the authors). When
the proximal portion out of the AC. this occurs, there are several options, depending on
whether a suture or catheter is being used.
3.2.5. Aspiration and reinsertion of viscoelastic from
the AC 3.3.2.1. Inability to circumnavigate microcatheter 360°
Slightly enlarge the nasal paracentesis in order to use a One reason the catheter fails to come around for
two-handed infusion/aspiration system to remove vis- 360° is usually entering and going down an adjacent
coelastic (Fig. 3m). Once the viscoelastic is removed, collector channel. This should be apparent under dim
the amount of flow through the collector channels is illumination when the microcatheter beacon starts to
visualized by injecting BSS into the AC and judging the stray away from the limbus. Mark this point and retract
blanch of fluid through the collector channels. Aggres- the catheter one clock hour. Use the blunt curve of a
sively irrigating BSS into the AC performs a lavage of muscle hook to indent the area of the limbus to close
the outflow system and likely dilates the downstream off the collector channel and try pushing the catheter
collector system. A marked whitening of the episcleral through that area again. Oftentimes, the catheter will
tissue indicates a patent outflow system (Fig. 3n and stay in the canal through the area of the closed off
3o) and approximately a 25% refill with viscoelastic adjacent collector channel. This maneuver is repeated
can be cautiously used to help tamponade postoper- several times if necessary. If this fails completely,
ative bleeding in the case of an extensive episcleral withdraw the catheter, reinject viscoelastic into the
venous fluid wave and/or a decent amount of blood AC if needed, and create a second nasal paracentesis
reflux into the AC. opposite to the first one, allowing one to cannulate
the canal going the opposite direction. Reinsert the
3.2.6. Subconjunctival steroid microcatheter, create a second goniotomy site, and
At the end of the procedure, subconjunctival steroid is cannulate going the opposite direction of the first try.
administered to inhibit postoperative inflammation. Oftentimes, the microcatheter will easily go around
360°. If this fails and the microcatheter has traversed
3.3. Intraoperative complications for several clock hours, the surgeon repositions and
cuts down over the catheter at its stopping point. The
3.3.1 Intraoperative hyphema distal end is retrieved and externalized to create the
Hyphema is by far the most common intraopera- trabeculotomy.
tive complication of GATT. Avoiding hypotony with
3.3.2.2. Inability to circumnavigate suture 360° hyphemas clear quickly within a two-week period. If
In general, it takes slightly more force with more the hyphema is excessive, or causing persistent IOP
push attempts to circumnavigate the globe with a problems, one can perform an AC washout, which
suture, especially for the last couple of clock hours. usually improves the situation. We do not use GATT in
Use gonioscopy as necessary to determine the exact patients that are unable to withhold their anticoagu-
location of the suture. If the suture fails to go around, lants. A case report describes two patients with pseu-
retrieve it and try cannulating in the opposite direction. doexfoliation glaucoma who underwent combined
If this does not work, consider opening only a portion phacoemulsification-GATT and developed an intracap-
of the canal. For example, if one can see the suture has sular hemorrhage requiring YAG-laser capsulotomy.21
progressed for nine clock hours, that may be all that is
needed to achieve a reasonable postoperative IOP. An 3.4.2. Inflammation
advantage of the suture technique is that the distal tip Inflammation is usually mild but may be excessive in
of the suture does not have to be retrieved to cleave some patients, especially with hyphema. There is a
open the canal because the resistance in the canal with delicate balance between suppressing inflammation
the suture is high enough that it does not pull out easily. and using excessive steroids that may elevate IOP.
Use that to your advantage by grasping the suture as Pilocarpine may be useful to control IOP during these
it enters the canal and slowly create the trabeculoto- difficult situations. One report in the literature suggests
my by pulling it circumferentially towards the distal tip a worsening of preexisting uveitis following GATT.22
that is several millimeters away. Regrasp as necessary
to cleave open the angle. Oftentimes, if the suture gets 3.4.3. Steroid responder
completely stuck, simply pulling on the proximal end Most glaucoma patients are steroid responders. Sur-
of the suture will create a segmental trabeculotomy. prisingly, trabeculotomy does not prevent the elevated
Passing the suture in the opposite direction in order the IOP associated with steroid use. This is likely due to the
treat the remaining aspect of the TM is slightly easier, as production of extracellular matrix by cells lining the
once half of the angle is opened, the resistance to cir- distal canal structures. A pressure rise from steroids is
cumnavigate the canal significantly decreases. so universal that it should be anticipated and controlled
beforehand with antiglaucoma drops, occurring usually
3.3.3. Inadvertent iridodialysis or cyclodialysis at around postoperative weeks two or three.
It is imperative to know the angle landmarks well before
incising the angle. Preoperatively, if one is unsure of 3.5. Results
the angle landmarks in the clinic, the view of angle The authors reported on 198 patients with at least
structures is even harder in the operating room. These 18 months follow-up.23 In 119 patients with primary
patients are not good candidates for beginner angle open-angle glaucoma, IOP decrease was 9.2 mmHg
surgeons. Make sure one can always distinguish the (37%) with 1.4 less medications at 24 months. In the
scleral spur before surgery. Obviously, trying to insert a remaining 79 patients with secondary glaucomas,
microcatheter or suture into anything besides the canal IOP decrease was 14.1 mmHg (49.8%) with 2 less
may result in a cyclodialysis or iridodialysis, causing medications at 24 months. The cumulative proportion
considerable damage to adjacent angle structures. of failure at 24 months (Fig. 4) ranged from 0.18 to 0.48,
depending on the group. The pseudophakic primary
3.4. Postoperative complications open-angle glaucoma group had the highest failure
rate, even though their postoperative IOP was similar
3.4.1. Hyphema to all other groups. This particular group of patients
Hyphema is the most common complication of GATT were older and had more severe visual field damage
and is universal on postoperative day one in various (-10.9 dB) than the other groups, and likely needed a
amounts. Patients are instructed to sleep with their head lower IOP to prevent further damage.
elevated for one to two weeks and refrain from activities Rahmatnejad reported on 66 patients who
that would increase episcleral venous pressure. Most underwent GATT with an average follow-up of 11.9
of eyes at 24 months. A mean preoperative IOP of 25.7

mmHg on 3.2 medications was lowered to 15.4 mmHg
on 2.0 medications (P < 0.001). Even though the canal
may become atrophic after prior traditional glaucoma
surgery, this study suggests that cleaving it open with
GATT may significantly lower IOP without incising the
conjunctiva or sclera.
The authors reported on 14 eyes of 10 patients
(age range: 17 months to 30 years) with primary
congenital and juvenile glaucoma who underwent
GATT with greater than 12 months follow-up.2 The
mean IOP decreased from 27.3 to 14.8 mmHg on 1.8 less
medications. A 360° trabeculotomy was accomplished
in all eyes except one eye, where only 180° could be
opened. The ab interno GATT results were similar to
ab externo trabeculotomy in the treatment of primary
congenital and juvenile glaucoma.
Fig. 4. Kaplan-Meier curve demonstrating cumulative proportion 4. Place of GATT in modern-day

of failure post-GATT. POAG: primary open-angle glaucoma patients
undergoing GATT alone; POAG Combined: patients undergoing glaucoma surgery
combined GATT and phacoemulsification; POAG prior CE: patients
with POAG and prior phacoemulsification; Other: secondary The role of GATT continues to find its place in the surgical
open-angle glaucomas; Other combined: patients undergoing management of glaucoma worldwide. The results
combined GATT and phacoemulsification; Other prior CE: patients
undergoing GATT with secondary glaucoma and prior cataract are very encouraging for juvenile glaucoma, primary
surgery congenital glaucoma, post failed traditional glaucoma
surgeries with open angles, secondary open-angle
months (range: 3 to 30). Mean IOP was 26.1 ± 9.9 mmHg glaucomas, and most open-angle glaucomas that
preoperatively and 14.6 ± 4.7 mmHg at 12 months (44% are early-to-moderate stage disease. Avoid GATT in
IOP decrease; P < 0.001). Mean number of medications patients with uncontrolled bleeding diathesis, unable
decreased from 3.1 ± 1.1 preoperatively to 1.2 ± 0.9 at 12 to hold their anticoagulants, unstable IOLs, aberrant
months (P < 0.001). They found an overall success rate angle anatomy, and patients with advanced disease
of 63%, with a difference in success among white (69%) where a subnormal postoperative IOP is needed. GATT
and black patients (42%) (P < 0.05).24 may be easily combined with phacoemulsification.
Aktas first reported on the outcome of GATT with For beginner angle surgeons, the illuminated micro-
a 6-0 prolene suture in patients with moderate to catheter may provide helpful clues as to the location
advanced glaucoma. At 18 months, IOP reduction was of the catheter in the canal, along with its ease of
40% in open angle glaucoma and 28% in secondary traversing the canal in a circumferential fashion.
glaucomas. Surgical success was achieved in 87 of 104 However, experienced angle surgeons or those who do
eyes (84%).25 not have access to the catheter can safely perform GATT
GATT is also effective in steroid-induced glaucoma. with a 5-0 or 6-0 prolene suture, as numerous surgeons
Boese and Shah found a 55-63% IOP reduction up have done around the world.
to two years postoperatively along with a significant
reduction in topical glaucoma medications from 3.1 to
0.8.26
In 35 eyes with prior incisional glaucoma surgery and
open angles,3 GATT was safe and successful in 60-70%
References 14. Maumenee AE. The pathogenesis of congenital glaucoma. Am J

Ophthalmol. 1959;47:827.
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Fellman RL. Gonioscopy-assisted transluminal trabeculotomy, omy:An improved procedure for primary congenital glaucoma
ab interno trabeculotomy: technique report and preliminary (Abstr). Ophthalmology. 1988;95(supplement):168,
results. Ophthalmology. 2014;121(4):855–861. 16. Beck AD, Lynch MG. 360º Trabeculotomy for Primary Congenital
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transluminal trabeculotomy: an ab interno circumferen- 17. Shakrawal J, Bali S, Saurabh V, et al. Randomized trial on illu-
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4. Rosenquist R, Epstein D, Melamed S, Johnson M, Grant WM. 454.
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1969;68:4
8. Hydrus® microstent
Department of Ophthalmology and Visual Sciences, Washington University in St. Louis, St. Louis, MO, USA
Abstract
The Hydrus® Microstent (Ivantis, Inc, Irvine, CA, USA) and 21). In 2007 Ivantis, Inc. (Irvine, CA, USA) was then
is an 8 mm crescent-shaped nitinol intracanalicular founded in order to support the development of the
implant. This microinvasive glaucoma surgery (MIGS) device. Initially envisioned as both a Schlemm’s canal
device serves both as a stent and as a Schlemm’s (SC) scaffold and a bypass of the trabecular meshwork
canal (SC) scaffold, allowing direct passage of aqueous (TM), or, more precisely, of the TM and the inner wall of
through its lumen and also dilating the canal. The SC, the Hydrus developers had the intention to provide
implant facilitates aqueous outflow through natural a low resistance outflow pathway for the aqueous
pathways, does not require filtration blebs, and is and also dilate the SC, ensuring that such fluid would
inserted ab interno. have access to more collector channels (CC) and that
In August of 2018, the FDA approved the Hydrus to be SC compression/occlusion caused by high intraocular
implanted with concomitant cataract surgery (CS) upon pressure (IOP)4-7 would be mitigated. The goal would
publication of the pivotal HORIZON trial.1 Worldwide, then be a trimodal mechanism of action: bypassing
however, the device had already been implanted the TM; dilation and scaffolding of SC; and enabling
over 3,300 times, being in use in the European Union outflow through more CC.
as early as 2011,2 and since then also being marketed Development of such a device was the result of
in Canada, Australia, New Zealand, Costa Rica, and a series of scientifically guided decisions, starting
Colombia.3 In addition to supporting the approval, the with the selection of the material. Nitinol, an almost
HORIZON study also boasted excellent results, with equiatomic alloy of nickel and titanium (55% Ni +
77% of patients showing a ≥ 20% intraocular pressure 45% Ti), possesses superelasticity, shape memory,
(IOP) decrease after 2 years of the procedure, or 20% resistance to corrosion, and a track record of high
more patients than those submitted to CS alone. biocompatibility,8-12 making this material the ideal for
a scaffold with complex geometry to be inserted in a
Keywords: glaucoma, Hydrus, microstent, microinva- delicate structure such as SC. To enhance biocompat-
sive glaucoma surgery (MIGS) ibility, the implant is electropolished, smoothing its
surface and, more importantly, creating a less corrosive
outer layer composed of titanium-oxide.13
1. Design The shape and form of the device was also carefully
chosen, with the original design being modified based
Andrew T. Schieber and Charles L. Euteneuer, on insights acquired from preclinical studies conducted
experienced engineers with contributions to coronary with the support of Ivantis. Originally, the unit was
stent devices, are the minds behind the initial concept designed with a length of 15 mm and an almost circular
of the Hydrus (also discussed in Chapters 1, 3, 6, 9, 17, cross-section of 284º. After fluid dynamics,14,15 and
Correspondence: Arsham Sheybani, MD, Department of Ophthalmology & Visual Sciences, Washington University School of Medicine in
St. Louis, 517 South Euclid Avenue, St. Louis, MO, USA.

scanning electron microscopy16 studies showed that a clinical trials outside of the USA, with preliminary
smaller version provided similar outflow ease with less results showing similar efficacy and safety outcomes
anatomical deformation to SC, the Hydrus’ design was as those observed in the HORIZON.3
revised to the current 8 mm long, half-circle cross-sec- Finally, a close look at the implant itself reveals
tion (Fig. 1). several design features that enable its IOP-lowering
The surgical delivery system has also been modified effect, as depicted in Figure 2. In the proximal tip, the
from its original inception, 3 with the manufacturer inlet houses the side interlocking mechanism, where
reporting that a new, easier to use delivery system will the inserter attaches. This part is 1 mm long, has a
be present in the commercially available version of the 290 µm diameter cross-section and, once implanted,
Hydrus, differing from the one used in the HORIZON protrudes outside of SC, allowing the fluid to bypass
trial.3 This newer side interlocking delivery system will the TM. The remaining 7 mm of the device spans 90º
enable the surgeon to advance and properly release into the canal. Three windows in its TM-facing side
the implant in the canal while rotating the wheel in the enable aqueous humor to be filtered into the canal
delivery system forward only, whereas before the user while the spines provide structural support. With its
had to reverse the wheel rotation after advancing the open-back design, the implant enables unobstructed
device into the canal satisfactorily. The revised side fluid outflow to multiple CC.
interlocking mechanism will also enable the device
to be easily reattached to the delivery system in case
it needs repositioning. This slightly modified implant
design has been used in two multicenter randomized
Fig. 1. The 8 mm-long (a) and 15 mm-long (b) versions of the Hydrus®, along with their respective cross-sections. Figure reproduced from
Sampathkumar et al.40
Hydrus® microstent 109
Fig. 2. Design features of the Hydrus®. Image courtesy of Ivantis, Inc.
2. Surgical procedure access through typical temporal clear corneal incisions

commonly done in CS.
Insertion of the Hydrus is ab interno, therefore After positioning of the patient, viscosurgical device
requiring a clear corneal incision. In the United States, is injected into the anterior chamber in order to
the FDA has provided approval for this procedure only expand the angle. The Hydrus injector cannula is then
when conducted together with CS. In these cases, the advanced inside the anterior chamber and, pointing
patient’s head is repositioned after customary CS in it slightly upward (anteriorly), the TM is incised with
order to allow better viewing of the angle structures. the cannula’s beveled tip, allowing the implant to
For insertion into the nasal inferior quadrant, the be inserted 90º into SC. As previously stated, the
patient’s is tilted nasally 20-30º, away from the commercial version of the inserter will advance and
surgeon, with the microscope also repositioned and release the stent with the surgeon rolling the tracking
a gonioprism is then employed to allow viewing of the wheel with their thumb in just one direction, making
angle. The Hydrus can be inserted into any quadrant, the process literally straightforward. After successful
but preference is given to the nasal inferior, since it is insertion and visual confirmation of the device’s
home to a higher number of CC17 and is the easiest to position, with 1-2 mm of its inlet visible outside of SC,
the inserter is withdrawn, viscoelastic removed, and a impact of microstent implantation, one pair of eyes
balanced salt solution inserted. Postoperative care is were sent for histological analysis after C assessment,
similar to that of CS alone, with prescriptions of topical where no important alterations were seen except for
antibiotic for seven days and topical corticosteroids for stretching of SC.
four weeks in a tapering scheme. A year later Gulati et al. published a similar study,14
now evaluating C with the updated 8 mm-long device.
Dissecting 22 paired eyes in the same manner as above,
3. Preclinical studies half had the Hydrus inserted while the other eyes had
their TM punctured with the beveled tip of the implant’s
Development and regulatory approval of the Hydrus inserter, serving as control. C was not significantly
was informed by several preclinical studies supported different between the two groups at baseline, but a sta-
by Ivantis. Camras et al. were the first to put the Hydrus tistically significant difference was indeed detected at
to the test.15 At the time evaluating the 15mm-long all perfusion pressure levels (10, 20, 30, and 40 mmHg),
version, they examined outflow facility (C) in 16 anterior demonstrating a clear benefit to implanting the Hydrus.
segments (cornea, anterior sclera, and TM separated by Mean C increased by 58% in the eyes that received the
cutting along the equator of the globe) of ophthalmo- device. Authors also analyzed outflow resistance (R),
logically healthy human eyes from deceased donors. defined as the inverse of C. Figure 3 depicts the variation
Nine eyes received the Hydrus while seven served as of R according to initial R after implantation for both the 8
controls, receiving a sham procedure. C was measured mm and 15 mm devices (graphing for the latter was done
at perfusion pressures of 10, 20, 30, and 40 mmHg using data from the work by Camras et al.). No statisti-
before and after insertion of the device, resulting in cally significant difference was seen in the R-lowering
no differences in baseline C but a significant increase, effect of these two versions, although numerically, the
favoring the Hydrus, detected at all but the 10 mmHg 15 mm-long device proved to be superior. Based on this
perfusion pressure. Overall, mean C in treated eyes curve, hypothetical values for aqueous dynamics, and
increased by 105%, while no statistically significant Goldmann’s equation, the authors report that the 8 mm
difference was seen in controls. In order to assess the Hydrus is able to provide a 0.84 mmHg IOP drop for
Fig. 3. Change in outflow resistance (R, the inverse of outflow facility) with the 15 mm and 8 mm-long Hydrus microstents for different
baseline R. Reproduced from Gulati et al.14
every additional 1.0 mmHg IOP increase. Researchers on SC’s external wall, resulting in altered endothelial
also investigated the interaction between the presence cell profiles.
or absence of the microstent and perfusion pressure After a final design had been decided on, a third
levels on the outcome variable C by using a two-way study on outflow facility was done, this time comparing
ANOVA. They sought to evaluate whether the C aug- the 8 mm Hydrus with the iStent, or, more precisely,
mentation (not C itself) provided by the Hydrus would with two iStents.23 Hays et al. explained that such is a
be higher at higher perfusion pressures (analogous to fair comparison, given that two iStents would cover
IOP), therefore confirming the theory that a SC scaffold a quadrant of SC, like the Hydrus, and thus provide
would prevent the canal’s collapse at higher IOP. This, comparable circumferential flow improvement. Using
however, was not confirmed by their analysis. 12 pairs of eyes with one of each pair receiving the
Ivantis also commissioned an aqueous outflow Hydrus and the other the iStents, the authors measured
mathematical model study, done by Yuan et al.18 While C in perfusion pressures of 10, 20, 30, 40, and 50 mmHg,
previous models had contributed with considerations with no difference in baseline measurements. Mean C
regarding the positioning of CC,19 compressibility of increase was 57% in Hydrus eyes vs 28% in iStent eyes,
SC,20 and more recently, the implantation of trabecular and while C significantly increased in every perfusion
microbypass devices (iStent),21,22 none had incorpo- pressure for the Hydrus, iStent eyes had a statistically
rated in the same model all of those variables. Taking significant difference only at 40 mmHg. Similar to Gulati
into account the precise measurements of the Hydrus et al., the authors stated their interest in detecting an
and of the iStent, the authors found that average C interaction between device and perfusion pressure
increased 105% for the 8 mm Hydrus, 222% for the 15 on C, therefore analyzing if the rate of outflow facility
mm Hydrus, 36% for a single iStent, and 88% for two increase varies with perfusion pressure, by device.
iStents. They also concluded that the length of SC Unfortunately, they did not explicitly report such test
dilation is correlated with an increase in C, but that the in their results, but they do conclude that there is not
rate of improvement diminishes with longer spans. This a statistically significant decrease in C with higher
emphasizes the importance of choosing an optimal perfusion pressures after implantation of the scaffold
length, where effectiveness and anatomical compatibil- or the two microbypasses. While this does not lead to
ity are maximized. In addition to a lower C increase than a definitive conclusion that indeed the Hydrus provides
either version of the Hydrus, the authors also reported a scaffolding effect to counteract SC compression at
that iStent’s C improvement is more dependent on its higher IOP, it does provide evidence for consistent
positioning relative to a CC and that such variability IOP-lowering action across any pressure level. Similar
can be mitigated with the implantation of two devices. to Camras et al., a pair of eyes (a Hydrus receiving
This was the first of many comparisons drawn in the and a 2-iStent receiving eye) was sent to histologi-
literature between the Hydrus and the iStent. cal examination, where a greater dilation of SC was
To further elucidate the appropriate device length, observed in the eye that received the scaffold. No other
a scanning electron microscopy (SEM) study was com- notable changes were seen.
missioned by the manufacturer, in order to compare While these studies support the efficacy of the
the morphological impact of the 8 mm vs 15 mm-long Hydrus, arguably more important was evidence of its
implant. Johnstone et al.16 reported their analysis of safety before in vivo effectiveness could be assessed
12 anterior segments dissected from human eyes, in clinical studies. Grierson et al. reported the in vivo
with 3 receiving the smaller version, 2 the longer, and response of implantation of the microstent in two
6 serving as controls. The experimental eyes had the animal models: cynomolgus primates and New Zealand
microstents properly inserted and then removed, the white rabbits.13 Insertion of the Hydrus was done ab
external wall of SC was exposed by TM excision, and externally in the primates’ eyes. Given these are much
the eyes were finally fixated and prepared for SEM. smaller than human eyes, this was expected to be a
The results showed minimal disruption to SC and CC worst-case scenario in regards to tissue stretching and
anatomy from the insertion process. However, it was compression. Observation occurred for 90 days and no
seen that the 15 mm-long version caused depression abnormalities were seen in periodic ophthalmologic
exams. The animals were then euthanized, and their Institute (ANSI) Z80.27 for Glaucoma Implantable
eyes sent to histological examination, which found no Devices.25 One-hundred eyes from 100 patients were
significant inflammation, evidence of metallosis, or randomized 1:1 to either CS + Hydrus or CS alone
tissue degeneration. The only noticeable changes were (control). Patients had open-angle glaucoma (primary
related to the tissue compression associated with the open angle glaucoma [POAG], pseudoexfoliation, or
presence of the microstent. In the rabbit model, one of pigment dispersion glaucoma) and cataract, but no
the eyes received the implant while the other received other relevant ophthalmic alterations or past history.
a sham procedure. New Zealand white rabbits are a Baseline and postoperative months 12 and 24 IOP mea-
species known for their eye reactivity, but to really surements were done under medication washout, as
test a worst-case scenario, researchers implanted per Ocular Hypertension Treatment Study protocol,26
the stent in a sampling of tissues of the eye (sclera, and as an average of 3 Goldmann tonometries taken
orbital tissues, conjunctiva) instead of its anatomically 4 hours apart from 8 AM to 4 PM (diurnal IOP [DIOP]).
designated place. After the initial four weeks and until Baseline DIOP was required to be between 21 and 36
six months of follow-up, all eyes were quiet. Histolog- mmHg for recruiting. Initial patient DIOP and number of
ical examination evidenced a negligible inflammatory glaucoma medications in use were similar between both
reaction with a small increase in immune cells around groups, at roughly 26.5 ± 4.2 mmHg (after washout) and
the stent, but no degenerative, necrotic, or apoptotic 2 ± 1 medications. The authors reported results for 78
changes seen. Allying the negligible inflammation from eyes at 24 months follow-up, when 80% of patients had
the rabbit model with the positive results from the a DIOP decrease ≥ 20% in the CS + Hydrus group vs 46%
primate model, this research provided solid evidence in the CS alone, a significant difference. The number of
to allow implantation in human eyes. glaucoma medications was lower in the eyes that had
the microstent implanted, at 0.5 ± 1.0 medications vs
1.0 ± 1.0, reflecting the higher number of unmedicated
4. Clinical studies patients in the Hydrus group, 72.9% vs 37.8%. The
authors also monitored patients to assess the safety of
The Hydrus’ inaugural study in the clinical stage was the combined procedure, which proved to be akin to CS
presented in the European Society of Cataract and alone. The HYDRUS II was the first randomized clinical
Refractive Surgery 2011 Meeting in Vienna, the HYDRUS I.24 trial to report unequivocal effectiveness of a MIGS
In this paper presentation, Manfred et al. report the device after two years of follow-up.
results of a clinical trial including a total of 98 eyes, Following the success of the HYDRUS II for Ivantis,
54 receiving the Hydrus as a standalone procedure Fea et al. published in 2017 the largest independent
and 54 with combined CS. Baseline IOP was 21.8 ± 4.5 Hydrus case series in the literature to date.27 Ninety-two
mmHg with 1.4 IOP-lowering medications and 21.4 patients received Hydrus + CS at 3 European centers
± 4.8 on 2.4 medications for each group, respective- (Italy, Poland and United Kingdom), with 74 completing
ly. Fifty-five eyes (35 for the standalone and 20 for the the first year follow-up and 67 completing the second
combined group) completed the 1-year follow-up, year. Patients were divided into 2 groups, those with
when IOP was measured at a mean of 16.0 ± 3.5 mmHg preoperative at or below 18 mmHg (group 1) or above
on 0.4 medications and 15.4 ± 4.4 on 0.2 medications 19 mmHg (group 2). Examining patient’s last follow-up
for the standalone and combined surgery groups, data, 64% of eyes were unmedicated (75% of those
respectively. The authors concluded that the Hydrus is in group 1 and 60% of those in group 2). The authors
safe and effective implanted in a standalone fashion or also reported a decrease in the mean number of
combined with CS. medications, which were 2.1 ± 1.0, 0.6 ± 1.0, and 0.7 ±
Following the HYDRUS I, we have the HYDRUS II, 1.0 at baseline, 1 year, and 2 years, respectively. IOP
published in 2015 by Pfeiffer et al. This randomized also showed a significant decrease, with measure-
clinical trial was conducted at seven European inves- ments at the same time points being 19.4 ± 4.4, 15.5 ±
tigational sites and was guided by the recently 2.7, and 15.7 ± 2.5 mmHg, respectively. The authors also
published standard of the American National Standards pointed out that six patients with advanced glaucoma
refractory to medical and surgical therapy benefited Baseline washed-out DIOP and medications in use
from the Hydrus, with an IOP decline from 20.2 ± 3.8 (before washout) were roughly 25.5 ± 3.0 mmHg and
to 15.0 ± 3.0 mmHg, albeit still on the same number of 1.7 ± 0.9 for both groups. At the 2-year follow-up visit,
medications. As in the HYDRUS II, no serious complica- the Hydrus enabled a significantly larger number of
tions were observed, further cementing the benefit of patients to reach a DIOP reduction ≥ 20%: 77.3% vs
this MIGS device. 57.8%, or a significant 19.5% difference. This was a
While all these results were promising, Ivantis still similar success rate as that of the HYDRUS II (80%) but
had not attained FDA approval for marketing in the a smaller difference when compared to controls (34%
United States, the world’s largest single market for such in the HYDRUS II) given the exceptional success of CS
device. This was about to change with the publication alone in the HORIZON study. At 2 years, 78% of eyes
of the HORIZON study, the largest clinical trial of a MIGS were medication-free after receiving the Hydrus vs
to date. The study randomized 556 patients in a 2:1 48% in the CS alone group, reflecting a mean number
fashion to either Hydrus + CS or CS alone, respective- of medications of 0.3 ± 0.8 vs 0.7 ± 0.9 in each group,
ly, with 95% of them completing the 2-year follow-up. respectively. Figure 4 depicts the unmedicated eyes
Also designed in accordance to ANSI Z80.27 standards, throughout the study period. Safety assessment was
this study took place at 26 sites in the United States and also of importance in this study, with the Hydrus being
12 international sites. Patients were required to have deemed, once again, as safe as CS alone. Some patients
mild to moderate POAG on 1-4 glaucoma medications, (18.7%) developed focal adhesions around the stent
washed-out DIOP between 22-34 mmHg, and an (peripheral anterior synechiae or iris tissue) but this did
absence of any significant ocular disease or history. not affect the effectiveness of the device or the function
Overall, the HORIZON study had a very similar design of the eye in any way, even when these adhesions were
to the HYDRUS II study, with a few notable differences: deemed obstructive from gonioscopic exam. With the
HORIZON came FDA approval in August of 2018, and
1. HORIZON selected exclusively mild to moderate now the Hydrus joins the ranks of a myriad of other
POAG patients (excluding anyone with visual field devices and procedures promising to free glaucoma
mean deviation between 0 and -12 dB); patients from eye drops while offering minimal risk.
2. randomization was 2:1 in the HORIZON vs 1:1 in While having more options is generally a positive
the HYDRUS II; and thing, more alternatives also make decision-making
3. randomization occurred in the surgical table more difficult. To assist ophthalmologists in deciding
upon confirmation of anatomical favorability which treatment is the best for their patient, a few
for implantation in the HORIZON vs right before comparisons have been drawn between the Hydrus
surgery in the HYDRUS II. and competing procedures. The authors of the
Fig. 4. Unmedicated eyes throughout follow-up in the HORIZON study. The microstent increased the frequency at which eyes remained
medication-free by approximately 30%. Image courtesy of Ivantis, Inc.
HORIZON draw a comparison between their results were medication free, at 46.6% vs 24%, also a statis-
and those from the COMPASS, 28 another large (> 500 tically significant difference. Additionally the mean
eyes) randomized clinical trial with similar design that IOP among the unmedicated eyes was lower with the
evaluated the effectiveness of the CyPass Micro-Stent Hydrus. In a logistic regression, after controlling for
(Alcon Laboratories, Fort Worth, TX, USA), another baseline visual field severity, demographics, and IOP,
MIGS device approved by the FDA in 2016. Hydrus the authors found that the Hydrus increased the odds
patients (vs COMPASS) had a DIOP drop of 2.3 mmHg of being medication free by four times when compared
(vs 1.7), 77.2% of them (vs 72%) had a DIOP drop ≥ 20%, to the iStent. Both implants showed favorable, similar,
and a mean reduction in the number of medications safety profiles.
of 1.4 units (vs 1.2), which might indicate a slight In addition to the comparisons between MIGS
advantage for the Hydrus. Also comparing effective- devices, comparisons between the Hydrus and
ness, Pfeiffer et al.29 contrasted their results with those selective laser trabeculoplasty (SLT) and canaloplas-
of previous iStent trials. Since there was no washout ty (CP) have also been published. Fea et al. conducted
regimen in the iStent studies, only data coming from a prospective, nonrandomized comparative case
unmedicated eyes was used. The authors compared series in Italy of 56 POAG eyes, 25 receiving 360º SLT
the difference in the proportion of eyes that achieved and 31 receiving the Hydrus implant without CS.33 At
IOP reduction ≥ 20% between those receiving the baseline, the only difference between the groups was
device plus CS and those receiving CS alone. At 1 year, a greater visual field loss in the Hydrus group. Age,
23% more eyes in the Hydrus achieved such goals gender, IOP, number of medications, etc. were all very
compared to CS alone, vs a difference of 18% in the similar numerically and not statistically different. A
iStent trials.30 While these numbers are very similar, similar 88% and 90% of patients in the SLT and Hydrus
the discrepancy surged at 2 years, when a difference groups, respectively, had an IOP reduction ≥ 20%, and
of 39% vs 9% was detected, 31 thus suggesting a more there were no significant differences in terms of mean
lasting effect of the Hydrus. IOP reduction between the groups. However, given
To further investigate these differences, Ivantis that there was no washout regimen, a more important
supported the COMPARE study.32 This was a metric in this study is the number of medications in
randomized controlled clinical trial involving a total of use. In this regard, those receiving the Hydrus had
152 eyes from 9 countries comparing the standalone a clear advantage, with the average patient using 1
implantation of the Hydrus against two iStents less medication than the SLT receiver, and a total of
(GTS-100, the first version) in patients with mild to 47% of Hydrus patients being medication free vs 4%
moderate open angleglaucoma. Initially the study of SLT subjects. Without any serious, lasting compli-
was aimed at comparing washed out IOP at 12 months cations occurring in either group, this study provides
follow-up, but given that practitioners were not willing further evidence of the benefit of the Hydrus, even as
to wash out more than 20% of the iStent patients, the a standalone therapy. Gandolfi et al. also conducted
protocol was updated and proportion of patients with a nonrandomized comparative case series in Italy,
IOP decrease ≥ 20% or IOP ≤ 18 mmHg were then the this time retrospective and comparing the Hydrus
primary outcomes. The Hydrus showed better results (standalone) to CP.34 Twenty-one Hydrus and 24 CP
on every metric used in this study. The proportion of patients were followed for 2 years, with very similar
patients in lower IOP levels (≤ 21, 18, or 15 mmHg) sig- baseline characteristics. At the end of follow-up, 50%
nificantly increased compared to baseline, even with of the CP eyes were unmedicated and 8.3% required
less medication usage, while no statistically significant IOP-lowering surgery vs 33.3% and 9.5%, respectively,
difference was observed in the iStent group. Of the in the Hydrus group. Neither difference was statistical-
patients, 30.1% had IOP reduction ≥ 20%, as opposed ly significant, which prompted the authors to warrant
to 9.3% in the iStent group, a significant difference. The caution in declaring CP a winner. They also add that
Hydrus patients had a significantly greater decrease in the practitioner should consider that CP does not
medication usage, a difference of -0.6 medications/ spare the conjunctiva, making future limbal filtration
eye when compared to the iStent group. More patients surgery, if necessary, more challenging.
5. Safety been shown to arise after a much longer period of

time, as the recent withdrawal of the CyPass illustrates.
Current evidence shows the Hydrus to be safe and Alcon recalled their recently FDA-approved device
effective, as an FDA-approved device should be, but true after important endothelial cell loss was detected at a
assurance can only be provided by longer-term studies. five-year follow-up study, even though such alteration
Even though Fea et al. reported in an independent was not seen in the two-year results published in the
study that corneal endothelial cell loss in Hydrus + CS vs COMPASS study.36
CS alone is comparable at six months of follow-up,35 — Wang et al. raised questions on the biocompatibili-
adding to the two-year evidence gathered at the FDA ty of nitinol as an eye implant.37 The authors studied
approval3 — alterations to that cell population have primary human TM cells growing on substrata made
Table 1. Cumulative adverse events through 24 months. Adapted from the HORIZON study.1
HMS NMS
Characteristic
N = 369 N = 187
Intraoperative events
Device malposition 1.6% 0
Hyphema obscuring surgeon’s view 1.1% 0
Postoperative events
Surgical re-intervention in study eye 2.4% 4.8%
Uveitis/iritis requiring steroids 5.6% 3.7%
Conjunctivitis 5.7% 7.0%
Layered hyphema, > 2 mm after 1 day 0.5% 0.5%
BCVA loss ≥ 2 lines ≥ 3 months 1.4% 1.6%
Corneal abrasion 1.1% 0
Corneal edema 1.4% 0
Elevated IOP ≥ 10 mmHg over baseline 0.5% 2.7%
Device obstruction/focal PAS
Nonobstructive 14.9% 2.1%
Obstructive 3.8% -
Cystoid macular edema 2.2% 2.1%
Epiretinal membrane 1.6% 1.6%
Subconjunctival hemorrhage 2.4% 0
Worsening of VF MD by 2.5 dB 4.3% 5.3%
Secondary IOP-lowering surgical interventions (total) 1.1% 2.7%
Tube shunt 0 2.1%

Paracentesis 0.3% 1.0%
Laser membranectomy/synechialysis 0.8% 0
SLT/trabeculoplasty 0 0.5%
BCVA: best-corrected visual acuity; HMS: Hydrus Microstent group; IOP: intraocular pressure; MD: mean deviation: NMS: no microstent
group; PAS: peripheral anterior synechiae; SLT: selective laser trabeculoplasty; VF: visual field
from machine-polished titanium, machine-polished adverse events for the Hydrus throughout 24 months
nitinol (50%-50% alloy), sandblasted and acid-etched of follow-up. After analyzing all the published evidence
pure titanium, and glass as control. They found that cells present in this chapter, there have been no reports
growing on the nitinol substratum showed significantly of hypotony, shallow chamber, device migration, or
more cell necrosis and apoptosis. The Hydrus utilizes a endophthalmitis associated to Hydrus implantation.
55% Ti + 45% Ni alloy and has its external layer electrop- Current accumulated evidence tells us that the most
olished, forming a less reactive titanium oxide layer, common adverse event for Hydrus implantation is
which might avoid those effects. On the other hand, (seemingly inconsequential) adhesion around the stent.
even the more innocuous (according to the research by Perhaps more important are the few cases of hyphema
Wang et al.) titanium can be detrimental to some eye during stent implantation that interfered with or even
structures. In their analysis of tissue obtained intraop- impeded insertion of the device.1,29,39 Although this
eratively from three patients who had undergone iStent is a reality for other MIGS as well, surgeons should be
implantation in the past (1-4 years prior), Young et al. prepared to deal with these situations.
reported that TM tissue around the bypass experienced
loss of cells, fibrosis, and formation of a basement
membrane-like material.38 The iStent is composed of 6. Conclusion
100% Ti, so the long-term impact of a nitinol alloy could
be more detrimental to TM cells, which could mean The Hydrus microstent is a safe, effective, and novel
an unhealthy eye or could be completely innocuous. implant for the surgical treatment of glaucoma. Future
Long-term studies will tell. studies should examine its long-term effectiveness,
Aside from cellular complications, one should always compare it to other competing therapies, and analyze
expect adverse events to be part of a surgical procedure. its cost-effectiveness. Attention should also be given to
Although so far the Hydrus has been deemed very safe, its long-term safety.
future monitoring is necessary. Table 1 summarizes the
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9. The iStent devices: iStent, iStent inject, and
iStent Supra
Department of Surgical Sciences, Glaucoma Unit, Ocular Clinic, Università degli Studi, Turin, Italy
Abstract
The goal of current glaucoma treatment is to stop or this chapter we will present and discuss the devices
slow disease progression, characterized by optic disc produced by a single company, Glaukos. The chapter
cupping and a distinctive pattern of permanent visual is divided into an introductory part, which outlines
field loss. Current glaucoma interventions (medications, the pathways and the potential advantages of these
surgery, laser, etc.) achieve this goal almost exclusively devices, a second part, which mainly deals with the
by reducing the intraocular pressure (IOP), which is the implantation procedures, and a final part, in which
only modifiable risk factor. Nevertheless, with medical personal opinions and some potential developments
therapy, IOP control relies on patients’ adherence and are presented. Some of the points are highlighted in
persistence, and poor patient compliance remains boxes for ease of reading.
a major factor of disease progression, leading to the
need for invasive surgery. Minimally invasive glaucoma Keywords: glaucoma surgery, MIGS, Schlemm’s canal,
surgery (MIGS) aims to provide a less invasive and trabecular meshwork
safer means of reducing IOP than traditional incisional
glaucoma surgery, with a reduction in dependency on
topical medications and minimal undesired effects. This 1. Targeting the conventional
is an essential shift in glaucoma surgical philosophy. (trabecular/Schlemm’s canal) outflow
The current MIGS approaches include techniques with
system
different mechanisms of action: increasing trabecular or
suprachoroidal outflow, reducing aqueous production, 1.1. General considerations
or increasing subconjunctival filtration. Nevertheless, The balance between aqueous humor inflow and
the original MIGS paradigm was to provide a restoration outflow controls the fluid volume and determines
of the natural outflow pathway, and Glaukos (San the intraocular pressure (IOP).1 In the conventional
Clemente, CA, USA) was one of the first companies to outflow system, the aqueous humor passes through
address both the conventional (trabecular/Schlemm’s the trabecular meshwork (TM), enters Schlemm’s
canal) and the alternative (uveoscleral/suprachoroidal) canal (SC), then the collector channels, and finally the
pathways. The opportunity to produce miniaturized, aqueous veins to return to the venous system through
drug-releasing devices, together with the observation the episcleral veins. If IOP is in a steady state, the
that a minimal percentage of medication is delivered outflow of the aqueous humor equals its secretion from
into the eye by traditional means (eye drops), recently the epithelium of the ciliary body. On average, aqueous
paved the way for the development of slow-releasing humor formation gradually slows with age by about
devices to be implanted into the anterior chamber. In 4% per decade of life.2,3 From 20 to 80 years of age,
Correspondence: Antonio M. Fea, Corso Montevecchio 62, 10129 Torino, Italy.


120 A.M. Fea, S. Scalabrin and C. Lavia
aqueous humor formation decreases by approximate- result in the maintenance of IOP.18-20 The term funneling
ly 25% while anterior chamber volume decreases by refers to aqueous humor converging at the JCT to exit
40%, resulting in a 20% faster turnover rate of aqueous through pores present in the inner wall of SC.21 The
humor.2-5 In eyes with primary open-angle glaucoma convergence of flow caused by funneling reduces the
(POAG), secretion of aqueous humor is unchanged,6 area of the JCT that is actively involved in filtration,
whereas outflow resistance in the trabecular outflow thereby increasing its hydraulic resistance.
pathway is higher than in age-matched, normal, control Further resistance may be generated by sites
eyes.7 In normal eyes of men and women, mean aqueous distal to SC,1 presumably located in the region of the
humor flow through the anterior chamber during hours deep scleral plexus and the collector channels. The
of wakefulness has typically been reported from 2.2 observation that minimally invasive surgical procedures
to 3.1 ml/min.2,6 When the subjects are awake, their generally lower IOP less than would be expected if all
aqueous humor flow rates vary little. During sleep, the the outflow resistance were in the JCT further suggests
rate of aqueous flow diminishes to 0.4-1.3 ml/min.2,6 A the presence of distal sites of resistance.1,22 The area
simplified version of the IOP equation: near SC where the deep scleral plexus and the collector
channels are located possesses a unique geometry,
outflow
IOP = ___________
      
outflow activity
+ episcleral pressure and recent studies using OCT showed that the collector
channel entrance (CCE) and intrascleral collector
predicts that an increase in outflow facility will result channels (ISCC) geometries can change in response to
in a consistent decrease of IOP when the starting IOP pressure changes.23-25
is very high, and that IOP will subsequently reach a
physiologic plateau. Restoring the physiologic outflow 1.2. Pulsatile flow
as such holds the promise of significantly reducing IOP The aqueous humor outflow system is peculiar, because
without incurring significant side effects mainly caused nowhere else can the flow pattern of an extravascular
by an IOP below normal levels. fluid be directly observed as it returns to the vascular
Resistance sites are portions that act in the regulation system. Asher26,27 identified and described the outflow
of aqueous outflow. They can be divided into proximal of aqueous humor through the scleral veins (Fig. 1).
and distal resistance. The juxtacanalicular tissue (JCT) The same procedure can be used in clinical settings to
and inner wall endothelium represent key candidates identify aqueous veins, by applying a gentle pressure
for the TM site of resistance. A synergistic interplay to the eye to create a slight increase in pressure, which
between the extracellular outflow pathway of the JCT, results in a transient bolus of aqueous entering the vein
the geometrical distribution of the TM relative to SC, and displacing the blood. If IOP is then reduced below
and the pores of the SC endothelium most likely are the the homeostatic setpoint, aqueous transiently fails to
main generators of proximal resistance. flow, which favors the flow of episcleral blood into the
The observation of segmental pigmentation of vein previously containing aqueous humor, thus making
the TM is suggestive of possible segmental changes its identification easier (for complete discussion and
in aqueous outflow, which have been confirmed in images see Johnstone28 and Carreon et al.1).
humans and monkeys with the use of various tracers.8-16 Several observations show that aqueous flow —
Although it has been observed that tracer patterns may both from SC into the aqueous veins and from the
be an artefact of ex vivo or experimental conditions, aqueous veins into the episcleral veins — is pulsatile;
recent studies using the rho kinase inhibitor Y-27632 it represents an active phenomenon driven by means
determined a change from a patterned distribution of a mechanical pump.28 A bolus of blood often enters
near collector channels to a more uniform distribution an aqueous vein during each cardiac cycle, to be
of the fluorescent microspheres used as a tracer.17 The followed by an aqueous pulse wave that sweeps the
TM can therefore be separated into regions of high and blood bolus along the vessel. The volume of flow has
low outflow, which appears to be consistent across been quantified by in vivo measurement of vessel
species (human, monkey, bovine, and mouse). There diameter and flow velocity of the blood bolus. Stepanik
are various factors that affect segmental outflow and found flow through a single aqueous vein to average
The iStent devices: iStent, iStent Inject, and iStent Supra 121
Fig. 1. The influence of pressure differential on the flow in the episcleral veins according to Ascher. (A) A deep and superficial vein
combine to form a stratified flow. (B) Retrograde flow after compression. (C) and (D) Resumed aqueous flow in opposite directions.
Reproduced from Asher.27
1.08 ml/min.29 The distribution of aqueous veins in the main OCT platform has been developed, which images
human eye is highly asymmetric, with the majority of the outflow system with the OCT beam facing the TM
them below the horizontal midline and the greatest surface in ex vivo preparations. The resolution is high
number in the nasal quadrant.30 Ascher observed that enough — comparable to scanning electron microscopy
two aqueous veins could account for all of the aqueous — to permit detailed imaging of TM and CCE structures.
outflow.31 As a consequence, the motion of the aqueous-outflow
Several pulsatile flow abnormalities are well structures and resultant SC and CCE lumen dimension
documented in open-angle glaucoma.26,27 First of all, changes have been recently quantified.25
as glaucoma pathology advances, pulsatile aqueous Cannulating SC and then connecting the cannula to
flow decreases until it eventually disappears.32 Another reservoirs at controlled heights provides a hydrostatic
difference between healthy and glaucomatous eyes is pressure head that makes it possible to systemical-
represented by the compensation maximum test: in ly monitor the resultant pressure changes within the
normal eyes, when IOP is increased, pulsatile aqueous canal. Dilating SC to study TM motion is the same
flow increases, while in glaucomatous eyes pulsatile approach used during clinical gonioscopy to directly
flow is reduced or stops.33 Pulsatile flow in open-angle observe blood filling SC. Blood reflux is a surrogate
glaucoma improves in response to instillation of marker for TM motion that results in TM collapse and
glaucoma medications; three classes of medications causes the SC lumen to enlarge. In detail, SC pressure
are reported to cause an increase in pulsatile aqueous reversal in vivo identifies TM motion changes that
outflow: miotics, adrenergics, and prostaglandins.34 distinguish normal from glaucoma patients.
In the past, OCT imaging of the dynamic motion of The high-resolution OCT platform permits
the outflow-system tissues had not been possible due measurement of real-time changes in the lumen
to limitations — e.g. tissue penetration, light scattering, dimensions of SC, CCE, and ISCC, which occur within
motion artefacts determined by slow acquisition — milliseconds. In addition, videography and a calibrating
that did not allow sufficiently rapid image acquisition micrometer allow measurement of the aqueous
to detect pulse-induced motion.35 To circumvent these stratum diameter, while determination of the speed of
limitations, an extremely high-resolution spectral-do- movement of a bolus of blood provides a measurement
of velocity. Following instillation of epinephrine and 2. The nonconventional outflow pathway

brimonidine, the typical onset of a directly observable
increase in pulsatile flow is about 5 min, while with The physiological role of the nonconventional or
miotics it takes 5-20 min and with prostaglandins 20-30 uveoscleral outflow route is not completely clear, and
min. The pulsatile aqueous flow elevation has been its role is species- and age-dependent in humans. In
observed to last about four hours following miotics, up nonhuman primates, 40-50% of aqueous leaves the
to two hours with epinephrine, and up to an hour with eye by the uveoscleral route, and indirect calculations
brimonidine and prostaglandins. These combined mea- suggest that a similar fraction may be present in healthy
surements provide the ability to measure the volume of human eyes. Furthermore, potent pharmacological
aqueous flow, showing that the use of each of the above agents take advantage of this route. The observation
medications causes an increase in stroke volume and that the scleral tissues offer little resistance to flow, and
velocity.26 that the choroidal vessels can easily absorb the amount
of aqueous delivered, suggests that the main resistance
Relevant information from basic studies to uveoscleral outflow is within the ciliary muscle. The
on the conventional outflow pathway: production of a cyclodialysis cleft opens the route for
1. Although some resistance may be a free flow of aqueous humor into the suprachoroidal
generated distal to SC, the majority space and a potentially significant decrease in pressure.
of authors agree that the main site of Previous authors reported a decreased risk of fibrosis in
resistance in the conventional outflow the supraciliary space, where there is the formation of
pathway is proximal to SC. A bypass loose, fibrous, connective tissue rather than scar tissue.
created between the anterior chamber Nevertheless, previous attempts of implantation into
and SC will thus significantly increase this area resulted in scarring and the choice of material
conventional outflow facility. may be of foremost importance, since it is not clear how
2. Increasing conventional outflow facility cicatricial processes can be modulated in this area.
will never result in abnormally low IOP
because of the resistance distal to SC.
3. Conventional outflow is segmental, and Relevant information from basic studies
maximal results will be achieved by on the nonconventional outflow pathway:
targeting the areas of higher outflow. 1. The suprachoroidal space has a pressure
4. Based on anatomical observations, these of approximately 4 mmHg.
areas are localized more frequently in the 2. Most of the resistance is within the ciliary
nasal inferior quadrants. muscle and may be bypassed by producing
5. There is no direct, clinical mean of a cyclodialysis cleft.
identifying such areas, but the presence of 3. Aqueous humor will easily exit the
pigmentation in the TM and areas of blood suprachoroidal space through the sclera
reflux within SC may assist in correct and will be reabsorbed by the choroidal
placement of draining devices. vessels.
6. Clinically, there are several potential 4. The choice of material may be important to
maneuvers that can help identify the guarantee long-term results .
location of the episcleral veins, and get
information concerning the presence of an 3. Avoiding the traditional way of
effective pumping mechanism.
7. The TM/SC/episcleral veins form a administering drugs
complex system with multiple potential
The chronic use of eye drops can cause persistent
interactions and a minimal disruption may
be beneficial. damage to the ocular surface with significant
symptoms,36-38 loss of compliance,39 and potentially
higher failure of bleb surgery.40 The use of drops is
a poor way of administering drugs because it is well
known that 50% of the eye drop is lost immediately diffuse peripheral anterior synechiae (PAS) and, more
after instillation, and up to 80% if reflex tearing is importantly, with neovessels.
considered. Of the compound reaching the cornea, less A precise identification of the angle structures is
than 5% will reach the aqueous humor and be pharma- less important for suprachoroidal devices because
cologically active. Several sustained-release devices the identification of the iris root is straightforward.
have been developed (e.g. contact lenses, punctal However, the relationship between the tilting of the
plugs, subconjunctival reservoirs), but the opportunity microscope and of the patient’s head is crucial for
of delivering the drug within the anterior chamber is viewing. The microscope head should be tilted towards
exciting because it will completely eliminate most of the surgeon’s head, while the head of the patient should
the problems of topical administration, provided the face in the opposite direction. It is usually suggested to
releasing window is sufficiently large. tilt the microscope head 30-40°, but this should just
be considered a suggestion because the angle formed
with the patient’s head is of greatest importance; the
4. TM visualization microscope may be tilted less — if the surgeon feels his
position is too awkward — provided that the head can
All ab interno minimally invasive glaucoma surgery be tilted more. On the other hand, the microscope head
(MIGS) procedures require some degree of angle visu- should be tilted more in patients who have problems
alization, but this is especially true with the trabecular/ turning their head.
SC ones, because a poor view is a serious obstacle Before entering the anterior chamber with the shaft
to the correct implantation and to inspection after carrying the device, it is always advisable to place the
implantation (Video 1). The trabecular MIGS need to be goniolens on the cornea and check that the best view
implanted in the TM and a precise knowledge of each has been achieved. Personally, I allow the patient’s head
patient’s anatomy is mandatory. Three major steps to be free of any constraint so that I can rotate it further
are suggested: a presurgical observation at the slit if needed, and before entering the operating room I
lamp with accurate gonioscopy, a correct placement inform patients of this eventuality so that they will hold
of the microscope and of the patient’s head, and some the final position required. Once the best possible view
dexterity in the use of a goniolens. is obtained, it may be important to magnify the angle
The study of each patient’s angle at the slit lamp more to achieve perfect focus (Video 2).
allows the surgeon to recognize and eventually draw Several intraoperative gonioscopes are available,
some specific landmarks, and to precisely identify either autoclavable or single use. The Hill gonioprism
the characteristics of the TM relative to the other developed by Ocular Instruments (Bellevue, WA,
structures. The use of a short and narrow beam inclined USA) has been on the market since the first introduc-
from the angle of the oculars in a dark room allows tion of this kind of procedure; it exists for right- and
one to identify two corneal reflections, which form left-handed surgeons and is autoclavable. It allows a
the corneal wedge and locate the anterior border of reasonable field of view and is in direct contact with the
the TM (for reference and for a complete set of images cornea, so the surgeon should place it without exerting
please refer to the Color Atlas of Gonioscopy41). Once the any pressure to avoid corneal striae, which will signifi-
area of the TM is located, it is recommended to note its cantly decrease visibility. To reduce the pressure on the
color, the presence of areas where some blood reflux cornea, the Vold goniolens (Volk Optical, Inc., Mentor,
or some pigment is present, because this can indicate OH, USA) has a ring that helps stabilize the globe over
areas where the segmental outflow may be particu- which the lens is floating, thus minimizing the pressure
larly active and therefore present a favorable location on the cornea. By pivoting the lens on the cornea the
for the implant. The entry into the anterior chamber relative angle of observation can also be changed,
may be modified to achieve better access to these reducing the need for microscope tilt. Nevertheless,
areas, especially when the device is implanted as a solo when used under local anesthesia, the patient can still
procedure. Similarly, a precise identification of the TM feel the teeth of the ring, which are pressing on the
at the slit lamp enables the surgeon to avoid cases with conjunctiva. The single-use Glaukos (San Clemente, CA,
USA) goniolens allows a wider field of view and easier

access to the surgical incision. The enhanced field of
view is advantageous because it allows the surgeon to
identify the areas for implantation without the need
for changing the angle of the goniolens, which may be
cumbersome for novices; the reduced magnification
can be compensated by the use of the microscope
(Video 3). The viscoelastic used for the procedure is Fig. 2. Dimensions and features of the G1 iSent. Image courtesy of
generally the preferred choice to couple the goniolens Glaukos Corp.
with the cornea, and there is no significant difference
in terms of visualization between different viscoelastic
materials. A sufficient amount of viscoelastic should be
used to avoid the formation of bubbles.
5. iStent
The Glaukos devices, iStents (also discussed in Chapters

1, 3, 6, 8, 17, and 21), are MIGS devices used to treat
open-angle glaucoma; they target trabecular outflow
(iStent and iStent inject) and uveoscleral outflow (iStent Fig. 3. The iStent inserter is held with the index finger on the
Supra). releasing button. Image courtesy of Glaukos Corp.
5.1. Technicalities inlet, the longer, pointed end facilitates entry into SC,
and the three retention arches secure its position. The
5.1.1. iStent device is produced in right- and left-eye versions.
The iStent device (generation 1 [G1]; Glaukos) is a stent The iStent design facilitates its implantation via
that connects the anterior chamber directly to SC.42-45 an ab interno approach, with the help of a surgical
By creating and maintaining a permanent opening gonioscopy lens. The device is most easily implanted in
between the anterior chamber and SC, the iStent inferior and nasal sectors, where the largest number of
bypasses the JCT, which represents the site of highest aqueous veins are located. The stent is positioned with
resistance to aqueous outflow. In 2012, the iStent was an applicator, which uses sliding 26-g stainless-steel
approved by the US Food and Drug Administration tubing over a smaller-diameter, laser-slotted tube that
(FDA) when combined with cataract surgery; it is CE holds the device via the snorkel. After implantation, the
marked both alone and in combination with cataract device is released by depressing a button (Fig. 3). Using
surgery in Europe. gonioscopy, the placed device can be visualized within
The device is made of medical-grade titanium SC and in the anterior chamber, promoting aqueous
(6AL4V) and is coated with Duraflo heparin to allow for outflow between these spaces.
self-priming. It is one of the smallest medical implants, The TM and SC have many functions, some of which
with dimensions of 1 mm in length and 0.3 mm in height. are not completely understood; however, as previously
It has an angular, pointed tip and arch-shaped retention discussed, one validated theory is the presence of a
ridges that continue on to a tubular inlet device, known pumping effect secondary to motion of the TM, which is
as the snorkel, with an inner and outer diameter of 120 induced by pressure changes from the cardiac cycle.28
and 180 μm, respectively (Fig. 2). The body of the iStent For this reason, when implanting surgical devices, it is
is arch-shaped so that the slit-like SC can be stented important to preserve the structural integrity of the TM
open and the posterior wall containing the collector in order to guarantee its dynamic abilities. Therefore,
channels tented maximally open. Perpendicular to the the iStent was designed to be only 1 mm long and not
Fig. 4. Dimensions and features of the iStent inject. Image courtesy

of Glaukos Corp.
to preclude any pumping mechanism. Fig. 5. Image showing the inserter of the iStent inject and its
releasing mechanism. Image courtesy of Glaukos Corp.
5.1.2. iStent inject
A second-generation (G2) model with a proper injector, the device, allowing it to be retained at the midportion.
the iStent inject, has been developed in order to After implantation, a small disc-like surface with a
facilitate device implantation (Fig. 4).46 While the G1 central canal will be seen in gonioscopy. The aqueous
iStent is a very useful device, its correct implantation inlet is along the central axis of the device, and there
requires a higher level of surgical know-how than the G2 are four exit points located posteriorly at a 90° angle to
model. The iStent inject has been designed to eliminate the main channel; they represent additional exit routes
the steps of lifting, sliding, and tapping necessary for from the central channel lumen, which is most likely
a successful implantation of the G1 iStent. The iStent occluded by the posterior wall of SC. Conceptually, this
inject device has been CE marked for use in Europe for device preserves the pumping function of the TM just as
both combination and standalone surgery, and was the iStent does.
recently approved (July 2018) for combination surgery
by the FDA. 5.2. Implantation: iStent and iStent inject
The iStent inject is an axially symmetric device made The essentials of visualization are common to both
of medical-grade titanium (6AL4V). It is 0.36 mm high, methods, as are some parts of the implantation
with an outer diameter that varies between 0.20 and techniques described below; nevertheless, part of the
0.23 mm. The main inlet and outlet diameter is 0.08 implantation is quite different between the iStent and
mm, whereas the side flow outlets have a lumen of 0.05 the iStent inject, which will be treated separately.
mm. Unlike the G1 stent, the G2 device is inserted via 1. Anesthesia: The implantation of both the iStent
an injector (Fig. 5) and driven in at high speed. A 23-g, and the iStent inject can be performed under
stainless-steel insertion sleeve covers the injector, either local or topical anesthesia. Topical
which is preloaded with two iStents, so two devices anesthesia has the advantage of allowing
can be injected without exiting the eye.47 During device the patient to rotate the eye into the proper
placement the stent is driven into and through the TM, position. Nevertheless, the area where the stent
which gets stretched up over the cone-shaped end of is implanted is rather small and there are several
important structures (e.g. endothelium, iris root) such cases. An alternative is to move the main
that must be avoided, which may be easier under cataract incision to the superior, temporal
local anesthesia. Therefore, topical anesthesia quadrant or superiorly and perform a temporal
is recommended for surgeons with some 1 mm incision for stent placement.
experience and with collaborative patients. 5. Combination surgery: The stent placement can
2. Viscoelastics: At the start of the operation, be performed either before or after cataract
the anterior chamber is filled with viscoelas- surgery. Implanting beforehand has the main
tic material. Healon GV (Johnson & Johnson advantage of having the best possible view, but
Surgical Vision, Inc., Santa Ana, CA, USA) is some blood reflux — which can happen due to
usually considered the best choice because pressure fluctuations — can disturb the view
it provides a good view of the angle, keeps during phacoemulsification. Implantation after
the spaces open, and is easily removed; when completion of phacoemulsification has several
implanted as a solo surgery, removal can be advantages: due to IOP fluctuations, SC will be
done by bimanual irrigation and aspiration, partly or fully filled with blood, indicating the
but can be equally achieved by simply washing best site of implantation. Nevertheless, when
the anterior chamber through the side port. the canal is completely swollen with blood, the
A second side port can be made in order to surgeon should try to implant precisely with
infuse through one side port and allow the vis- his first attempt since bleeding can occur and
comaterial to exit through the other to avoid an obscure the TM, making the second attempt
excessive rise of IOP during this maneuver. Other more difficult.
viscomaterials can also be used provided they 6. Insertion of the sleeve: Once the chamber is filled
are not dispersive; dispersive viscoelastics are with elastics, the sleeve should be passed across
more difficult to remove and can be responsible the eye and stopped close to the center of the
for postoperative IOP spikes, especially when anterior chamber. The best position of the sleeve
used in solo procedures and in phakic eyes. is in the center of the corneal incision. If it is very
Some surgeons do not fill the anterior chamber close to the side, the surgeon may risk moving
completely in order to maintain a lower IOP and the eye while trying to find the perfect site for
allow some blood to be present in SC to guide implantation or, if the pressure is marked, the
the insertion of the stent. However, a preoper- surgeon may risk the formation of corneal striae
ative study of the angle should be enough to and impede his own view. When using the side
guarantee proper identification of the area of port, it is advisable to open the incision slightly
implantation, and completely filling the anterior more (1.0-1.5 mm) to avoid this complication.
chamber guarantees an optimal view and a 7. Some viscoelastic is poured on top of the cornea
bigger space for maneuver in the angular region. and the goniolens is put in place. Minimal
3. Use of miotics: Miotics may be used but are pressure should be applied to the gonioprism to
not essential and do not significantly change avoid problems in the visualization of the angle.
the view of the angle. They are advisable, nev- 8. Once the angle is visualized, the tip of the sleeve
ertheless, if solo surgery in phakic patients is is advanced close to the TM. The preferred area
performed. of implantation is somewhat different between
4. Incision: In combination surgery, the main the iStent and the iStent inject, being the
temporal incision may be used, but the view of anterior TM for the former and the center of the
the angle may be impaired if a corneal edema is TM for the latter.
present. Hydrosuture of the main incision should
never be performed prior to stent implanta- 5.2.1. iStent: implantation tips and potential problems
tion because it may severely hinder the view There are two potential ways to implant the iStent:
of the angle. The Glaukos gonioprism uses a approaching the meshwork at a 15° angle or using a flat
more central corneal area and can be useful in approach (Videos 4a and 4b). For the first approach,
the TM is engaged at 15°, the tip of the iStent is passed positioned and the view is still suboptimal,
through the TM into SC until the tip encounters the further viscoelastic can be injected or, in extreme
back wall of the canal, and then the TM is gently pulled cases, the viscoelastic can be washed out and
while advancing the iStent tip until the snorkel reaches completely replaced, taking care to inject close
the TM incision. At this point, especially during the first to the insertion area first to remove as much
implants, it is important to relax completely all lateral blood as possible.
forces on the inserter and on the stent before pressing 3. Malpositioning: iStent implantation is a very
the release button. safe procedure; one of its major complications is
For the flat approach, the stent is advanced flat malpositioning. The stent can be placed insuffi-
until it is adjacent to the TM, which can even be gently ciently into SC, in which case one should tap on
dimpled. At this point, the iStent is tilted with an angle the snorkel to push the stent forward (Videos 7a
< 5°or just enough to raise the heel while engaging the and 7b). The stent can also be oblique and not
tip; then it is slowly advanced, engaging the tissue with tangential to the TM. The sleeve can be used to
the stent tip and sliding the stent under the TM and into push the stent forward, but if this maneuver is
the canal. This glide path should be continued until the ineffective, it is usually best to remove the stent
iStent is fully advanced and the stent snorkel meets the using the insertion sleeve and choose another
TM. site of implantation (Video 8a and 8b).
Whatever the insertion method, it is advisable to 4. Losing the stent: The stent can be lost from the
check its correct position by tapping the stent (Videos injector in the anterior chamber. In this case, the
5 and 6a), checking that it is completely inserted, and stent can be retrieved using the insertion sleeve
that the snorkel opening is not perpendicular to the or vitrectomy forceps. If properly oriented, the
TM nor pointing towards the iris (Video 6b). If this is stent can be grabbed directly using the insertion
the case, gently tapping on the snorkel is sufficient to sleeve and reimplanted. It is infrequent to lose
remove the problem. the stent and not be able to visualize it again.
Nevertheless, it can happen if viscoelastic
Frequently encountered problems: material was injected after the stent was lost,
1. Excessive resistance can be encountered when which can displace the stent. If it is impossible
implanting the iStent, and forcing the implan- to visualize the stent — especially if the view is
tation may result in loss of view and even eye unobscured by blood — it may have got caught
rotation. Usually this problem is encountered in the iris tissue (more frequent with the iStent
when the implantation site is incorrect and inject). Titanium is highly biocompatible and
generally too anterior, which can happen in leaving the stent in the tissue will not cause any
eyes with multiple pigmentation lines (e.g. long-term problems.
Sampaolesi line). The stent should glide into 5. Misclassified angle: Although a proper angle
position without encountering any resistance; if evaluation is essential as pointed out previously,
resistance occurs, checking the implantation site the surgeon may have a patient on the surgical
will solve the problem. table with PAS. Synechiae can be removed
2. Bleeding: Profuse bleeding at the beginning of easily using a spatula or the insertion sleeve of
the procedure (i.e. when the tip of the stent is just the iStent inject — it is not advisable to use the
inserted) is a clear sign of a wrong site of implan- pointed tip of the iStent as it may cause some
tation (too posterior, digging into the iris root). bleeding — and the TM can be immediately
Blood may impair the view, making it impossible visible, especially if more viscoelastic is injected,
to check if the stent has been properly implanted. allowing a straightforward implantation.
Usually the injection of some additional visco-
elastic material in proximity of the area that
needs to be visualized should be sufficient to
displace the blood. If the stent is incorrectly
5.2.2. iStent inject: implantation tips and potential

problems
The iStent inject is inserted into the anterior chamber in
a similar manner as the iStent. The iStent inject comes
with an insertion sleeve (Video 9a and 9b), which has
to be retracted by pulling back the green button on the
injector, revealing the trocar within the shaft. The trocar
must be placed perpendicular to the TM and the surgeon
should dimple the tissue to see a small indentation on
the TM. The inserter side window allows one check that
the trocar is perpendicular to the TM. If the trocar is too
close to the inserter, the force transmitted by the firing
mechanism to the stent may be lessened.
The device is released by pressing on the black trigger
button, which shoots the stent into position; the trigger
button should not be released before pulling back from Fig. 6. Image of the iStent Supra, courtesy of Glaukos Corp.
the implanted stent and having checked that the stent
is correctly positioned (Video 9a and 9b). Releasing the 5.3. iStent Supra
button charges the injector with the following stent and The iStent Supra is the third generation (G3) Glaukos
if one needs to push the first stent forward one may risk device. It has been CE marked for use in Europe.46
shooting the second stent. The injector is then moved The device differs from precedent iStents through its
to a different position to implant the second stent. It has mechanism of action: it has been designed to target
been demonstrated that the iStent inject collects flow uveoscleral outflow; it is a suprachoroidal shunt that
from at least one clock hour on each side, so it would directs aqueous outflow to the suprachoroidal space in
be unwise to place the stents close to each other; it a controlled way (Fig. 6).
would be best to have at least two clock hours between The suprachoroidal space is a fascinating target for
the stents (Videos 10a and 10b). The stent is correctly the development of new surgical procedures for many
positioned when the flange of the stent is outside the reasons:46
TM. It is advisable to indent the TM only slightly for the 1. prostaglandins — the most effective topical,
first iStent and a little more for the second, because the hypotensive drugs — exert their effect by
firing force is higher at the first shooting compared to targeting this pathway;47
the second. Although it may seem difficult to implant 2. there is a negative pressure gradient that drives
correctly, usually a few trials are enough to get the aqueous humor in the direction of the supracho-
visual and tactile feeling to reach proficiency (Videos roidal space;48 and
11, 12a, and 12b). 3. a cyclodialysis cleft lowers the IOP.49
Frequently encountered problems (most have Consequently, iStent Supra represents a very promising
already been listed above): approach to lower IOP.
Malpositioning: The stent may be too superficial, The iStent Supra is made of polyethersulfone, which
and in this case, it is usually easy to rethread it into the guarantees favorable biomaterial interaction with
trocar and fire it again because the injector has four minimal fibrosis. Furthermore, it is curved to conform
firing opportunities. If the stent is too deep in the TM to the suprachoroidal space. The device is 4 mm long
it is almost impossible to retrieve it, so it is advisable with a lumen diameter that varies between 0.16 mm
not to press too strongly on the TM. If the stent is lost and 0.17 mm, while the outer diameter varies between
into the anterior chamber, it can be recharged directly 0.3 and 0.4 mm. Retention ridges are present on the
on the trocar within the anterior chamber or can be surface of the stent to hold it in place. The entry site
retrieved with vitrectomy forceps and recharged on the for implantation is not the TM, but rather the uveal
trocar outside the eye (Video 13). insertion site on the scleral spur.
Fig. 7. Schematic drawing of the iDose device. Image courtesy of Glaukos Corp.
5.4. iDose 50% of the control group (P < 0.001) reached an IOP ≤
The iDose is a minimally invasive, drug-eluting stent 21 mmHg at one year, which was the primary efficacy
that is implanted in the TM (Fig. 7). It is a titanium measure.50
implant (1.8 mm x 0.5 mm) with a drug reservoir and Recently, a systematic review by our group compared
an elution membrane for controlled release of a novel MIGS techniques, including iStents, alone or combined
travoprost formulation. By bypassing the cornea, the with cataract surgery, medical therapy, standalone
quantity of drugs necessary to achieve a definite effect cataract surgery, and other MIGS techniques.51
is reduced, which means a longer duration can be Furthermore, three randomized controlled trials
achieved. Compared with other slow-eluting anterior (RCTs) compared iStent implantation combined with
chamber implants, it has the advantage of an anchor cataract surgery with standalone cataract surgery
that keeps the device in place, reducing the potential in 266 patients. In one of these RCTs, by Craven et
risks of endothelial cell loss or damage to other anterior al., 52 medicated IOP data were reported and at one
chamber structures. The anchor may also facilitate year showed a mean change of 1.6 ± 3.0 mmHg in
exchange of the device upon drug depletion. the MIGS group, and 0.9 ± 3.3 mmHg in the control
group. The weighted mean difference (WMD) was -0.7
(95% confidence interval [CI]: -1.58, 0.18), in favor of
6. What we have learned during the past iStent surgery. The change in the number of glaucoma
years medications was 1.4 ± 0.8 in the MIGS group, and 1.1
± 0.8 in the control group, with a WMD of -0.3 (95% CI:
6.1. Efficacy of iStent devices: review of literature -0.52, -0.08), in favor of iStent surgery. The IOP-lower-
An increasing amount of literature has been published ing effect of the iStent remained stable over two years,
on the iStent and iStent inject in the last few years, less as well as the glaucoma medication reduction.
so on the iStent Supra and a minimal amount on the In an RCT by Fea et al., 53 medicated IOP data showed
iDose. The published results on the iStent and iStent a mean change of 3.1 ± 2.6 mmHg in the MIGS group
inject will be analyzed first, and due to the amount and 1.1 ± 2.9 mmHg in the control group at one year.
of literature, they will be subdivided according to the The WMD was -2.0 (95% CI: -4.04, 0.04), in favor of iStent
comparator. surgery. Unmedicated IOP data were also reported
and at one year showed a mean change of 1.7 ± 2.8
6.2. iStent vs cataract surgery mmHg in the MIGS group, and 1.7 ± 3.6 mmHg in the
The pivotal trial for iStent FDA approval in the USA control group, with a WMD of -3.4 (95% CI: -5.74, -1.06),
involved 240 eyes randomized to receive one iStent in favor of iStent surgery. The change in the number of
during cataract surgery or cataract surgery alone. glaucoma medications was 1.5 ± 0.8 in the MIGS group
The study showed that 72% of the treatment group vs and 0.8 ± 1.0 in the control group; the WMD was -0.7
(95% CI: -1.35, -0.05), in favor of iStent surgery. 2.2 mmHg in the iStent and medication group, respec-
In an RCT by Fernandez-Barrientos et al., 54 IOP data tively. The WMD was -0.60 (95% CI: -1.25, 0.05), in favor
were reported as unmedicated and medicated values of iStent surgery.
at baseline and one year after double iStent surgery. In an RCT by Vold et al., 59 54 naïve eyes were
The mean change in IOP was 6.6 ± 3.0 mmHg in the MIGS randomized to double iStent implantation and 47
group and 3.8 ± 2.7 mmHg in the control group, with eyes to medical therapy (prostaglandin). The authors
a WMD of -2.8 (95% CI: -4.75, -0.85), in favor of iStent found a greater IOP reduction in the iStent group (11.8
surgery. In the systematic review mentioned above, 51 ± 2.65 mmHg) than in the medication group (11.2 ± 4.4
meta-analysis was performed considering the studies mmHg), with a WMD of -0.60 (95%CI: -2.05, 0.85).
by Craven et al. and Fea et al. with moderate hetero- Implantation of two iStents caused a slightly larger
geneity (24.3%). The WMD was -1.01 (95% CI: -2.1, 0.08; reduction in IOP compared to medical therapy, with
P = 0.07), suggesting an advantage of iStent compared a WMD of -0.60 (95% CI: -1.23, 0.03), I2 = 0.0%, and
to cataract surgery, but this estimate was imprecise P = 0.060; however, this benefit was modest and the
and the 95% CI showed no difference. 95% CI revealed no difference. Nevertheless, these
Results with the iStent inject seem to be comparable studies support the idea that the implants can be as
to the iStent. A multicenter, prospective RCT55 included effective as drugs in lowering IOP.
121 mild to moderate glaucoma patients with IOP
≤ 24 mmHg; they underwent either implantation of 6.4. iStent vs other MIGS procedures
two iStent inject devices with cataract surgery or In an RCT by Katz et al.,60 38 subjects received one
standalone cataract surgery. At one year, 72% of the stent, 41 subjects received two stents, and 40 subjects
MIGS group had an IOP ≤ 18 mmHg vs 24% of controls, received three stents. One year later, a greater efficacy
while at two years 68% of the MIGS group and 24% of of two vs one iStents was confirmed, with mean
the control group achieved the IOP goal. The efficacy differences in IOP reduction of 1.90 mmHg (95% CI:
of iStent implantation has recently been confirmed by 1.18 ± 2.62). Greater IOP lowering resulted after the
a study evaluating the reduction of topical hypotensive implantation of three iStents, with mean IOP change
agents in a cohort of patients from a US managed-care of 8.2 mmHg from baseline, compared to 5.4 mmHg
network.56 Of the patients who underwent combined after implantation of one iStent. Considering washout
cataract surgery, 73,5% were medication free at 20-24 IOP, the difference in reduction between one and two
months compared to 55.3% of those who underwent iStents was 1.30 mmHg (95% CI: 0.38, 2.22), in favor of
cataract surgery alone. Sustained reduction in two iStents. The number of medications was reduced
medication use was more likely in patients receiving by 1.60 in the one-iStent group, 1.64 in the two-iStent
at least three medications at baseline. In patients group, and 1.43 in the three-iStent group. These
with combined-mechanism angle-closure glaucoma, results have recently been updated with a 42-month
a recent study reported a similar efficacy for iStent follow-up, which is one of the longer follow-ups for this
implantation combined with cataract surgery as type of procedure, confirming an incrementally greater
obtained in open-angle glaucoma patients.57 and more sustained reduction in IOP and medication
in multistent eyes.61 The implantation of multiple
6.3. iStent vs medical therapy iStents is favorable because it provides the possibility
An RCT by Fea et al.58 involved 94 eyes in the double of addressing more collector channels.
iStent implant group and 98 eyes in the medication There is a lack of studies comparing different
group (i.e. beta-blocker in combination with pros- procedures. A single, retrospective study comparing
taglandin). The medicated IOP change was 8.1 ± 2.6 cataract surgery with a single iStent or with goniotomy
mmHg in the MIGS group and 7.5 ± 2.2 mmHg in the — performed with the Kahook Dual Blade (KDB) —
98 eyes on medical therapy. The WMD was -0.60 (95% reported more favorable results, both in terms of IOP
CI: -1.29, 0.09), in favor of iStent surgery. Considering and medication reduction, for the latter. However, this
baseline washout IOP values, IOP changes showed study is somewhat flawed by the fact that it is nonran-
reduction in both groups: 12.2 ± 2.3 mmHg and 11.6 ± domized, retrospective, and with a short follow-up of
Fig. 8. Absolute IOP reduction of the iDose at different time points for fast elution (blue), slow elution (orange), and topical timolol 0,5%
(grey). Image courtesy of Glaukos Corp.
only six months. Considering the width of TM excised 6.6. iStent Supra
by the KDB, a comparison with two iStents would Few papers have been published on the iStent Supra.
be more justified. A study comparting the efficacy The implantation of the iStent Supra as the sole
of two iStents with the Hydrus SC scaffold has been procedure in 40 patients with POAG, uncontrolled on
completed, but the results are not yet available. two medications, resulted in an IOP decrease from a
mean preoperative level of 20.8 ± 2.2 mmHg to 13.8
6.5. Predictability of trabecular device efficacy ± 3.6 mmHg at 12 months, with a net reduction of
One of the major limitations of the iStent and iStent one topical medication.65 A recent report66 provided
inject is the great variability in IOP reduction reported information up to four years of patients with prior failed
both in the literature and in clinical practice. Intra- trabeculectomy who underwent the implantation of
operative methods to detect the best locations for two iStents and one iStent Supra. All patients were on
the device may be interesting, but are of limited use a single medication (travoprost) post operation. The
as the information is obtained under nonphysiologi- authors reported that more than 91% of the eyes had
cal conditions. The infusion of fluids into the anterior an IOP decrease of more than 20% at all postoperative
chamber during surgery may potentially open outflow visits, and that at four years 97% and 98% had an IOP ≤
channels that are not functional in physiological 15 or 18 mmHg, respectively.
conditions.62 The use of the episcleral fluid wave63 as
a predictive marker for iStent success, although 6.7. iDose
clinically attractive, needs more validation and is highly The iDose data are only preliminary and provided by
subjective. Furthermore, the episcleral fluid wave is Glaukos. In a 12-month study using two drug-eluting
potentially subject to confounding factors, such as systems — i.e. slow and fast — both achieved a 32%
administration of drugs increasing the aqueous humor IOP reduction compared to baseline, with a consistent,
outflow, hemodynamic factors, patient anxiety, or absolute reduction of IOP: 7.9 and 8.2 mmHg for the
caffeine intake. In vivo visualization of SC and some of slow and fast elution systems compared to baseline,
the distal outflow pathway may be easily obtained with respectively (Fig. 8). The comparator was timolol, which
diffusing eye drops (i.e. drops containing indocyanine), achieved 7.6 mmHg absolute IOP reduction (30%) at 12
and this approach may need further attention.64 months. In this preliminary study, no serious adverse
intraocular events were reported and patients had no
hyperemia in either treatment arm. The iDose is not
approved by the FDA but has the CE mark and several 7.3. iDose
studies are underway in Europe and the USA. The iDose safety information is limited to a single study
and the safety data are reported in the section above.
7. Safety
8. Economic outcomes: cost of treatment
7.1. iStent and iStent inject and cost-effectiveness
iStent devices have proven to have a good safety profile,
with a small number of expected adverse effects. The Economic evidence suggests that iStent implantation
number of complications observed is missing in some and follow-up costs are higher than trabeculectomy
studies, but is minimal whenever reported. In particular, costs, but the incremental cost-effectiveness of these
there are no reports of infection or reduced best-cor- implants remains unknown.71 As part of the Manchester
rected visual acuity.51 Few cases of hyphema have been iStent study, Tan et al. reported that in 36 patients
reported for iStents,67 which is not surprising and is in who completed the 3-year follow-up, the overall cost
some ways considered as proof of correct implanta- of combined iStent implantation and cataract surgery
tion. Furthermore, the hyphema is usually minimal and was £829.32 more than conservative management with
limited in time. branded eye drops, and £14,176.90 more compared to
Other adverse effects reported with the iStent the use of generic drops.72
include stent malpositioning or occlusion early in the Considering the limited, available evidence on the
postoperative period, affecting 2.6-18.0% of cases, cost-effectiveness of MIGS as primary interventions for
without significant sequelae. However, studies have not glaucoma, it is still unclear whether the cost of using
provided details about the qualifications for malposi- MIGS is outweighed by cost savings through decreased
tioning, nor a specific protocol for determining whether medication and need for further interventions.73
intervention was necessary. Across all studies, malpo- Moreover, the few available studies are retrospective
sitioning and occlusion necessitated surgical interven- case studies or industry-sponsored RCTs with short
tion in 4.5-11.3% of study subjects.51 follow-up times.74
Corneal erosion has also been reported in one study, In a study by Iordanous et al.,75 medical management,
attributed to repeated intraoperative gonioscopy.68 standalone cataract surgery, and cataract surgery with
IOP spikes constituted another reported adverse event iStent implantation were compared over five years in
(1.1-10.1% in solo procedures, 0.0-21.0% in combined patients with cataract and glaucoma but inadequate-
procedures).69,70 Less common events reported51 ly controlled IOP (with two medications). The study
included: anterior chamber collapse during phacoemul- used a Markov model and a public third-party-payer
sification (2.1%); vitreous wick incarceration (2.1%); perspective (Ontario Health Insurance Plan). Compared
posterior, capsular opacity (4.3%); and presumed ste- with medical management, the incremental cost-effec-
roid-related IOP increase (3.8%). Reports of complica- tiveness ratio (ICER) of iStent combined with cataract
tions with the iStent inject are similar to those reported surgery was CAD $6824/quality-adjusted life year,
with the G1 iStent.51 compared with $4179/quality-adjusted life year (cost
year not stated) for cataract surgery alone.
7.2. iStent Supra Recently, more favorable results have been published
The reports of complications with the iStent Supra comparing two trabecular microbypass stents vs
are very limited. No significant complications were selective laser trabeculoplasty (SLT) or medications
reported in one study.66 Nevertheless, implantation only in patients with open-angle glaucoma.76 A major
into the suprachoroidal space may carry significantly limitation of this paper is that it relies on clinical-ex-
more risks, which may appear once this kind of device is pert-panel opinion and would benefit from real-world
applied on a larger scale. Thus, the iStent Supra should evidence. Similar results were reported in a study
probably be reserved as a second-line treatment in the performed in Colombia.77 Finally, cost-effectiveness is
MIGS algorithm. obviously very dependent on the costs of medications
or alternative procedures in different countries; this due to pseudoexfoliation may be a potential risk for
is particularly evident in Europe where the cost of occlusion in the long term.
treatment may vary considerably. There is some speculation and a single paper78
suggesting that trabecular devices may be useful in
failed trabeculectomy patients. Our experience in this
9. Personal opinion and understanding: subgroup is minimal, but it has always been disappoint-
next steps ing in the long term. Special subtypes of such patients
— e.g. patients minimally over target IOP — may benefit,
Both the literature and the authors’ personal experience but the diversion of outflow from the natural pathway
suggest that the trabecular devices iStent and iStent is a potential protracted stimulus for occlusion, and
inject are the safest and least-invasive form of surgery further studies should carefully report the patient char-
for glaucoma, even considering other MIGS procedures. acteristics and be watchful of potential bias. The same
In our opinion, the best candidate still remains the holds true for closed-angle patients; a single study
patient with mild to moderate glaucoma. To avoid any has been published.57 From our personal experience,
confusion, the definition of mild to moderate glaucoma it can happen that one operates on patients that
should be tailored to the patient’s target pressure. One have been misclassified: the manual reopening of the
is unlikely to achieve IOP lowering below 16 mmHg with anterior chamber with successive stent implantation
a single stent and no adjunctive medical therapy. has provided generally significant reductions of IOP,
The use of two stents is always suggested because but all cases were either pseudophakic or underwent a
the chances of achieving better IOP control are combination surgery, and their long-term data are not
maximized: the problem of slight malpositioning of yet available.
one stent will not preclude the effect obtained by the Considering the well-known damage of the ocular
other one; the chances of implanting into an area with surface caused by topical medications and the
high flow are optimized; even in the event of a perfect problem of compliance, the use of trabecular stents as
placement in the best outflow area, different parts of substitutes for some or all medical therapy is an issue
the TM may be working differently during the day or that deserves further consideration and more real-
throughout the year; and in the event of an occlusion, world evidence. At present, this kind of procedure is
it will be unlikely that both stents will be occluded. limited to non US nations and is certainly a possibil-
Furthermore, the final IOP may be lower than 16 mm ity in patients with low tolerance to topical drugs or
in some the patients. Although patients with controlled whenever compliance may not be guaranteed. In this
open-angle glaucoma may benefit from the implan- respect, the slow iDose implant presents a potential
tation of trabecular stents, the reduction of pressure alternative. The success of this device will largely be
in these cases is usually minimal, as predicted by the determined by the duration of elution; the available
IOP equation described in p. 120, and should probably data are still preliminary. The introduction of new
be limited to patients with medication intolerance or compounds that influence episcleral venous pressure
compliance issues. may also have a beneficial effect on trabecular proce-
One of the major issues with the trabecular outflow dures. A general problem is the cost of such devices
system is the lack of a clinically reliable way of compared to medical therapy. Furthermore, in Europe
identifying the best implantation areas; equally, it is the absence of a common regulatory framework may
impossible to exactly predict the results that may be determine different standards of care in different
achieved in a single patient. Although a lot of data has countries.
been accumulated over the last few years, there is still Studies on patient acceptance of a surgical procedure
no evidence to determine if this type of device is more (although minimal and with minimal or no complica-
effective in some glaucoma subtypes. Patients with tions) are also warranted. Although a paper79 comparing
some trabecular types of glaucoma may potentially be a SC scaffold vs SLT demonstrated the superiority of the
the best candidates for iStent procedures. However, the former, other studies that include patient acceptance
continuous release of debris into the anterior chamber and quality-of-life measures are needed. We still believe
that suprachoroidal devices, although the simplest to to investigation and at present relies on the surgeon’s
implant, should be used as a second-line therapy. The perspective and expertise as well as the patient’s
issue of endothelial cell loss has recently been raised wishes.
by a similar device (CyPass), which as a result it is no We personally believe that the failed diffusion and
longer available, but other problems may be related acceptance of trabecular devices is partially due to the
to long-term hypotony and lack of efficacy. Although misconception that this type of MIGS will be effective in
no such adverse events have been reported in the few reducing IOP to the low teens, and to the comparison
studies available on the iStent Supra, some caution is with much more aggressive types of surgeries, such
still warranted. as trabeculectomy. This is not the scope of trabecular
Since the introduction of the Glaukos devices, devices; the people who are affected by moderate forms
new MIGS procedures have been brought to market of glaucoma numerically outweigh the ones who need
and some of them rely on bleb formation. One of the a massive decrease in IOP, and a great proportion of
original claims of MIGS procedures was to preserve the them would benefit from minimally invasive surgery or
conjunctiva for potential further surgery. Subconjuncti- the implantation of long-term, drug-releasing devices.
val devices should be again considered in patients with If compared with other procedures, the costs are
a more severe phenotype and have to be compared certainly an issue and more cost-effective, comparative
mainly to trabeculectomy as far as IOP reduction is studies should be designed. Our personal opinion is
concerned. Obtaining similar levels of postoperative that one of the greatest needs of the clinician is to have
IOP with less invasive surgeries, even at the cost of a reliable method for choosing the best candidates for
continuing some medical therapy, should be subject this type of surgery.
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684.
10. Ab interno trabecular meshwork incision,
ablation, and disruption
Hamed Esfandiari1, Si Chen2, Ralitsa T. Loewen2, Susanna Waxman2, Kevin Kaplowitz3, Nils A. Loewen4
1
Department of Ophthalmology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; 2Department
of Ophthalmology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; 3Department of Ophthalmology,
Health Sciences Center L2, New York, NY, USA; 4Department of Ophthalmology, University of Würzburg, Würzburg,
Germany
Abstract 1. Introduction
Ab interno disruption and ablation of the trabecular Among microincisional glaucoma surgeries (MIGS), the
meshwork (TM) increases outflow at the level of the disruption and ablation of the trabecular meshwork (TM)
juxtacanalicular TM and the inner wall of Schlemm’s from ab interno is an attractive initial approach because
canal (SC). This resistance was mostly bypassed by it eliminates the primary pathology, a decreased outflow
external glaucoma surgeries in the past (i.e. trabe- facility at the level of the juxtacanalicular TM1,2 and the
culectomies and tube shunts). Recent studies have also inner wall endothelium of Schlemm’s canal (SC).3 The
validated the use of ab interno TM disruption in more TM has a unique developmental origin, the neural crest,4
advanced glaucoma and additional types of glaucoma. while SC is a lymphatic-like vessel.5 These structures are
Techniques and instruments discussed in this chapter the Achilles heel of ocular pressure homeostasis despite a
include: trabecular incision in classic goniotomy; remarkably small size and seemingly basic function with
trabecular ablation using the Trabectome; trabecular minuscule fluid movements of no more than 2.5 to 3.0 μl/
excision using the Goniotome; Goniotome with irrigation minute.6 Both were estimated in the past to be respon-
and aspiration; the Kahook Dual Blade; trabecular sible for about 75% of total outflow resistance.7–9 At the
disruption by endoscopic laser trabeculotomy; the level of the TM, extracellular myocilin10 and other extra-
Tanito microhook; and catheter or suture-assisted cellular matrix material11,12 can reduce flow. In glaucoma
transluminal trabeculotomy. The concept behind each and with age, both the TM13–15 and SC have a reduced cel-
procedure is discussed first, followed by the methods lularity,16 increased stiffness, and decreased propensity
and pearls that we have developed over several years to to form pores, among other notable changes.17
excel at each of them. A literature review is provided to While in the past this hindrance to outflow was mostly
evaluate and summarize the efficacy and safety of each bypassed by conventional glaucoma surgeries (trabe-
procedure and its place compared to other MIGS. culectomies and tube shunts),18–22 advances in microen-
gineering have provided new tools for a gentler yet faster
Keywords: ab interno trabeculectomy, goniotomy, approach that improves the physiological outflow route.
Kahook Dual Blade, Trabectome, trabeculotomy These newer MIGS were primarily intended to fill the gap
between medications and conventional filtering surger-
ies, but recent studies have validated their use also in
more advanced glaucoma and additional types of glau-
coma.23–27
Correspondence: Nils A. Loewen, MD, PhD, Josef-Schneider-Straße 11, 97080 Würzburg, Germany.

138 H. Esfandiari et al.
Techniques and instruments discussed in this chapter to hold the goniolens and focus on maximizing the
include: trabecular incision in classic goniotomy used goniotomy and on not allowing the corneal incision to
in pediatric glaucoma,28,29 trabecular ablation using gape. This setup was dictated by historic restrictions
the Trabectome30 (NeoMedix, Inc., Tustin, CA, USA), that required reusable surgical instruments and a lack
trabecular excision using the Goniotome31 (NeoMedix, of ophthalmic surgical microscopes, AC maintainers, or
Inc.) or the Kahook Dual Blade (KDB, New World viscoelastics.
Medical, Rancho Cucamonga, CA, USA),32 as well as Performed this way under topical anesthesia as by
trabecular disruption by ELT, Tanito microhook (Inami Barkan,43 the procedure places considerable demands
& Co. Ltd, Tokyo, Japan),33 and catheter or suture-as- on the surgeon but can now be performed more easily
sisted transluminal trabeculotomy (also called gonios- with a surgical microscope, bright coaxial illumination,
copy-assisted transluminal trabeculotomy [GATT]).34 and disposable hollow needles or goniotomy knives that
can be connected to an irrigation system to maintain
the chamber. A microvitreoretinal (MVR) blade or similar
2. Trabecular incision: goniotomy instrument under viscoelastic can also be used.44
Locking toothed forceps are placed posteriorly on the
2.1. Principle and history vertical rectus muscle insertions to avoid distortion of
Goniotomy can be seen as the earliest form of micro- the cornea, and to enable a slight elevation of the eye
incisional glaucoma surgery, requiring only a goniolens and cornea away from the lid margins to facilitate entry
and a goniotomy knife. It was introduced by Otto Barkan of the goniotomy knife through clear cornea adjacent to
in 1936,34 who defined the procedure as an “operation the limbus.45 The tip of the goniotomy knife is inserted
for the relief of that form of chronic glaucoma which into the mid-TM and incised over 120-180° (Fig. 1).46
is characterized by an open angle and normal depth
of the anterior chamber.”35 He termed it already then 2.3. Results
a “micro-surgery for chronic simple glaucoma.”36 The Barkan operated on 76 eyes and achieved success (IOP
surgeon creates a linear incision of the TM and the inner ≤ 21 mmHg at 3 months) in 87% of cases with a 29%
wall of SC for a direct conduit between the anterior reoperation rate over an average follow-up period of
chamber (AC) and SC. Some pediatric goniotomists 4 years.43 It remains one of the most widely used surgical
maintain it is possible to so precisely judge and maintain methods for congenital glaucoma due to its efficacy
the depth of the blade that only the TM and not the inner and low complication rate,47 especially in younger
wall of SC is incised, which produces an IOP reduction.37 patients who often have more aggressive fibrosis.37,48,49
This has been interpreted as the substrate of the hypo- Goniotomy has also been used in juvenile open-angle
thetical38,39 Barkan’s membrane.40 A discussion of the glaucoma (JOAG),37 uveitic glaucoma,50 steroid-induced
indications, methods, and results of pediatric glaucoma glaucoma,51 Sturge-Weber syndrome,52 and aniridia
management is well beyond the scope of this chapter; glaucoma.53,54
interested, readers should consult a textbook on the
topic.41,42 What follows is a brief review of goniotomy as 2.4. Conclusion
a predecessor of modern MIGS. Goniotomy is a first-line procedure for congenital and
infantile glaucoma.55 In such young patients the scleral
2.2. Method spur is quite elastic and the goniotomy knife causes “an
The traditional goniotomy knife is an elegant instrument immediate downward movement of the iris root, and
with a flat tip that has a blade edge on one side, which the appearance of SC,”56 thereby keeping the anterior
allows it to pass directly through the clear cornea to and posterior lip of the TM apart. The scleral spur is more
then deliver the cut in the angle. In experienced hands, rigid in adult patients and can cause a reapproximation
it is possible to complete the procedure without an of the bisected TM as described after mechanical TM
AC maintainer or viscoelastic device. In traditional disruption by trabeculotomy.8 Peer-reviewed evidence
goniotomy, an assistant rotates the eye counter to that goniotomy does not work as well in adults is scant.
the direction of the incision, which allows the surgeon Its reduced use might simply reflect a trend towards
Ab interno trabecular meshwork incision, ablation, and disruption 139
Fig. 1. Goniotomy, a microincisional glaucoma surgery introduced by Otto Barkan in 1936, shown here with a pass toward the right
bisecting the TM (goniolens not shown). Figure adapted from Barkan.29
increasing subspecialization among providers. To make goniectomy instrument58 and consists of a disposable
it more effective, Dr. Scheie introduced goniopuncture, 19.5-g handpiece with bipolar electrodes that operate
the result of accidental perforation of the outer wall of at 550 kHz and a power of 0.8-1.2 W to generate an
SC with the formation of a filtering bleb.57 His success approximately 50-micron plasma bubble that molecu-
rate of goniopuncture combined with goniotomy larizes the TM and the inner wall of SC.
was 76%, compared to goniopuncture at 52% and A key feature of the handpiece is a ramping footplate
goniotomy at 57%. that lifts and slightly stretches the TM to position it
for ablation.60 The TM can then be molecularized and
aspirated without drag.30,61 Due to the collapsible nature
3. Trabecular ablation and excision: of plasma, the heat dissipation is mostly confined to
Trabectome, Goniotome, Goniotome the space between the electrodes and does not exceed
1.2oC at the level of the outer wall of Schlemm’s canal,60
with irrigation and aspiration, KDB, and
which distinguishes it from cautery. Active irrigation
others and aspiration maintain the AC. Progressive steps of
irrigation, aspiration, and ablation are controlled with
3.1. Trabectome surgery: trabecular ablation the foot pedal. Continuous irrigation can be engaged
by a switch on the socket of the foot pedal. Upon first
3.1.1. Principle depression of the pedal, irrigation is started followed
The Trabectome is the result of National Institutes of by nonlinear aspiration (adjustable via the peristaltic
Health (NIH) funded research (R44-EY015037; Small pump setting up to 10 ml/minute) and ablation that is
Business Innovation Research (SBIR)); it was developed accompanied by an audible indicator (Fig. 2).
to address the problems of reapproximating TM lips Since the Trabectome has the most data on adults
after goniotomy and trabeculotomy (discussed below) of all the devices described in this chapter and many
in adult patients. It was described 15 years ago by of the devices share a similar setup, the perioperative
Baerveldt and Chuck58 and approved by the US Food care and initial surgical steps will be explained here in
and Drug Administration on February 9, 2004, for greater detail. Similar to cataract surgery, the surgeon
the treatment of adult and pediatric glaucoma.59 It sits at the temporal side of the patient. A right-hand-
represents the refinement of a mechanical dual-blade ed surgeon creates a left paracentesis, applies intra-
Fig. 2. (A) The Trabectome system with handpiece and tip (inset). (B) Plasma-mediated ablation of TM with the Trabectome tip removes
nearly the entire TM. This prevents reapproximation seen in other MIGS and exposes the outer wall of SC with its collector orifices.
(C) Electron microscopic view of the TM (left) and the outer wall (right). (D) Hematoxylin and eosin-stained sagittal section of the unablated
(left) and ablated (right) TM. Images courtesy of Neomedix, Inc.
cameral lidocaine and fashions a right-sided 1.7 mm approximately 240-300° of outflow structures because
clear corneal incision as for cataract surgery. This of additional flow beyond the ablation endpoints.63
incision is approximately 2 mm anterior to the limbus — Once the ablation is completed, viscoelastic is injected
more anterior than in cataract surgery or traditional along the ablation arc to minimize reflux, clotting at
goniotomy — planar to the iris, and slightly flared on the the ablation site, and hyphema. The typical postoper-
inside to prevent corneal striae when the instrument ative regimen follows that of phacoemulsification and
is moved along the ablation arc. Since there is active consists of a fourth-generation fluoroquinolone four
irrigation and aspiration, no viscoelastic is required. times a day for a week and steroid eye drops for at
In fact, viscoelastics are discouraged because they least one week. Glaucoma drops are typically stopped
obscure the ablation target by creating different optical following surgery. Although Trabectome surgery is
interfaces and can cause carbonization and decreased highly effective in steroid-induced glaucoma,64 some
function of the electrodes. Tilting the patient’s head patients are steroid sensitive despite ablation of the
30-45° away while tilting the microscope 30-45° toward TM. Therefore, standard steroid eye drops (e.g., pred-
the surgeon improves the gonioscopic view. The angle nisolone) and short-acting, intracameral steroids
can be visualized with a modified Swan-Jacob goniolens should be used with caution, while subconjunctival
(Ocular Instruments, Bellevue, WA, USA) provided by depot steroids (e.g., triamcinolone) should be avoided.
the Trabectome manufacturer. Inducing reflux of blood Some surgeons prefer loteprednol or nonsteroidal
into SC by tapping on the posterior lip of the corneal antiphlogistic eye drops. The amount of inflammation
incision can help identify the ablation target. This after Trabectome surgery is relatively low compared to
lowers the risk of accidentally engaging the ciliary body standalone cataract surgery, allowing for a rapid taper:
band instead of the TM, which can be difficult to see if from four times per day for one week, three times per
not pigmented. day for one week, twice a day for one week, and once a
Under direct visualization, the tip of the instrument day for the final week.65–67 Pilocarpine 1-2% four times
is pointed up at a 45° angle to pierce into SC. This can daily is often used for one to two months to reduce
be achieved more easily if the Trabectome is inserted the incidence of peripheral anterior synechiae (PAS),
into SC slightly off to the left instead of directly across but the one study that actually analyzed its efficacy
from the clear corneal incision; it is then advanced found that pilocarpine did not affect the outcome on
parallel to the canal. The tip moves without significant average.68
resistance when inserted properly. Surgeons should
avoid pushing outward during ablation against the 3.1.2. Results
outer wall to prevent damage to the endothelium Originally, the Trabectome was described for use
and collector channel orifices because of the adverse in eyes with open-angle glaucoma to assure the TM
healing response this triggers.62 Rotation of the eye in could be easily engaged.60 However, later studies
the direction of the ablation indicates that the tip of the showed its safety and efficacy in a wide range of
footplate might be caught in the outer wall of SC, the glaucomas, including pseudoexfoliation,69 uveitic,69
cornea, or the ciliary body band. pigmentary,27 steroid-induced,64 and angle-closure
The first 60° can be ablated continuously without glaucoma.70 Trabectome surgery is also effective in
adjustments, and an additional 30° can be completed eyes that have failed tube shunts or trabeculecto-
by progressive supination of the right wrist and coun- my.71,72 Eyes with narrow angles have similar outcomes
terclockwise rotation of the gonioscopy lens in the to open angles, regardless of same-session cataract
direction of the ablation. The tip is then disengaged surgery.70 Advanced glaucoma may not be a contra-
and rotated 180° counterclockwise to avoid hitting indication since more severe glaucomas experience
the cornea. The tip is inserted into SC at the origin of the a larger IOP reduction.73–75 While Trabectome surgery
ablation now pointing into the opposite direction to the can avoid the potentially sight-threatening complica-
right. Ablation is continued in the opposite direction. tions of traditional glaucoma surgery, surgical failure in
With practice, a total of 180° can be ablated through a advanced glaucoma is a risk in itself. The magnitude of
single clear corneal incision. This can provide access to IOP reduction is limited by the downstream resistance
comprising collector channels, intrascleral plexus, and complications, such as endophthalmitis and retinal
episcleral veins. Even though the theoretical floor for detachment, are uncommon and have a similar rate as
postoperative IOP is the episcleral venous pressure cataract surgery.24
(EVP) near 8 mmHg, a common longer-term average IOP Most Trabectome studies used IOP as the main
after Trabectome surgery is 16 mmHg.24 If normal-ten- outcome measure. The success criteria, based on the
sion glaucoma is treated, additional medications will Tube versus Trabeculectomy study,82 consisted of IOP
likely be needed to achieve the desired target IOP. ≤ 21 mmHg, with a 20% decrease from baseline and no
Trabectome surgery may still be helpful in normal-ten- reoperation. The Data Safety Monitoring Committee
sion glaucoma since IOP peaks often occur at night76,77 aborted the only randomized controlled trial comparing
causing accumulative, progressive damage. Conditions Trabectome combined with cataract surgery to tra-
with a high EVP may fail to respond. Active neovas- beculectomy combined with cataract surgery due to
cularization of the angle is thought to be an absolute similar IOP reductions and low patient enrollment.83
contraindication because the outer wall and collector Analysis of a post-market surveillance database,79,84–86
channels are often blocked as well. used to certify new surgeons, found a 26% IOP reduction
The most commonly reported postoperative obser- 7.5 years after surgery with a success rate of 60% on
vations are microhyphema and hyphema.24 They 1.6 drops.86 This is remarkable as the database contains
indicate a patent outflow tract and so may not be the first 20 surgeries of Trabectome surgeons who are
considered as a complication. The reported incidence still well on the learning curve.87 Other studies showed
of late hyphema (occurring two months to two years an approximately 35% reduction to a final IOP around
later) is 5%.78 PAS, adhesions between the iris and 16 mmHg.24,78,88 Our five-year data from a single surgical
angle, are the second most common observation center with experienced Trabectome surgeons found a
reported in 24% of patients, but do not appear to be higher success rate of 68%.78
a risk factor for failure.79 Transient IOP spikes above 10 The most consistently reported risk factor for failure
mmHg were more frequently seen in 4-10% of cases.80,81 is a lower baseline IOP that is possibly due to a floor
Unlike conventional surgeries, Trabectome surgery is effect (Table 1).24,89 Younger patients are at a higher
not associated with cataract progression.21,22,24 Serious risk of failure.24,90 A predictive surgery calculator67
Table 1. Risk factors for Trabectome failure
Variable Effect Comment
Low baseline IOPs associated with decreased IOP Preoperative IOPs of > 30mmHg: 48% IOP
reduction reduction
Baseline IOP
Higher baseline IOP associated with increased IOP IOPs 23-29 mmHg: 33% IOP reduction
reduction24,67,85,89,179 ≤ 17 mmHg: 7% IOP reduction24,89
Age correlated to larger IOP reduction67
IOP reduction increased by 0.03 × age
Age Younger age associated with increased risk of
(years)67
failure 24,90
Thicker cornea associated with increased risk of

Central corneal thickness
failure78
Neutral78 to greater IOP reduction with more IOP reduction increased by 0.09 ×
Medications
medications at baseline67 medications67
Secondary open-angle glaucoma Associated with greater IOP reduction78,89,91–93
Axial length Neutral24,90,78
Prior SLT Neutral180
One-year cumulative probability of
success was 81% in Trabectome and 87%
Prior traditional glaucoma surgery Neutral 71
in phaco-Trabectome surgery after failed
trabeculectomy
IOP: intraocular pressure; SLT: selective laser trabeculoplasty

was consistent with some of these findings and device.65 Trabectome surgery can be performed in
indicated that higher baseline IOPs, older age, more most eyes regardless of glaucoma severity,73–75 prior
medications at baseline,67 and presence of secondary glaucoma surgeries,71,72 and degree of angle opening.23
open-angle glaucomas (especially pseudoexfoliation Learning this procedure is fast and straightforward30,87
glaucoma)78,89,91–93 favored a larger IOP reduction. A due to the high visibility conferred by the active
thicker cornea, thought to be reflective of biomechan- irrigation and aspiration system.31
ical properties94,95 that could impact proximal outflow
tract features,96,97 was associated with a higher risk of 3.2. Goniotome with irrigation and aspiration:
failure while axial length was not.78 Adding cataract TM excision with active irrigation and aspiration
surgery did not improve IOP reduction in eyes with
open67,98 or narrow angles,23 contradicting this common 3.2.1. Method
assumption. It has been speculated that descemeti- The Goniotome with irrigation and aspiration (I/A) was
zation of the angle99 or distal outflow resistance97,100 made available to address the need for a device that
is a cause of failure after Trabectome surgery, but this does not require the high-frequency generator and
theory is lacking evidence. Trabectome surgery can peristaltic pump of the Trabectome. This dual-blade
be combined with other glaucoma procedures — for device was invented in 2004 (https://patents.google.
instance with epibulbar drainage implants such as com/patent/US9358155B2) and its development
the Ahmed glaucoma valve (AGV; New World Medical, precedes the Trabectome. The Goniotome is charac-
Rancho Cucamonga, CA, USA)101 or the Baerveldt terized by v-shaped, serrated sharp blades made with
glaucoma implant (BGI; Abbott Medical, Lake Bluff, IL, femtosecond laser to induce a dual cut along the anterior
USA)102 — to further reduce the IOP, medications, and and posterior TM, and a rounded bottom to protect
incidence of a hypertensive phase without creating the outer wall from trauma (Fig. 3). It is available with
venting slits.102 Propensity-score-matched comparisons active aspiration and irrigation that can be connected
of Trabectome to AGV103 and BGI104 indicate that to the irrigation and aspiration ports of a phacoemul-
Trabectome patients had fewer complications, lower sification or vitrectomy machine. The active irrigation
IOPs, and fewer medications than highly similar tube ensures a well-maintained chamber and debris-free
shunt patients. A study comparing Trabectome surgery view throughout the procedure. Since the Goniotome
to a TM-bypass stent65 found that the average IOP has to stretch and excise the TM mechanically, it is less
increased following a stent so that Trabectome cases drag free than the Trabectome. The Goniotome is also
had a larger IOP reduction, perhaps because TM-bypass available without irrigation and aspiration.
stents can lead to fibrosis105 and a biofilm deposition, Preparation and setup for Goniotome surgery are
which can intrude into the lumen.106 identical to Trabectome surgery. The aspiration allows
excision and also retrieval of the emerging TM strip,
3.1.3. Conclusion which is more easily accomplished than with nonaspi-
Trabectome-mediated ab interno trabeculectomy is rating devices. A modified technique, termed “dip and
a mature MIGS with a 15-year track record of safety strip,” can simplify the excision:
and efficacy that can provide a TM ablation up to 180° 1. the tip is moved to the left end of the intended
through a single clear corneal incision. A meta-analysis ablation;
found that on average the IOP was reduced by 36% to a 2. the TM is punctured by entering SC with the tip
final mean IOP of 16 mmHg.24 While a Cochrane review — pointing left;
based on three studies — suggested that adding a single, 3. the tip is withdrawn from SC;
first-generation TM-bypass stent to phacoemulsifica- 4. the tip is moved to the right of the intended
tion only lowers the IOP by an additional 1.4 mmHg,107 ablation;
a few reports have shown that cataract surgery does 5. SC is entered with the tip pointing left;
not make Trabectome surgery more effective.67,98 One 6. aspiration is engaged; and
comparative study found a greater IOP reduction with 7. with the tip positioned in SC, the tip is moved
Trabectome surgery compared to a single TM-bypass toward the left excising the TM.
Fig. 3. The Goniotome has an irrigation and an aspiration port that maintain the AC and provide a clear view of the TM (right and middle).
V-shaped, serrated blades lift the TM and initiate a simultaneous dual cut. Images courtesy of Neomedix, Inc.
3.2.2. Results above. The KDB is produced by electrical-discharge

An evaluation by anterior segment optical coherence machining, resulting in relatively blunt edges that allow
tomography in an ex vivo model showed the Goniotome a tight fit in SC without catching the scleral spur. Similar
with I/A had high AC stability and visibility compared to the Goniotome, the tip of the KDB elevates and
to passive chamber maintenance with a viscoelas- stretches the TM as a strip of TM is excised (Fig. 4).109
tic device.31 The AC depth increased by 100% at the
beginning and remained unchanged with Goniotome 3.3.2. Method
with I/A. In contrast, during the passive dual-blade As with most angle procedures, performing the KDB ab
excision that used viscoelastic, the AC depth increased interno trabeculectomy before other surgeries takes
by 50% after viscoelastic injection and decreased to advantage of the best corneal transparency during a
20% of baseline at the conclusion. Notably, immediate given case. A clear corneal incision of at least 1.2 mm
postoperative outflow enhancement was similar needs to be fashioned.109 A standard cataract incision
following both techniques.31 A different porcine ex vivo for phacoemulsification and lens implantation can
study that compared three ab interno trabeculecto- also be used. Care should be taken not to underin-
my procedures found a similar outflow enhancement flate the AC with viscoelastic, which can cause corneal
by the Goniotome with I/A and the KDB, but a slightly striae, whereas high pressurization might collapse SC.
higher outflow following Trabectome surgery.108 The technique is similar to the dip-and-strip method
described in the Goniotome section; it involves piercing
3.2.3. Conclusion into SC using the tip of the device on one side before
In an ex vivo model, the Goniotome with I/A provided advancing it over a total of 90-150°.110,111 If a TM strip
better visualization than MIGS that rely on viscoelas- cannot be amputated, it can be left in the eye or
tics for chamber maintenance, but resulted in similar removed with intraocular forceps.112
outflows.31 In nonclinical models, the Goniotome
performs equally well as the KDB.108 3.3.3. Results
An initial case series (N = 52) found that KDB with
3.3. KDB: TM excision in viscoelastic-maintained phacoemulsification lowered the IOP by 26% on 1 less
chamber medication after 12 months from a baseline IOP of 17
mmHg.113 Almost 58% of cases had at least a 20% IOP
3.3.1. Principle decrease. A similar study (N = 53) for standalone KDB
The KDB is a disposable stainless steel dual blade that is found that the IOP decreased by 36% after six months
similar to the Trabectome58 and Goniotome31 discussed from a baseline IOP of 24 mmHg, while 68% of cases
Fig. 4. The Kahook Dual Blade. (A) Magnified view of the tip with its distinct, blunt, electrical-discharge-machined surface. (B) Handpiece
and tip.31
were able to stop at least one medication.32 Almost 70% short-lived due to the small openings created.117,118 As a
of cases had at least a 20% IOP decrease. As is the case result, erbium-doped yttrium aluminum garnet (Er:YAG;
with many other MIGS,114 patients with a higher IOP had Sklerotom 2.9, Endognost, Schwing, Germany119) and
a greater IOP decrease. The largest study (N = 197, 84% excimer lasers (AIDA, TUI-Laser, Munich, Germany120)
of which were combined with phacoemulsification) were developed to create much larger trabeculoto-
found that KDB lowered the IOP by 20% on 0.5 fewer mies that persist. Similarly, the idea to create trabec-
medications after 12 months from a baseline IOP of ular-bypass stents to maintain patency also originated
17 mmHg.111 About 44% of cases sustained at least a here.121–123
20% IOP decrease. Suggestions for variables to be
studied as possible protective factors against failure 3.4.1.2. Method
include mild glaucoma and pseudoexfoliation. The Under gonioscopic guidance, the laser probe tip is
only reported complication besides hyphema was an brought into direct contact with the TM.124,125 With the
unquantified IOP spike, which occurred in 3%. One Er:YAG laser, 18 pulses of 16 mJ are applied for 160 μs.126
patient (0.5%) had a hyphema requiring washout, and With the excimer laser, only 8-10 spots are applied.125
an additional 2% required reoperation. The TM typically blanches, and bubbles are visible.
Reflux of venous blood from SC confirms successful
3.3.4. Conclusion penetration.
Goniotomy becomes a goniectomy when performed
with a dual blade that removes a strip of TM instead 3.4.1.3. Results
of merely incising it. The early results suggest that IOP One of the larger studies followed 75 patients treated
can be reduced by close to 25% in at least 50% of adult with excimer laser.125 After one year, there was a
patients for the first year, with greater IOP decreases 30% decrease from a relatively high baseline of
seen in cases with higher baseline IOP. 24 mmHg. Medications could not be decreased, and
the reoperation rate was 28%. Only 46% reached
3.4. Trabecular ablation by other approaches an IOP ≤ 21 mmHg with a 20% reduction. There were
also 60 cases combined with cataract surgery that
3.4.1. Endoscopic laser trabeculotomy had a 27% IOP decrease from a baseline of 22 mmHg.
Here, medications were also not decreased, but the
3.4.1.1 Principle reoperation rate was only 7% as 66% reached an IOP
Endoscopic laser probes can create circular TM and SC ≤ 21 mmHg with a 20% reduction. Excimer ELT was also
ablation effects that span the entire width of the TM compared in a randomized study (N = 30) to 180° of
(Fig. 5). In 1973, Krasnow reported on laser-assisted selective laser trabeculoplasty (SLT).124 After an average
trabeculotomy,115,116 but early efforts were relatively of two years, the mean IOP decreased by 30% with
Fig. 5. Endoscopic laser trabeculotomy. The probe is placed on a slide with a hematoxylin and eosin-stained anterior segment section
pointing towards the TM. Image courtesy of J. Funk.120
excimer ELT compared to 21% with SLT. The success 4. Trabeculotomy: trabecular disruption
rates were similar. The only reported complication
was a transient IOP spike up to 8 mmHg in 20% of ELT 4.1. TM disruption through external approach: ab
compared to 13% of SLT cases. externo trabeculotomy
3.4.1.4. Conclusion 4.1.1. Principle and history

Endoscopic lasers have been used to create multiple Trabecular disruption was described by Hermann
trabeculotomies that are large enough to persist, M. Burian in 1960 for bilateral glaucoma in a 17-year-old
negating the need for a TM-bypass stent to maintain girl with Marfan syndrome,132 using an ab externo
patency. The success rate is similar to SLT. approach with a trabeculotome. This procedure is now
most commonly used in pediatric glaucoma,41,42,133 but
3.4.2. Ablation with plasma-generating wire-probes we provide a description since the original procedure
Other methods of plasma-mediated TM ablation overlaps with present trabecular MIGS used in adults.
include the Fugo blade127,128 (MediSurg Research and In 1970, Harms and Dannheim created a superior limbal
Management Corp., Norristown, PA, USA) and the scleral flap to identify SC better,134 and introduced
Oertli Glaucoma Tip (Oertli Instrumente AG, Berneck, the Harms trabeculotome to disrupt the inner wall of
Switzerland).129–131 Both generate plasma and can be SC and the TM over a total of 120° (Fig. 6). A left- and
used for goniopuncture, goniotomy, or deep sclerotomy. a right-sided trabeculotome are used for this, and
The number of studies examining these procedures is they have two parallel arms for external guidance.
limited and not recent. Injury to the outer wall is known While some studies showed that both goniotomy and
to be counterproductive and causes reactive fibrosis,62 ab externo trabeculotomy yield similar results,47,133,135
a frequent challenge with ELT and the Fugo blade, but others reported higher success rates with the
also with any device that is forcefully inserted into SC. latter.136,137
Fig. 6. Trabeculotomy with the Harms trabeculotome. (A) Left-sided trabeculotome. (B) After insertion of the trabeculotome into SC, it is
rotated into the AC. (C) The outer prong of the trabeculotome serves as a guidewire. The right-sided trabecular disruption is performed
after the left-sided disruption in the same way, by inserting a dedicated, right-sided trabeculotome towards the right. Images courtesy
of Surgiway.
4.1.2. Method 4.1.4. Conclusion
Ab externo trabeculotomy in children is performed Ab externo trabeculotomy is an effective procedure for
under general anesthesia. Due to the scleral dissection, surgical management of congenital glaucoma.
at least a local block is needed. A small fornix-based
peritomy is fashioned in the temporal or superior 4.2. Tanito microhook trabeculotomy
quadrant. The temporal approach leaves the superior Tanito et al. described trabeculotomy with a microhook
conjunctiva intact should a trabeculectomy be needed that initially follows the same steps as a goniotomy
in the future. After fashioning a rectangular scleral flap using an MVR blade.33 After creating a slit with the MVR
with a 3 mm limbal base, a radial incision is made to blade, a microhook (for instance, a Sinskey microhook
expose SC. Scleral cut down starts from the blue zone [Inami & Co., Ltd.]) is inserted to complete a trabeculot-
up to the white zone until aqueous is seen to ooze out omy of up to 180° or more through a second incision.144
from the cut ends of the canal. The trabeculotome is Three modified Sinskey hooks (M-127 straight, right-an-
then passed into each end of SC and rotated into the gled, and left-angled; Inami & Co., Ltd.) were developed
AC. The scleral flap is sutured with an 8-0 absorbable to pierce the TM without using an MVR blade.
suture and the conjunctiva closed with 10-0 absorbable One case series of 24 eyes with a trabeculotomy
sutures. of 220° decreased the IOP from 26 mmHg by 43% to
15 mmHg at 6 months while also decreasing
4.1.3. Results medications by 0.5.145 About 79% of patients had an IOP
When treated within the first year of life, the success ≤ 18 mmHg with a 15% decrease from baseline. Blood
of angle surgery is 70-95%.135,138,139 Complications reflux occurred in 100%, vitreous hemorrhage in 8%,
include transient hyphema, choroidal detachments and there was one case each with an IOP spike above
or hemorrhage, and false passage into the eye; less 30 mmHg and cataract progression. The second cohort
common complications are iridodialysis and rupture of 68 eyes combined with phacoemulsification had a
of the Descemet membrane.47 A more extensive significantly lower baseline IOP of 16 mmHg, which
disruption is associated with a higher success rate.140,141 decreased to an average of 11 mmHg at 1 year, a 32%
At one year, a 360° trabeculotomy has a 90% success decrease on 0.4 fewer medications.146 In this study, the
rate compared to a 70% success rate with 120°.142 The authors defined success as an IOP ≤ 15 mmHg with a
need for repeat trabeculotomy after 120° treatment 15% decrease from baseline. This was achieved in 79%
is 40 to 80%.136,143 As with goniotomy, trabeculotomy of patients. Hyphema washout was required in 9%, and
ab externo was found to be less effective in adults two cases (3%) required reoperation within one year.
compared to children, presumably due to reapproxi- One-year data suggests that ab interno trabeculoto-
mation of the TM edges.8 my with this simple microhook can control glaucoma
reasonably well.146
4.3. Catheter or suture-assisted transluminal tra- 4.3.3. Results

beculotomy Early descriptions and case series lead to two larger
series. The first had 66 cases where the IOP was
4.3.1. Principle and history reduced from 26.1 ± 9.9 mmHg to 14.6 ± 4.7 mmHg (44%
By threading SC with a suture (e.g. a 4-0 nylon), as decrease) on 2 fewer medications after 1 year.151 Two
described ab externo by Smith in 1960147 or internally risk factors for failure were identified: IOP spike > 30
under gonioscopic view (GATT, also discussed in mmHg (which occurred in 25%) and African American
Chapter 7) with a suture or illuminated microcatheter ethnicity. Hyphema was reported at one week in
(iTrack, Ellex iScience, Inc., Fremont, CA, USA),148 the TM 37%, but none were reported to require washout.
can be ruptured over 360°.149 There is also a device with The only other complication reported was one case
a retractable suture (TRAB360; Sight Sciences, Inc., (2%) of inflammation at one month (presumably
Menlo Park, CA, USA) but no peer-reviewed reports are persistent nongranulomatous iritis). A less stringent
available yet (Fig. 7).7 definition of success (either IOP ≥ 5 and < 21 mmHg or
a 20% decrease from baseline without reoperation)
4.3.2. Method was achieved in 63% at one year. There was no IOP
Patient positioning is similar to the other ab interno difference reported between cases with or without
procedures. Once visualization of the angle is achieved, combined phacoemulsification. The largest study had
a 25-g MVR blade is inserted across the chamber and 198 cases.150 The authors divided their results into six
used to make a slit goniotomy for 1-2 mm.34 Micro- groups and reported that the IOP decreased by 37% in
forceps are used to thread the 4-0 suture through POAG cases and by 50% in secondary open-angle cases,
the goniotomy and around the circumference of SC. from a baseline IOP ranging from 23-31 mmHg, on one
The suture is then pulled and externalized, ripping to two fewer medications (no results were presented
through the TM. For a discontinuous SC that impedes for the overall group). Reoperation rates ranged from
cannulation, a second slit can be made to thread the 9-43% at two years, and risk factors for failure were
other direction. Although an illuminated catheter may pseudophakic POAG cases and mean deviation ≤ 15
improve visualization and make handling easier, the dB. A small study of 35 eyes suggested that GATT could
reported outcomes appear to be similar.150 The micro- still be successful (40% IOP decrease from 26 mmHg
catheter offers an option of adding viscodilation.151 The after 2 years) following previous glaucoma surgery (tra-
transluminal suture trabeculotomy can be made easier beculectomy was the most common).153 A pilot study
by marking the tip of a 4-0 nylon suture and blunting of ten patients with congenital or juvenile glaucoma
it with ﬁne tip cautery (Bovie Medical Corporation, (where three patients were less than two years old)
Clearwater, FL, USA).149 Sato et al. suggested performing reported no complications besides hyphema not
a Trabectome procedure first to make it easier to insert requiring a washout.148 The frequency of postopera-
a catheter or suture.152 tive IOP spikes has been reported to vary from a low
percentage150 to 25% of patients,151 approximately
Fig. 7. Gonioscopy-assisted transluminal trabeculotomy (GATT) can be performed in many ways. Shown here is a suture insertion towards
the right with a dedicated instrument, the TRAB360, which disrupts 180° at a time; it is then rotated towards the other direction and the
procedure is repeated. Images courtesy of Sight Sciences, Inc., Menlo Park, CA, USA.
three times as common as in trabecular ablation,154 bypass the conventional outflow tract (tube shunts) or
reflecting our experience with both. reduce the aqueous humor production (trans-scleral
or endoscopic cyclophotocoagulation). Trabectome
4.3.4. Conclusion surgery has been combined with epibulbar glaucoma
GATT can effectively lower IOP, with early data suggest- drainage devices to improve IOP reduction and decrease
ing an IOP drop to near 16 mmHg. GATT is not more suc- the incidence of a hypertensive phase and the need for
cessful in lowering IOP than ab externo trabeculotomy venting slits in nonvalved implants that are tied off.101,102
with the Harms trabeculotome, but the latter one has AGVs have a 30-82% incidence of a hypertensive phase
fallen out of favor for use in adults.8 Some proposed that begins 1-13 weeks after surgery.160–162
theories include more accurate entry into SC, lower Although AGVs are typically used in more advanced
incidence of inducing false passages, and increasing cases of glaucoma with greater IOP decreases,163 we
the arc of opening.140 compared the efficacy and survival rates of same-ses-
sion Trabectome and AGVs (48 eyes) to AGVs alone (59
eyes).101 IOP decreased by 45% from a baseline of 27
5. Comparison of ab interno TM ablation mmHg for combined cases vs 42% from a baseline of 29
and disruption surgeries mmHg for standalone AGVs. The number of medications
at baseline was comparable in both groups (2.6 ± 1.2 in
Compared to a trabecular microbypass (TMB),63 the AGVs with Trabectome surgery and 2.5 ± 1.3 in AGVs
devices and methods discussed here have the advantage alone), but was reduced by 1.4 in combined cases and
of providing more comprehensive access to the distal increased by 0.3 with AGVs alone at one year. A hyper-
outflow tract. Physiological septations and areas of dis- tensive phase occurred in 19% of combined eyes and
continuity in SC155 normally prevent a circumferential 36% of AGV-only eyes.
flow of aqueous, limiting it to approximately 60° when The BGI is another commonly used glaucoma drain-
a single bore-access device is implanted,156 such as a age device with even lower final mean IOPs, down to
TMB. Because of these septations, a 180° ablation can 13-14 mmHg in recent large studies.163,164 In contrast to
therefore provide about 30-60° additional flow beyond the AGV, it does not restrict flow early on but instead
the ablation ends, which means that a 180° KDB, requires time for a capsule to form around the implant.
Goniotome, or Trabectome ablation can theoretically The tube is therefore tied off with an absorbable suture
lead to access of 240-300°. to prevent any flow for one to two months, but this
An evident advantage of trabecular disruption or can lead to a poorly controlled IOP during the time of
ablation compared to TMBs is that no implant is left tie off.165 Fenestrations proximal to the ligation166–168
in the eye that could incite a foreign-body reaction, are often used to allow early, limited flow, but this can
as even the most inert materials such as gold,157 sili- produce effects from a negligible IOP reduction to
cone,103,104,158 polyimide,159 or titanium106 do. The most frank hypotony.167 Ab interno trabeculectomies can be
common TMB is made of titanium and was recently used to temporize peak pressures after implanting BGIs
shown to elicit a chronic, inflammatory response with that are completely tied off. This approach is similar
biofilm deposition and fibrosis,105,106 eventually causing to orphan trabeculectomies that are allowed to fail
an IOP increase when compared to exactly matched after some time when combined with glaucoma drain-
patients who received a TM ablation.65 age implants.169 We examined 60 eyes that underwent
BGI with Trabectome surgery and 115 eyes that only
received a BGI.102 At one year, the success rate was 61%
6. Combination of surgeries in BGI with Trabectome surgery, and 50% in BGI alone.
IOP decreased from a baseline near 23 mmHg in both
6.1. Ab interno trabeculectomy as an adjuvant pro- groups by 42% for the combined group vs 39% for the
cedure to tube shunts standalone BGI group, on 0.5 fewer medications on
Ab interno trabeculectomy can be used as an adjuvant average in the combined group. The combined group
procedure by combining them with other surgeries that needed fewer drops in all postoperative time inter-
vals and used 0.9 ± 0.9 drops versus 1.6 ± 1.2 in the BGI 7. Conclusions and outlook
group at the final follow-up visit (P = 0.004). Avoiding
fenestrations may result in less postoperative hypoto- Despite the differences in the design of each tool and
ny or hypertension. implementation of the surgical technique, the common
A caveat of combining any of the MIGS discussed goal among the procedures described here is to increase
above with traditional glaucoma surgeries is that an IOP the outflow facility to lower IOP. MIGS have changed
< 8 mmHg will induce reflux from the episcleral veins the landscape of glaucoma treatment, providing an
and cause hyphema, so we advise against combining excellent safety profile18 and reasonably high, although
these with trabeculectomy. The bleb is likely to shrink improvable, rates of long-term success.113,153,174
and fail similarly to autologous blood injections used Ablation methods that do not require viscoelas-
for hypotony.170 Such hyphema may also obstruct ab tic due to an active irrigation and aspiration system
interno gel microstents that drain into the subconjunc- provide superior AC stability and visibility.31 Because
tival space. There is only limited, anecdotal experience of this, they are easier to learn and excel at. New MIGS
of successfully combining cyclodestructive procedures surgeons have to be aware that there is a considerable
(endocyclophotocoagulation [ECP]) with Trabectome learning curve. While it may require about 5 cases to
surgery but ECP has been combined with trabecular-by- become comfortable, experience in at least 30 cases is
pass stents and cataract surgery with good results.171 necessary to consistently achieve high outflow rates.87
Reliably being able to visualize the ablation target
6.2. Combination with astigmatic procedures during gonioscopy is a central skill.30
The glaucoma procedures discussed here can also be While disruption, excision, and ablation of multi-
combined with astigmatism-reducing procedures (e.g. ple clock hours of TM should theoretically negate any
limbal relaxing incisions and toric intraocular lenses) TM-mediated outflow resistance, it is remarkable that
because they only require a clear corneal incision with both patients24,103,175 and experimental models108,176,177
a predictable, relatively minor impact on the shape of do not consistently achieve IOPs at the level of EVP,
the cornea. The induced astigmatism is reported to be suggesting an unknown outflow resistance down-
around 0.1 D, similar to phacoemulsification alone.172 stream of the TM. Recent research suggests a vasomo-
This amount of astigmatism was also observed with the tor ability97,178 of collector channels and implicates an
Tanito microhook.173 untargeted pathology. Future therapies may benefit
from targeting these downstream outflow structures
and features.
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11. iTrack™ ab interno canal-based glaucoma
surgery: the next evolution in MIGS
Mahmoud Khaimi1, David Lubeck2,3
Dean McGee Eye Institute, University of Oklahoma, Oklahoma City, OK, USA; 2Arbor Centers for Eyecare, Chicago, IL,
1
USA; 3UIC Eye Center, Chicago, IL, USA
Abstract
This article discusses the process that led to the lowering without the risk of penetrating filtration
development of ab interno iTrack™ canal-based surgery, thereby allowing for earlier surgical interven-
glaucoma surgery and reviews clinical results to date. tion in the management of glaucoma patients.1-6
A restorative procedure, iTrack™ canal-based glaucoma In this article, we focus on ab interno iTrack™
surgery is a minimally invasive surgical procedure canal-based glaucoma surgery, a restorative procedure
that restores the physiological pathways for aqueous that lowers IOP safely and effectively in cases of mild,
outflow rather than suppressing aqueous production moderate, and severe glaucoma by restoring the physi-
or channeling outflow via a nonconventional pathway. ological outflow pathways.7,8
The authors discuss the evolution of the procedure
from an ab externo to an ab interno approach and
present clinical results on safety and efficacy. 2. Description of the procedure
The chapter concludes that iTrack™ represents a
viable option for earlier treatment and management of Performed with the iTrack™ surgical system, (Ellex,
glaucoma, potentially eliminating or delaying the need Fremont, CA, USA) iTrack™ canal-based glaucoma
for more invasive glaucoma surgical procedures. surgery is designed to access, catheterize, and
viscodilate all potential sites of outflow resistance,
Keywords: ab interno, ABiC, canaloplasty, iTrack, i.e. the trabecular meshwork, Schlemm’s canal, and
Schlemm’s canal the distal outflow system beginning with the collector
channels. During the procedure, viscodilation of
Schlemm’s canal improves diffusion of the aqueous
1. Introduction through the proximal system into the distal system,
opening the ostia of the collector channels, and thereby
For over 30 years, trabeculectomy has been the “go-to” countering the pathological changes seen in glaucoma.9
surgical treatment for the management of glaucoma As with all glaucoma surgery, the iTrack™ procedure
resistant to medical therapy. Its intraocular pressure is performed in a standard operating room and with
(IOP)-lowering effect has been well established, but so the same surgical preparation for any ophthalmic
too have its significant risks and often complicated post- procedure. It can be performed as a standalone
operative management. In the past decade, minimally procedure or in combination with cataract surgery.
invasive glaucoma surgery (MIGS) was developed to Typically, it is done under a topical anesthetic, but a
provide an alternative surgical option for pressure local anesthetic can also be used.
Correspondence: Mahmoud Khaimi, MD, Dean McGee Eye Institute, University of Oklahoma, 608 Stanton L Young Blvd,OKC, OK 73104 USA.

158 M. Khaimi and D. Lubeck
Fig. 1. The iTrack™ microcatheter with illuminated tip. Fig. 3. iTrack™ being threaded into anterior chamber through para-
centesis.
Fig. 4. iTrack™ hub secured to drape. Note that the microcatheter

points away from the eye.
Fig. 2. The iTrack™ surgical system with Viscoinjector™ and iLumin™ In this chapter, we describe the technique as a stand-
fiber optic light source. alone procedure. If performing iTrack™ canal-based
glaucoma surgery in conjunction with phacoemulsi-
Prior to starting the surgery, the iTrack™ microcath- fication, all of the steps are carried out after cataract
eter is prepared and primed. Specifically designed for removal.
viscodilation of Schlemm’s canal, the iTrack™ microca- The surgeon begins by making a paracentesis incision,
theter features a 250-micron atraumatic bulbous tip, using a standard 1.0 mm sideport blade, placed infero-
designed to bypass collector channel ostia and push or superonasally, just in front of the limbal arcade, and
trabecular meshwork herniations out of the ostia with aimed toward the intended goniotomy site. Intracamer-
minimal tissue trauma (Fig. 1). The working length of al injection of preservative-free lidocaine is followed by
the iTrack™ microcatheter measures 200 microns in viscoelastic to form and stabilize the anterior chamber.
diameter and has a lubricious coating which provides A temporal clear corneal incision is then created (1.8
for an easier circumferential passage throughout to a maximum of 2.4 mm). The iTrack™ microcatheter
Schlemm’s canal. In addition, the iTrack™ microcathe- is then threaded into the paracentesis track and left
ter also contains a fiber optic which enables illumina- to rest in the angle (Fig. 3). The microcatheter hub is
tion of the tip so that its passage through the canal can taped to the cheek or forehead of the patient, making
be monitored continuously. An ampule of viscoelastic certain that the catheter points away from the eye
is placed into the ViscoInjector™, which is connected to (Fig. 4). Doing this better facilitates the position of the
the iTrack™ microcatheter. The microcatheter is primed iTrack™ microcatheter position when being inserted
and the fiber optic hub is connected to the iLumin™ and advanced.
light source before starting the procedure (Fig. 2). The patient’s head and surgical microscope are tilted
iTrack™ ab interno canal-based glaucoma surgery 159
a b
c
Fig. 5. Goniotomy with 27-g needle: (a) unpigmented trabecular Fig. 6. iTrack™ intubation of Schlemm’s canal.
meshwork; (b) pigmented trabecular meshwork; (c) Trypan blue-
stained trabecular meshwork.
to achieve a 70-80° angle between them, standard for

gonioscopically performed angle surgeries. Viscoelas-
tic is placed on top of the cornea, the gonioprism is
placed on the eye, and the angle is visualized.
Next, a 27-g needle, bevel up is used to create a 1
to 2 mm goniotomy. After scoring along its anterior
edge, the trabecular meshwork is then depressed
downwards, exposing the bright white, back wall of
Schlemm’s canal. It is important to hold down the
trabecular meshwork edge for a few seconds so that,
once released, it will stay down and keep the opening Fig. 7. Illuminated iTrack™ tip allows continuous visualization of
visible (Fig. 5). microcatheter position in Schlemm’s canal.
A microforceps is inserted through the temporal
clear corneal incision to grasp the tip of the iTrack™ If an obstruction in Schlemm’s canal is encountered
microcatheter, approximately 2-3 mm from its distal or if the iTrack™ microcatheter traverses into the
end. The illuminated tip of the microcatheter is then suprachoroidal space, the following maneuvers can be
inserted with a slightly upward orientation through attempted:
the goniotomy and into Schlemm’s canal (Fig. 6). Next, 1. The microcatheter can be withdrawn 2-3 mm
the iTrack™ microcatheter is advanced in 2-3 mm and then advanced again.
increments around the circumference of Schlemm’s 2. One to two microboluses of viscoelastic can be
canal. As it is in the canal and being advanced, the illu- injected and readvancement attempted.
mination can be placed in strobing mode, so it is more 3. Pressure can be applied externally with a spatula
easily visualized as it passes (Fig. 7). or forceps to redirect the microcatheter.
a b
Fig. 8. Blanching of limbus and vessels during viscodilation: (a) limbal vessels perfused with blood immediately prior to viscodilation; (b)
limbus and collector vessels blanched following viscodilation.
If the iTrack™ microcatheter cannot be passed more

than 180° it should be withdrawn with viscodila-
tion and then reinserted through a new paracentesis
incision before reintubation into Schlemm’s canal in
the opposite direction.
Once the iTrack™ microcatheter has fully circumna Fig. 9. IOP response following ab interno iTrack™ canal-based
vigated Schlemm’s canal, the gonioprism is kept over glaucoma surgery.
the cornea as viscodilation is initiated and the iTrack™
microcatheter is withdrawn. As the surgeon retracts finishing viscodilation. A paracentesis tract should be
the microcatheter, the assistant delivers microbolus- made into the area of detachment and trapped visco-
es of viscoelastic at a prescribed rate of approximate- elastic allowed to escape. Additional viscoelastic or an
ly 4-5 microboluses per clock hour with Healon Pro air bubble in the anterior chamber can help return the
(Johnson & Johnson Vision, Santa Ana, CA, USA) or 2-3 detached Descemet’s to a normal position. Leaving an
microboluses per clock hour with Healon GV (Johnson air bubble in the anterior chamber following viscoelas-
& Johnson Vision, Santa Ana, CA, USA). Blanching is tic removal will facilitate reattachment postoperative-
often seen as viscoelastic dilates Schlemm’s canal ly.
and permeates into collector vessels (Fig. 8). Once the
iTrack™ microcatheter reaches the goniotomy site, it
is removed from the eye, followed by irrigation and 3. Postoperative management
aspiration to remove the viscoelastic from the anterior
chamber. The incision is then closed using stromal Following the procedure, some patients will experience
hydration. an elevation of IOP between weeks 1-8, which usually
A small amount of intraoperative bleeding is not decreases thereafter (Fig. 9). This is likely related to a
unusual. If it obscures visualization of the angle, the number of factors, including glaucoma medication
working space can be cleared with additional viscoelas- withdrawal, some degree of steroid response, clearing
tic. It is important that the anterior chamber be firmly of inflammatory cells/hyphema, and reformation
inflated during viscodilation and that withdrawal of of the outflow pathway. Due to this elevation, it is
the iTrack™ microcatheter is smooth and continuous. recommended to use a lower-potency steroid and
Underinflation of the anterior chamber or overinflation antibiotic, along with an NSAID when the procedure
of Schlemm’s canal due to overinjection and/or dis- is combined with cataract surgery. Higher potency
continuous withdrawal of the iTrack™ microcatheter steroids, such as prednisolone or difluprednate, should
can cause a Descemet’s detachment. If a Descemet’s be avoided or used on a very limited basis. Glaucoma
detachment is noted, the iTrack™ microcatheter should medications are stopped at the time of surgery and
immediately be withdrawn a quadrant beyond before then restarted, if needed. Microhyphema is occasion-
ally seen, usually resolving within one week. Results to 5. Historical perspective and evolution
date indicate that hypotony does not occur following to iTrack™ canal-based glaucoma
iTrack™ canal-based glaucoma surgery.
surgery
iTrack™ canal-based surgery can be performed via
4. The position of iTrack™ canal-based both ab interno and ab externo approaches. During
glaucoma surgery in the glaucoma these procedures, the iTrack™ surgical system is used
to access, catheterize, and viscodilate the proximal
treatment armamentarium
and distal outflow system. Both approaches grew out
Due to its restorative approach and high safety and of the viscocanalostomy technique first developed
efficacy profile, iTrack™ canal-based glaucoma surgery by Robert Stegmann in the 1990s, where a cannula is
can be used as a primary glaucoma treatment to placed into Schlemm’s canal and viscoelastic is used
effectively reduce IOP. It can also be adopted in cases to open blocked areas and restore outflow.17 The
of controlled glaucoma to reduce the medication technique proved technically challenging and evolved
burden. Further, it can be used as a secondary into ab externo iTrack™ procedure, often referred to as
treatment option when IOP is not well controlled by canaloplasty, followed more recently by the ab interno
medical therapy in all primary open-angle glaucoma iTrack™ procedure.
(POAG) patients, as well as in pigmentary and pseu- iTrack™ canal-based glaucoma surgery, whether
doexfoliative glaucoma, as long as the angle is open performed via an ab externo or ab interno approach,
and accessible.10-16 The approach has also been used offers multiple mechanisms of action. First, the 360°
in juvenile glaucoma, secondary glaucoma, and can catheterization of Schlemm’s canal removes obstruc-
potentially be used in patients with failed trabeculecto- tions in the canal and pushes herniations of trabecular
mies, provided that Schlemm’s canal is intact. In cases meshwork out of collector channel ostia. Second,
of previous angle closure, after goniosynechiolysis and the process of viscodilation separates the trabecular
reopening of 120-180° of the angle, iTrack™ canal-based lamellae and creates microperforations, which
glaucoma surgery be performed. Given its impact on improves diffusion of the aqueous through the proximal
all segments of the conventional outflow system, it system into the distal system, thereby countering
has also been demonstrated as an effective adjunctive the pathological changes seen in glaucoma.18,19
therapy to other MIGS options, laser trabeculoplasty, Third, both approaches dilate the canal, the collector
and penetrating glaucoma procedures. Further studies channel ostia, and the distal outflow system. Studies
will be required to assess these treatment synergies. undertaken in human POAG eyes by Haiyan Gong,
The majority of MIGS options currently available can MD, PhD (University of Boston, Boston, MA, USA) have
only be performed in conjunction with cataract surgery. shown that many of the collector channels may be
In contrast, iTrack™ canal-based glaucoma surgery has blocked with herniated trabecular meshwork tissue at
been demonstrated to be a highly effective standalone 0 mmHg and become progressively worse as IOP rises.
treatment option, and can therefore be performed in Cannulating Schlemm’s canal with the iTrack™ micro-
phakic or pseudophakic patients to lower IOP and/or catheter via a process of viscodilation may “pop” open
reduce the medication burden. This offers surgeons these herniations and enable full access to collector
a highly effective, minimally invasive surgical option channel ostia for the egressing aqueous.20
that can be deployed following failed MIGS procedures Following, we explain the two approaches, along
in order to eliminate or defer the need for penetrating with the advantages and disadvantages of each.
filtration surgery.
Because of these attributes, iTrack™ canal-based 5.1. Ab externo iTrack™ canal-based glaucoma sur-
glaucoma surgery is a versatile option for treating gery
open-angle glaucoma of different etiologies and all This ab externo evolution of viscocanalostomy was
grades of severity. first described in 2005 by Kearney et al. and found
that canaloplasty, when performed as a standalone
procedure or in conjunction with cataract surgery, 5.2. Ab interno iTrack™ canal-based glaucoma sur-
provides good reduction and control of IOP similar to gery
that achieved with trabeculectomy, with minimal com- As noted, the development of the ab interno approach
plications.21-24 to iTrack™ canal-based glaucoma surgery occurred
During the ab externo procedure, the iTrack™ micro- because the ab externo equivalent was technically too
catheter is used to circumnavigate and viscodilate challenging, and angle-based MIGS procedures, such as
Schlemm’s canal, and to tow a prolene suture back the iStent (Glaukos Corp., San Clemente, CA, USA), were
around as it is removed. This tensioning suture is tied found to be surgically efficient and easier to master.
and left in place to create an inward distension of the However, given that stent-based MIGS bypassed just
trabecular meshwork. The procedure aims to restore one point of outflow resistance, it was theorized that
the physiological outflow pathways independent of that the ab interno procedure could provide better
any external wound healing and is indicated in patients efficacy by improving outflow through all segments of
with all degrees of open-angle glaucoma. the conventional outflow system.
As noted earlier, the ab externo approach to iTrack™ The notion was to place the iTrack™ microcatheter
canal-based glaucoma surgery does have fewer post- into Schlemm’s canal from a gonioscopically ab interno
operative complications compared to trabeculectomy, approach. There was initial uncertainty about inci-
as there is no bleb to manage, which makes postopera- sion location and architecture, instrumentation, and
tive care simpler for both patient and physician.25,26 surgeon ergonomics. For example, MK thought that a
One of the hallmarks of the ab externo procedure blade would be required to make the goniotomy, but a
is the placement of the 9-0 or 10-0 prolene tensioning 27-g ½” needle was found to offer the necessary rigidity
suture within Schlemm’s canal. The ab interno and sharpness. Insertion of the iTrack™ microcatheter
procedure does not employ this tensioning suture. into the eye through a temporal cataract incision would
A review of three-year data by Lewis et al., found that not place the microcatheter in an appropriate position
360° viscodilation alone, i.e. no suture placement, still for intubation of Schlemm’s canal. Instead, MK further
reduced IOP.26 When comparing the results of visco- found that a nasal paracentesis oriented toward the
dilation alone to eyes where a suture was placed, IOP trabecular meshwork provided much-needed function-
reduction was shown to be similar.27 al procedure architecture.
Mahmoud Khaimi (MK) has been performing the After overcoming the mechanical obstacles to
ab externo procedure for more than a decade, as ab interno passage of the iTrack™ microcatheter,
well as training surgeons from across the globe on additional thought was given to viscodilation. With
the technique. It was in training that the numerous the former ab externo procedure, 12-15 microbolus-
technical challenges as well as the time-consum- es of viscoelastic are commonly used. This same rate
ing nature of the procedure were best understood. of viscodilation was initially employed for ab interno
Despite the many benefits offered by the procedure as iTrack™ canal-based glaucoma surgery. However, MK
compared to trabeculectomy, he found that, for most subsequently determined that using more viscoelastic
surgeons, the technique was too technically demanding would provide greater efficacy in opening the outflow
to master. Scleral dissection down to Schlemm’s canal, pathways. Today, 36-48 microboluses of Healon Pro or
opening the canal, and not perforating into the anterior 18-36 of Healon GV are typically used.
chamber were beyond the training, experience, and The ab interno procedure reduces resistance to
comfort level of the majority of ophthalmologists. aqueous egress in all segments of the conventional
The realization that there might be a better and outflow system without the need for conjunctival and
less invasive approach came during the analysis of scleral dissection or the placement of a tensioning
three-year data and a subset of 33 patients who had suture. Published results demonstrate that the
undergone ab externo iTrack™ canal-based glaucoma outcomes seen with iTrack™ via an ab interno approach,
surgery without placement of a suture.28 either alone or in combination with cataract surgery,
provide for reduction and maintenance of IOP that is
comparable to the former ab externo approach.29-34
5.3. Clinical results the average decrease in IOP was 23.90%, with a mean
To date, one of the authors (MK) has performed more IOP of 15.79 ± 3.31 mmHg (P < 0.001). There was a
than 4,000 cases of iTrack™ canal-based glaucoma 67.82% reduction in medication use to 0.67 ± 0.76 at 12
surgery via an ab interno approach, with no cases of months postoperative (P < 0.05).
endophthalmitis and minimal complications. While In the combined phacoemulsification group, the
plans are underway to analyze the full cohort of this results of 36 patients were analyzed. Preoperative-
experience, a retrospective analysis highlights the ly, mean IOP was 17.93 ± 5.17 mmHg, with an average
success of the procedure at 24 months postoperative. of 1.95 ± 0.93 medications. At 12 months postopera-
tive, mean IOP was 14.69 ± 3.11 mmHg, with a mean
reduction in medications to 0.22 ± 0.48 medications.
6. Study method In this subset, there was a mean decrease of 18.07% in
IOP (P < 0.05) and an 88.59% reduction in medications
A retrospective analysis of ab interno iTrack™ (P < 0.05) vs baseline.
canal-based glaucoma surgery in patients with mild to
moderate POAG was conducted to assess reduction of
IOP, as well as antiglaucoma medications at two years 7. Published results with iTrack™
postoperative. The primary endpoints were mean canal-based glaucoma surgery
IOP and a mean reduction in the number of glaucoma
medications out to 24 months. Secondary endpoints Several recently published papers support the above
evaluated included surgical and postsurgical complica- findings. In Gallardo et al., the authors looked at the
tions. one-year results of patients with uncontrolled POAG
The study included 83 patients (mean age: 71.0 ± 10.2 who underwent ab interno iTrack™ canal-based
years) with a baseline mean preoperative IOP of 18.8 ± glaucoma surgery as a standalone procedure or in
5.5 mmHg and an average of 1.98 ± 0.94 medications conjunction with cataract surgery.35
used. Eighty patients (96.4%) had POAG, 2 (2.4%) had The retrospective analysis included 75 eyes of
pigmentary glaucoma, and 1 (1.2%) had narrow-an- 68 patients (mean age: 73.7 ± 9.9 years) and a mean
gle glaucoma. Thirty-nine patients had undergone baseline IOP of 20.4 ± 4.7 mmHg on 2.8 ± 0.9 medications.
previous glaucoma surgery, 36 laser-based surgeries: At 12 months postoperative, this was reduced to 13.3
selective laser trabeculoplasty (SLT, N = 21); laser ± 1.9 mmHg (N = 73) on 1.1 ± 1.1 medications (both
peripheral iridotomy (N = 8); and argon laser trabecu- P < 0.0001), with 40% of eyes not requiring medication.
loplasty (ALT, N = 7). Previous peripheral iridotomies In the combined procedure subgroup (N = 34 eyes),
were patent at the time of presentation on gonioscopy. mean IOP and medication decreased from 19.4 ± 3.7
The remaining three patients had undergone either mmHg on 2.6 ± 1.0 medications preoperatively to 13.0 ±
canaloplasty (N = 1) or endoscopic cyclophotocoagula- 1.8 mmHg on 0.8 ± 0.2 medications (both p < 0.001). Of
tion (ECP, N = 2). the 41 patients in the standalone iTrack™ canal-based
At 18 and 24 months postoperative, mean IOP glaucoma surgery subgroup, the mean IOP and
dropped to 15.90 ± 3.60 mmHg (P < 0.05), and 16.10 ± medication use decreased from 21.2 ± 5.3 mmHg on 3.0
2.70 mmHg (P < 0.05), with a 68.5% and 70.6% reduction ± 0.7 medications preoperatively to 13.7 ± 1.9 mmHg
in the medications used, respectively (P < 0.05). There on 1.3 ± 1.1 medications at 12 months (P = 0.001 and
were no intra- or postoperative complications. < 0.001, respectively). No serious adverse events were
In an earlier analysis of results at 12 months, we reported.
separated the results to evaluate the outcomes of ab Another study published by the same authors was
interno iTrack™ performed via a standalone approach, a retrospective comparison of iTrack™ performed via
and when combined with cataract surgery. ab interno and ab externo approaches. In this study,
In the standalone analysis, there were 28 patients Gallardo et al. found that there were no significant
with a mean preoperative IOP of 20.75 ± 5.74 mmHg and differences in IOP and medication use between the
a mean number of medications of 2.07 ± 0.94. Overall, two treatment groups at 12 months postoperative. No
serious adverse events were reported. In the ab externo a typical surgical schedule (MK), trabeculectomies will
group, mean preoperative IOP was 18.1 ± 3.9 mmHg on represent less than 15% of glaucoma procedures, the
2.4 ± 0.5 medications, which was lowered to 13.5 ± 2.2 rest being iTrack™. The paradigm has shifted such that
mmHg (P < 0.05) on 0.9 ± 0.9 medications (P < 0.001). In trabeculectomy is now positioned further down on the
the ab interno group, mean preoperative IOP was 18.5 ± list of surgical treatment options. iTrack™ has demon-
3.4 mmHg on 2.4 ± 0.5 medications and the postopera- strated its utility in our clinical practices, offering
tive IOP was lowered to 13.8 ± 2.2 mmHg (P < 0.05) on consistent lowering of IOP, reduction or elimination of
0.8 ± 0.8 medications (P < 0.05).25 medications and, very importantly, less complicated
A case series published by Korber reported on postoperative management with no risk of late endoph-
a consecutive case series of 20 eyes (20 patients) thalmitis. Following the iTrack™ ab interno procedure,
treated with iTrack™ canal-based glaucoma surgery patients can confidently be sent back to referring
and followed for 9 months.37 The study included doctors shortly after the surgical procedure.
POAG patients with both combined and standalone While prospective, comparative clinical studies with
iTrack™ procedures. The mean age of patients was longer term follow-up are underway, iTrack™ is today
76 years (range: 66-83 years). Mean IOP reduced from considered a welcome addition to the ophthalmic
18.5 ± 3.44 mmHg preoperatively to 14.88 ± 2.82 mmHg surgeon’s treatment armamentarium. It offers a 100%
(N = 17), 13.80 ± 2.05 mmHg (N = 12), 14.57 ± 2.59 mmHg ab interno procedure that restores the entire conven-
(N = 9), and 15.47 ± 2.42 mmHg (N = 6) at 1, 3, 6, and tional outflow pathway, including the collector channel
9 months postoperatively, respectively. The mean ostia for 360°. With other glaucoma treatments and MIGS
number of medications was reduced from 2.4 preoper- procedures, where only a segment of Schlemm’s canal
atively to 0.25 at the last follow-up visit. There was one or a single point of outflow resistance is addressed,
reported complication of limited descemetolysis near continued increased resistance including herniations
the limbus by the viscoelastic during the dilatation of of trabecular meshwork into ostia would likely limit
Schlemm’s canal. No adverse events were reported. improvement to outflow.20
Further, ab interno iTrack™ canal-based glaucoma
surgery offers an opportunity for earlier interven-
8. Conclusions tion in the glaucoma disease process, decreasing
medication burden, and potentially eliminating, or
Our collective experience indicates that iTrack™ at least deferring, the need for penetrating filtration
canal-based glaucoma surgery performed via an ab surgery. For the patient, this improves quality of life
interno approach is becoming a legitimate alternative and glaucoma treatment risk profile for all degrees of
to penetrating filtration surgeries. Now, in our hands, in disease severity.
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Schlemm’s canal surgery. Dev Ophthalmol. 2017;59:113–26. 27. Lewis RA, von Wolff K, Tetz M, et al. Canaloplasty: Three-year
11. Cagini C, Peruzzi C, Fiore T, et al. Canaloplasty: current results of circumferential viscodilation and tensioning of
value in the management of glaucoma. J Ophthalmol. schlemm canal using a microcatheter to treat open-angle
2016;2016:7080475. glaucoma. J Cataract Refract Surg. 2011;37(4):682–690.
12. Brusini P. Canaloplasty in open-angle glaucoma surgery: a four- 28. Khaimi M. Canaloplasty without Suture Placement for the
year follow-up. ScientificWorldJournal. 2014;2014:469609. Treatment of Open-Angle Glaucoma: Three-year outcomes.
13. Brusini P, Tosoni C, Zeppieri M. Canaloplasty in corticoste- Poster presentation, European Society of Cataract and Refrac-
roid-induced glaucoma. Preliminary results. J Clin Med. tive Surgeons Annual Congress, Lisbon, Portugal, 2017.
2018;7:31. 29. Koerber NJ. Canaloplasty in one eye compared with visco-
14. Lommatzsch C, Heinz C, Heiligenhaus A, Koch JM. Canaloplasty canalostomy in the contralateral eye in patients with bilateral
in patients with uveitic glaucoma: a pilot study. Graefes Arch open-angle glaucoma. J Glaucoma. 2012;21(2):129–134.
Clin Exp Ophthalmol. 2016;254:1325–30. 30. Khaimi M. Canaloplasty – Three-Year Outcomes of Canaloplas-
15. Korber N. Canaloplasty after trabeculectomy. Ophthalmologe. ty without Suture Placement for the Treatment of Open-Angle
2015;112:332–6. Glaucoma. Poster presentations, American Glaucoma Society
16. Xin C, Chen X, Shi Y, Wang H, Wang N. Modified canaloplasty: Annual Meeting, 2017.
a new, effective, and safe option for glaucoma patients with a 31. Khaimi MA. Paper Poster presenter: “Efficacy and Safety of a
disrupted schlemm canal wall. J Glaucoma. 2016;25:798–801. MIGS Ab Interno Approach in Primary Open-Angle Glaucoma
17. Stegmann R, Pienaar A, Miller D. Viscocanalostomy for open-an- Over an 18-Month Period”, American Society of Cataract and
gle glaucoma in black African patients. J Cataract Refract Surg. Refractive Surgery Annual Meeting, 2018.
1999;25(3):316-22. 32. Khaimi M. Efficacy and Safety of Ab Interno Canaloplasty in
18. Grieshaber MC, Pienaar A, Olivier J, Stegmann R. Comparing Primary Open-Angle Glaucoma Over a 18-Month Period. Poster
two tensioning suture sizes for 360 degrees viscocanalos- presentation, American Academy of Ophthalmology Annual
tomy (canaloplasty): a randomised controlled trial. Eye. Meeting, 2017.
2010;24(7):1220–1226. 33. Khaimi M. Efficacy and Safety of Ab Interno Canaloplasty in
19. Kearney JR, Ball SF, Field MW, Cameron BD. Circumferential Primary Open-Angle Glaucoma (POAG) Over an 18-Month
viscodilation of schlemm’s canal with a flexible microcannula Period. Poster presentation, American Glaucoma Society
during non-penetrating glaucoma surgery. Digit J Ophthalmol. Annual Meeting, 2018.
2006;12:1–9. 34. Khaimi M. Efficacy and safety of ABiC in primary open-angle
20. Cha ED, Xu J, Gong H. Variations in active areas of aqueous glaucoma (POAG) over a 24-month period, European Society
humor outflow through the trabecular outflow pathway. As- of Cataract and Refractive Surgeons Annual Congress, Vienna,
sociation for Research in Vision in Ophthalmology Annual 2018.
Meeting, 2015, Denver, CO. 35. Lewis RA, von Wolff K, Tetz M, et al. Canaloplasty: circumfer-
21. Brüggemann A, Despouy JT, Wegent A, Müller M. Intraindividual ential viscodilation and tensioning of Schlemm canal using
comparison of Canaloplasty versus trabeculectomy with mito- a flexible microcatheter for the treatment of open-angle
mycin C in a single-surgeon series. J Glaucoma. 2013;22(7):577- glaucoma in adults: two-year interim clinical study results. J
83. Cataract Refract Surg. 2009;35(5):814–824.
22. Klink T, Sauer J, Körber NJ, et al. Quality of life following 36. Gallardo MJ, Supnet RA, Ahmed IIK. Viscodilation of schlemm’s
glaucoma surgery: canaloplasty versus trabeculectomy. Clin canal for the reduction of IOP via an ab-interno approach. Clin
Ophthalmol. 2014 18;9:7-16. Ophthalmol. 2018;12:2149-2155.
23. Brüggemann A, Müller M. Trabeculectomy versus canaloplas- 37. Körber N. Ab interno canaloplasty for the treatment of
ty-utility and cost-effectiveness analysis. Klin Monbl Augen- glaucoma: a case series study. Spektrum Augenheilkd.
heilkd. 2012;229(11):1118-23. 2018;32(6):223-227.
24. Khaimi MA, Dvorak JD, Ding K. An Analysis of 3-Year Outcomes
Following Canaloplasty for the Treatment of Open-Angle
Glaucoma. J Ophthalmol. 2017;2017:2904272.
25. Gallardo MJ, Supnet RA, Ahmed IIK. Circumferential viscodila-
tion of Schlemm’s canal for open-angle glaucoma: ab-interno
vs ab-externo canaloplasty with tensioning suture. Clin Oph-
thalmol. 2018;12:2493-2498.
12. XEN: the evolution of the stent and technique
Vanessa Vera1, Daniel Lee2,3, Natasha N. Kolomeyer2,3, M. Reza Razeghinejad2,3, Jonathan S. Myers2,3
1
Department of Glaucoma, Caracas Ophthalmology Unit, Caracas, Venezuela; 2Glaucoma Service, Wills Eye Hospital,
Philadelphia, PA, USA; 3Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA
Abstract
Introduction: Microincisional or minimally invasive improved control over stent placement.
glaucoma surgeries (MIGS) can be categorized into Conclusions: The XEN Gel Stent brings science to the
internal drainage and subconjunctival drainage art of glaucoma surgery by harnessing the principles of
procedures. The XEN Gel Stent (Allergan, Irvine, CA, fluid dynamics. Applying the Hagen-Poiseuille equation
USA) was FDA cleared in 2016, making it the first sub- in the design of the device has greatly reduced the
conjunctival MIGS device approved in the USA. risk of clinically significant hypotony, improving the
Description: The XEN Gel Stent is a hydrophilic tube safety of subconjunctival drainage procedures while
constructed from porcine-derived gelatin crosslinked maintaining effectiveness. Furthermore, reduced con-
with glutaraldehyde and designed using the principles junctival manipulation may help limit proinflammatory
established by the Hagen-Poiseuille equation. Several factors predisposing to fibrosis.
implant models 6 mm in length with varying internal
lumen sizes were developed. As their names suggest, Keywords: ab externo transconjunctival placement,
the XEN140 had the largest internal diameter of 140 μm. bleb management, XEN Gel Stent
XEN63 had a smaller lumen at 63 μm and XEN45 was the
smallest at 45 μm.
Surgical technique: All steps pertaining to implanting 1. Introduction
the XEN45 should be performed with the following
guiding principles: control inflammation, minimize Subconjunctival drainage has been the cornerstone
bleeding, and reduce conjunctival resistance, which are of glaucoma surgical management for more than a
described in detail later in the chapter. century.1 Following full-thickness procedures and other
Postoperative management: Management decisions are fistulizing approaches, trabeculectomy has been the
often nuanced and are made depending on intraocular archetype procedure in which the surgeon manually
pressure (IOP) level and bleb morphology, fully fashions an aqueous drainage pathway from the anterior
discussed in the chapter. A well-timed and executed chamber (AC) to a subconjunctival reservoir or bleb.
bleb needling has been shown to be effective in While trabeculectomy is still considered the gold-stan-
lowering IOP long term. dard glaucoma procedure, its popularity has been
Alternative approaches: More surgeons are now opting declining.2 Outcomes are inextricably tied to a complex
to place the XEN implant using the transconjuncti- collection of variables, including patient factors,
val technique and open conjunctival implantation; tissue characteristics, and suture/scleral flap tension.
advantages and disadvantages will be addressed. In addition to the unpredictable outcomes, serious
Updated injector: An updated injector was introduced hypotony and bleb-related complications can occasion-
to enhance the ergonomics of the delivery system for ally occur. Glaucoma surgeons have been seeking an
Correspondence: Vanessa Vera, MD, 28372 Via Pasito, San Juan Capistrano, CA 92675, USA.

168 V. Vera et al.
alternative surgical procedure that will deliver better

outcomes with improved predictability and safety.
Microincisional or minimally invasive glaucoma
surgeries (MIGS) have emerged as a new class of
glaucoma procedures and shows promise to fill the
voids in surgical glaucoma interventions.3 MIGS can be
categorized into internal drainage and subconjunctival Fig. 1. The Hagen-Poiseuille equation expressed in standard fluid
drainage procedures. The internal drainage procedures kinetics notation. ΔP is the pressure difference at the two ends of
the tube. L and R describe the dimension of the tube and represent
can be further subdivided into trabecular and supracil- length and radius, respectively. μ and Q describe the dynamic
iary procedures, which lower intraocular pressure (IOP) viscosity and volumetric flow rate of the fluid.
by augmenting aqueous outflow through the conven-
tional and uveoscleral outflow pathways, respective- a given cylindrical pipe. Taking advantage of these
ly. The internal drainage MIGS have been criticized for principles brings science to the art of glaucoma surgery,
their relatively modest pressure reduction. However, allowing for more predictable outcomes.
these procedures offer surgical options for mild to The XEN Gel Stent is a hydrophilic tube constructed
moderate stage glaucoma patients with a safety and from porcine-derived gelatin crosslinked with glutar-
efficacy profile congruous with disease severity. In vivo aldehyde. The original conception of the gelatin-based
imaging of the internal outflow pathway is an emerging material was that it would be reabsorbed, leaving
field and shows great promise in allowing surgeons to behind a cell-lined trans-scleral microfistula. This
optimize patient selection and outcomes.4 idea was abandoned and a permanent version of the
As the name suggests, subconjunctival MIGS crosslinked gelatin tube was used.5 Preclinical testing of
procedures bypass the internal drainage systems this material was performed in rabbits and nonhuman
and allow aqueous to drain into the subconjunctival primates, which showed excellent long-term biocom-
space. Like trabeculectomy, this subclass of MIGS are patibility and tube patency.6 Several implant models
bleb-forming procedures. Although bleb-associated 6 mm in length with varying internal lumen sizes were
risks and issues with subconjunctival fibrosis remain, developed. As their names suggest, the XEN140 had
these devices reduce the inherent variability of manual the largest internal diameter of 140 μm. XEN63 had a
drain construction in trabeculectomy. The XEN Gel smaller lumen at 63 μm and XEN45 was the smallest at
Stent (Allergan, Irvine, CA, USA) was cleared by the FDA 45 μm (Fig. 2).
in 2016, being the first subconjunctival MIGS device
approved in the USA.
2. XEN Gel Stent
2.1. Design
The XEN Gel Stent (also discussed in Chapters 3, 6, 20,
and 21) is a novel drainage device with an IOP-lowering
mechanism involving the same principles as traditional
glaucoma filtering procedures. Similar to trabeculecto-
my, the device allows drainage of aqueous from the AC
into the subconjunctival space. In an effort to temper
the outcome variability seen in traditional techniques,
XEN was designed using the principles established by
Fig. 2. The XEN models. Three devices were designed with varying
the Hagen-Poiseuille equation (Fig. 1). The Hagen-Poi- internal diameters, ranging from 140 μm, 63 μm, and 45 μm from
seuille equation is a physical law in fluid dynamics that largest to smallest. The 45 μm was the first to become commercial-
gives the change in pressure as fluid flows through ly available. Image courtesy of Allergan.
XEN: the evolution of the stent and technique 169
a b
Fig. 3. The XEN45 Gel Stent (a) and injector (b). Image courtesy of Allergan.
The stent is implanted with an ab interno approach 2.3. XEN140 and XEN63
using a preloaded 27-g injector system (Fig. 3). Once In early pilot studies, Sheybani et al. evaluated the
deployed, the stent creates a channel connecting XEN63 and XEN140 in combination with phacoemul-
the AC to the subconjunctival space. The hydrophilic sification9 and XEN140 alone.10 Of note, antifibrotics
gelatin material is relatively straight and rigid when such as mitomycin C (MMC) were not used in either
dry, but becomes flexible and soft when hydrated. The study. The first study included 34 eyes with a baseline
softened implant conforms to the ocular tissue and IOP of 22.4 mmHg on 2.5 medications. At one year,
develops an “S” configuration as it traverses the scleral IOP was reduced to 15.4 mmHg on 0.9 medications.
channel.5 Implant flexibility is an important property in Significant subconjunctival fibrosis requiring needling
reducing the risk of migration and erosion. was observed in 32% of eyes. Hypotony was seen in
13 patients (35%) on the first postoperative day. Two
2.2. Hypotony protection patients (5%) experienced shallow ACs that required AC
After glaucoma surgery, the combined resistance refill. This was associated only after XEN140 placement.9
of trans-scleral outflow pathway and subconjuncti- The second study included 49 eyes that had received
val space determines IOP. Overfiltration through the the XEN140 alone. Baseline IOP was 23.1 mmHg on 3.0
outflow pathway and/or conjunctival leaks can lead medications. At one year, IOP was 14.7 mmHg on 1.3
to low IOP. Iatrogenic hypotony can lead to the most medications; however, 47% required bleb needling and
serious complications associated with glaucoma 9% experienced hypotony with shallow AC.10 Recently,
filtering procedures. Hypotony-related complica- Lenzhofer et al. published four-year results following
tions include flat AC, hypotony maculopathy, or XEN63 implantation.11 IOP was reduced from a baseline
serous choroidal effusions and hemorrhagic choroidal of 22.5 mmHg on 2.4 medications to 13.4 mmHg on 1.3
effusions, the latter of which especially portend a poor medications at four years. These patients were the
visual prognosis.7 The design of the XEN, with a very original group of patients receiving the XEN Gel Stent
small lumen vs its length, leads to outflow resistance and did not receive adjunctive MMC. Failure rate was
according to the Hagen-Poiseuille equation. The XEN45 10% per year, similar to the rates published in the Tube
provides a steady-state flow resistance of 7.56 mmHg versus Trabeculectomy (TVT) study.12
at an aqueous outflow rate of 2.5 μl/min, theoretical- Although not explicitly stated in the literature, the
ly eliminating the risk of hypotony.8 The XEN140 has hypotony rates seen with the larger lumen stents is
minimal flow resistance and the XEN63 provides 2-3 likely an important factor that led to the worldwide
mmHg of outflow resistance at physiologic aqueous release of XEN45 among the three developed models.
production rates.9 These larger diameter devices rely
more on subconjunctival resistance to limit hypotony.
170 V. Vera et al.
3. Surgical technique prior to the procedure and replacing with oral carbonic
anhydrase inhibitors for IOP control is recommended.
3.1. Guiding principles Preservative-free lubricating drops and eyelid hygiene
All steps pertaining to implanting the XEN45 gelatin may be necessary to reduce the effect of dry eye and
stent should be performed with the following guiding blepharitis. Oral doxycycline and/or topical eryth-
principles: control inflammation, minimize bleeding, romycin ointment may be needed to control severe
and reduce conjunctival resistance.13 Inflammation blepharitis. We recommend initiating topical steroids
is an important factor that controls postoperative at least one week prior to the procedure, with a longer
fibrosis and can increase the risk for bleb failure. Along duration as needed to control ocular surface inflam-
the same lines, bleeding should be minimized, as the mation.
extravasation of blood can incite the release of inflam-
matory cytokines, potentially leading to fibrosis.14 3.3. Planning stent positioning
Bleeding may further complicate the procedure, as The XEN45 implant was designed to be implanted
it obscures visibility during the procedure. Finally, in the superonasal or superior quadrants due to the
lowering conjunctival resistance increases the ergonomics of the ab interno approach. A temporal
likelihood of sustained pressure reduction. approach allows for the greatest freedom of movement,
which is paramount for the precise and controlled
3.2. Preoperative considerations movement necessary for any intraocular procedure.
As stated earlier, the XEN45 gel stent under physiologic More nasal rather than superior stent placement does
conditions confers a flow resistance of approxi- raise the concern for a more nasal bleb formation.
mately 6-8 mmHg.5,8 This resistance is a function of Nasal blebs have been associated with dysesthesia,
device length and internal diameter, which remains cosmetic issues, and bleb-related complications.18
unchanged. Therefore, variability in pressure outcomes Stent placement should be aimed closer to the 12
is directly related to outflow resistance of the sub- o’clock position, which may reduce the likelihood of
conjunctival space, potentially occlusion at the tip a nasally positioned bleb. MMC placement may be
or lumen, and possibly variable aqueous production a factor as well. Prior to making incisions, reference
with inflammation. Careful preoperative evaluation markings can be placed 3 mm posterior to the limbus
of the conjunctiva, especially in the region of planned in the planned position of the stent (Fig. 4A).
surgery, is critical. The presence of ocular surface
disease and resulting conjunctival injection creates a 3.4. Antifibrotic agents
proinflammatory environment and increases the risk There is a well-established precedent for using
for bleeding and fibrosis.15 Glaucoma patients who adjunctive MMC in subconjunctival outflow surgeries.
have been exposed to chronic topical medications are In recent years, intra-Tenon injection of MMC using
especially prone to poor ocular surface conditions.16 a 30-g needle has become the preferred method of
The presence of fibrosis from prior surgeries or delivery by most surgeons, supplanting the use of
prolonged inflammation confers a poorer prognosis.15 sponges. However, the timing, location, and concen-
These areas should be avoided if possible and patients tration of adjunctive antifibrotics are not standard-
should be counseled accordingly for appropriate post- ized. Concentrations and absolute dose of MMC used
operative expectations. vary between 0.1-0.4 μg/ml and 10-40 μg, respec-
The optimal setting for subconjunctival surgeries is tively. Currently, experts recommend injecting a
a white and quiet ocular surface with excellent tissue relatively lower concentration (0.1-0.2 μg/ml) at a low
mobility and elasticity.17 Reduced conjunctival mobility volume (0.1 ml) in order to limit the spread of MMC and
may indicate the presence of subconjunctival fibrosis. resulting conjunctival changes that may complicate
Controlling significant ocular surface disease, dry eyes, future surgeries.
and/or blepharitis may improve surgical outcomes. In terms of timing, some surgeons prefer injecting
If the eye is injected, reducing eye drop burden by MMC prior to stent placement for the added benefit
stopping topical medications for one or more weeks of hydroexpansion of Tenon’s capsule. After injection,
Fig. 4. Surgical steps of ab interno XEN placement.
care should be taken to avoid pooling of MMC at the 3.5. Incisions

limbal area (Fig. 4B). This is thought to reduce Tenon An approximately 1 mm paracentesis is made in the
resistance and prepare the space for improved aqueous superotemporal quadrant, approximately 90° away
flow and bleb formation. Proponents for supra-Tenon from the planned stent location (Fig. 4C). Intraca-
stent placement recommend injecting MMC after stent meral anesthesia and cohesive viscoelastic is then
placement to avoid embedding the distal tip within the injected into the AC (Fig. 4D). The primary incision is
expanded Tenon layer. Later injection allows greater then made temporal or slightly inferotemporal (Fig. 4E).
visualization during the procedure and fluid placement In combined cataract surgeries, the temporal main
at the distal end of the implant. Some surgeons have incision can often be used, as the incision is typically
concerns regarding the potential for reflux of MMC wide enough to pivot the injector toward the desired
into the AC through the XEN, where MMC would be location. The injector is then prepared, and the needle
potentially toxic, but this has not been documented to is introduced into the AC (Fig. 4F). Practice will improve
occur in pressurized eyes. a surgeon’s facility to pivot and allow more superior
New antifibrotic agents, approved systemic drugs rather than nasal placement. Rotating the eye with the
with potent anti-inflammatory effect and novel deliv- use of the paracentesis or traction suture may allow
ery methods are being tested to improve outcomes better access to the superior quadrant. Ergonomic
in subconjunctival surgeries. A gel-based application issues with the patient’s cheek and shoulder, as well as
with a slow release delivery matrix, might be helpful in the speculum are common and should be anticipated
the long-term healing battle. and resolved prior to approaching the angle with the
device.
172 V. Vera et al.
3.6. Engaging the angle this, tension should be fully removed from both hands
While some surgeons do not utilize a gonioscopy mirror and a gentle forward bias should be maintained with
to aid in stent placement, we especially recommend its the instrument until the injector slider is completely
use for novice XEN surgeons in the early phase of the forward and the needle is fully retracted (Fig. 4L).
learning curve. The mirrored view may initially pose a
challenge and care should be taken to avoid iatrogenic 3.8. Assessing stent placement and function
trauma. The ideal stent insertion site is above the The implant should be visible as a translucent yellow
pigmented trabecular meshwork and below Schwalbe’s tube and should be freely mobile underneath the
line. This relatively small target avoids the stent conjunctiva. The mnemonic “1-2-3” has been suggested
traversing Schlemm’s canal, where blood reflux may be as an approximate guide for ideal stent placement with
encountered. Once the target region is identified, the 1 mm visible in the AC, 2 mm traversing the sclera, and
needle tip is pushed forward and seated in the angle 3 mm visible in the subconjunctival space.13 The stent
(Fig. 4G). Engaging the angle preserves the position and should be freely mobile and straight under an intact
prevents inadvertent movement of the needle tip while conjunctiva. Steps for identifying and adjusting unsat-
handing off the gonioscopy mirror. Prior to advancing isfactory stent placement will be discussed in detail in
the needle, the surgeon should observe the positioning the next section.
of the needle and become accustomed to its appearance Once ideal positioning of the stent is confirmed, vis-
when it is in the proper position. If the surgeon chooses coelastic and any heme should be thoroughly irrigated
to wean off the gonioscopy mirror, we suggest a trial from the AC to reduce the risk of stent occlusion and
period of first engaging the angle and then checking elevated postoperative IOP (Fig. 4M). We suggest
positioning with the mirror. We recommend continuing hydrating the corneal wounds prior to viscoelastic
this practice until proper positioning can be consistent- removal to reduce the likelihood of wound leak and
ly achieved. shallowing. AC shallowing followed by aggressive
re-formation may increase the overall volume of basic
3.7. Implanting the stent salt solution (BSS) injected and lead to exuberant bleb
A second instrument is inserted into the paracente- formation. At this point, a diffuse bleb should have
sis for countertraction and the needle is advanced formed over the stent (Fig. 4N). A small or focal bleb
through the sclera. The needle should emerge approx- may indicate suboptimal flow through the stent or
imately 2.5-3 mm from the limbus; the bevel of the placement in deeper, tighter tissue. Exuberant blebs
needle should be completely visible (Fig. 4H). Some may also be seen due to flow around the implant
surgeons advocate for superficial placement with the (peritubular flow), which may happen with short scleral
goal of supra-Tenon placement of the distal end of the passes, thin tissue, or excessive eye manipulation
tube. Others aim deeper for the sub-Tenon space. No during implantation. If the XEN position is satisfactory,
consensus or data yet exists whether these positioning no intervention is needed, as peritubular flow generally
strategies improves outcomes, but overall agreement stops early on during the postoperative course.
on not leaving the distal end of the implant embedded
within Tenon’s seems to be accepted by most. 3.9. Adjusting malpositioned stents
To deploy the stent, the surgeons should gently and The ideal stent placement should be guided by the
methodically slide the injector plunger forward (Fig. “1-2-3” rule. If this is not achieved, the stent should be
4K). Once the needle tip begins retracting into the adjusted prior to concluding the surgery. Blunt-tipped
injector sleeve, care should be taken not to apply any forceps can be used to gently push or pull the implant to
extraneous forces on the eye to avoid abrupt movement a more ideal position from an external approach. When
of the sleeve (flick) once the needle is fully retracted and pulling the implant out, sliding the conjunctiva over the
the injector is no longer anchored to the sclera. Excess implant will avoid tearing the conjunctiva. Implants
residual forces on the injector lead to a characteristic with the subconjunctival portion too short for manip-
flick as the needle retracts that may result in damage ulation should be removed from the AC using microfor-
to the surrounding ocular tissue or the stent. To avoid ceps. The stent may be reloaded in the injector and a
second implantation attempt can be performed. If the lead to additional aqueous filtration through the needle
stent position is deemed to be too nasal, the implant tracks. Potentially serious causes of hypotony may
should be removed, reloaded, and a second implanta- arise from corneal wound leaks and inadvertent cyclo-
tion maneuver should be performed. dialysis clefts created during a complicated implan-
Immobile or curling of the stent often suggests Tenon tation. Patient factors can include reduced aqueous
tissue interference with the stent tip and is believed to production from continued hypotensive medications
be associated with a greater risk of XEN failure. Gentle or uveitis (ciliary body shutdown). Additionally, eye
manipulation of the conjunctiva with a blunt instrument rubbing or a thin sclera from myopia may cause inordi-
should first be attempted to free the stent from the nately high outflow, leading to low pressures.
surrounding tissue. If unsuccessful, primary needling The specific management of hypotony will vary
may be performed to release adhesions and free the depending on the underlying cause. Hypotony with
implant. Care not to engage nearby blood vessels is preserved visual acuity and deep AC can be monitored
important to maintain an adequate view. without intervention. Topical cycloplegic medications
and closer monitoring should be initiated if poor vision
or a shallow AC is present. In the rare event of a shallow
4. Postoperative management or flat AC where re-formation is needed, judicious
amount of dispersive (low molecular weight) viscoelas-
There are several parallels between the postoper- tic should be used. High molecular weight or cohesive
ative management of trabeculectomy and XEN. For viscoelastic may be best avoided, as IOP spikes may
both procedures, management decisions are often occur and prolonged stent obstruction may confer a
nuanced and are made depending on IOP level and poor prognosis for long-term IOP control. Air or BSS
bleb morphology. The fixed dimensions of the XEN Gel mixed with viscoelastic may be used in the setting of
Stent, however, protect against clinically significant severe shallowing or flat ACs.
hypotony and confer a more predictable course, at
least in the early postoperative period. 4.1.2. Early high IOP
When IOP is higher than expected, a connection
4.1. Early postoperative period (< 1 week) between AC and subconjunctival space should be
An IOP of 3-10 mmHg should be expected in the early confirmed. After a connection is confirmed, the next
days following a properly implanted XEN. During this possible mechanism is obstruction either at the
initial period, subconjunctival resistance should be proximal or distal end of the stent. The proximal ostium
at its lowest levels. Pressures higher or lower than may be blocked by a number of mechanisms in the early
the expected values should prompt investigation for postoperative period. Common mechanisms include
underlying causes. While successful outcomes are still iris occlusion and blood, as well as retained viscoelas-
possible in these scenarios, identifying the cause and tic and lens fragments. The distal outflow at the ostium
prompt reversal will improve the likelihood of success. may be restricted by subconjunctival hemorrhage or
obstruction by Tenon tissue. Management should be
4.1.1. Early low IOP determined on a case-by-case basis, with treatment
Low IOP is uncommonly encountered due to the inherent directed toward reversing the mechanism of the
resistance of the device. The causes of hypotony can be obstruction. Occlusions by blood or viscoelastic can
broadly divided into surgery-related and patient-relat- be self-limiting and close monitoring with topical
ed factors. Surgery-related factors typically deal with glaucoma medications or AC tap may suffice.
peritubular flow, which can occur early on as the outer Conditions that give rise to iris occlusions with the
diameter of the 27-g needle is 408 microns compared to XEN Gel Stent likely mirror those seen in tube shunts.
the 210-230-micron diameter of the hydrated implant. These factors include more posteriorly directed stents,
Other factors, such as reduced scleral elasticity or short shallow ACs, floppy iris syndrome, phakic status, and
scleral pass, may also contribute to peritubular flow. peripheral iris abnormalities.19 Available treatments
Multiple needle passes made during the surgery may include topical miotic agents, argon laser iridoplasty/
174 V. Vera et al.
iridotomy, or mechanical repositioning of the stent.13 Early and aggressive bleb needling may be necessary in
Ab interno repositioning with microforceps has been this scenario.
reported as well.20 Peripheral iridotomy is commonly A diffuse and elevated bleb may represent steroid
performed in the setting of tube shunts, but is not response. In this setting, bleb needling plays a limited
advisable with XEN stents as iris debris may further role. While steroid response typically presents after
occlude the thinner 45 μm lumen.21 prolonged steroid use, early steroid response has been
If early obstruction of the distal stent is suspected, observed in glaucoma patients. Topical glaucoma
a wet cotton tip applicator may be used to mobilize medications along with steroid tapering (or transition
the overlying conjunctiva to help free the Tenon to a milder steroid) are recommended in this setting.
block. Forceful slit lamp maneuvers should be A localized and cystic bleb is caused by bleb encap-
delayed, if possible, to avoid the risk of disturbing sulation, uncommonly seen after XEN in the authors’
stent positioning and to minimize patient discomfort. experience. Topical glaucoma medications and con-
Topical medications can be used to temporize elevated tinuation of steroids is indicated in this situation. If
pressures for a few more weeks. However, early bleb IOP is inadequately controlled by topical medications,
needling should be considered if significant curvature needling can be considered to broaden the bleb.
of the stent is noted. Such findings may indicate risk
of early fibrosis or intra-Tenon implantation. Bleb 4.3. Bleb needle revision
needling techniques will be covered in more detail Bleb needling after XEN Gel Stent placement is fairly
below. common, with reported rates in the range of 20-40%.
The timing of needling is guided by IOP and the extent
4.2. Late high IOP (> 1 week) of subconjunctival and peritubular fibrosis, and tends
Beyond the early postoperative period, IOP is related to coincide with the timing for performing laser suture
to changing tissue resistance as the bleb evolves over lysis (LSL) in trabeculectomy.22 In parallel with LSL, late
time. Outcome variability generally occurs at this needle revisions tend to confer a lower success rate due
stage and targeted management will vary depending to scar maturation. A well-timed and executed bleb
on IOP goals, bleb morphology, and degree of fibrosis needling has been shown to be effective in lowering
surrounding the stent. IOP long-term.23 Based on our experience, the optimal
After ruling out a proximal ostium occlusion, the first window for needling seems to fall between postopera-
step in management is to ascertain the presence and tive week 3 and 6.
degree of fibrotic response. Bleb morphology as well The extent of needle revision depends on the location
as mobility of the conjunctiva and stent are key factors and extent of fibrosis. Peritubular fibrosis manifests as
to be considered. A mobile stent and conjunctiva an immobile or curved tube. An immobile and inelastic
and a low/flat bleb indicate a restrictive/obstructive conjunctiva signifies more extensive subconjunctival
process and, in the authors’ experience, carries a fibrosis. The goal of needle revision is to free subcon-
more favorable prognosis. Digital ocular compression junctival fibrosis to allow for bleb formation and lyse
(DOC) or ocular massage can be attempted to clear the peritubular fibrosis to allow free, unrestricted flow of
occlusion and assess interstitial resistance. Unlike tra- aqueous.24
beculectomy compression, digital compression with Topical vasoconstrictive agents such as phenyleph-
the XEN may require a bit more prolonged pressure, rine can be given prior to the procedure to lower the
as the lumen limits the rate of aqueous egress. If risk of inducing subconjunctival hemorrhages. A 30-g
significant IOP reduction with bleb elevation is noted, needle is introduced superiorly into the subconjunctival
close monitoring is indicated. If intermediate to no space approximately 2 o’clock away from the stent. First,
improvement is observed, a low threshold for needle delicate needling is performed to free the implant from
revision with or without adjunctive antifibrotics (5-flu- the subconjunctival space. If significant subconjuncti-
orouracil or MMC) should be considered. An immobile val fibrosis is encountered, needling may be required
stent and/or conjunctiva indicate significant fibrosis to separate the conjunctiva from the sclera to allow
and are unlikely to respond favorably to massage alone. for bleb formation. Gentle sweeping with the tip of the
needle above and below the subconjunctival portion of tion in patients without prior incisional filtering surgery
the implant is often effective in freeing the tissue cap. found no significant difference in efficacy, safety
A successful revision is accompanied by an enlarging profile, or risk of failure.34 A multicenter prospective,
bleb surrounding the implant. No flow through a freely randomized clinical trial comparing the Xen Gel Stent vs
mobile implant often signifies the presence of a fibrotic trabeculectomy is currently in progress (NCT03654885).
cap at the distal ostium. If the presence of a fibrotic Complications reported after XEN stent implantation
cap is suspected, the distal tip of the implant can be include hypotony, choroidal effusions, hyphema, iris
transected with the needle tip. In some cases, very thick, prolapse, wound leak, corneal edema, implant exposure,
dense, opaque tissue may make needling challenging. and endophthalmitis. As discussed above, hypotony is
Open revision with meticulous dissection of the tissue more likely to be transient and rarely becomes visually
is often effective, and may lead to better long-term significant. A small portion of eyes required additional
success, but these eyes are at increased risk of fibrosis glaucoma surgery (2.4-15.3%).25,26,32,34 Bleb needling or
and failure. Adjunctive injection of antifibrotic agents revision was required in a significant proportion of eyes
is often useful after needling to prevent recurrence (22-51%).26,29-32,34,36,37
and reduce interstitial resistance with hydroexpansion Synthesizing what is known on the clinical course
of compact Tenon tissue. There may be a role in DOC following XEN, average IOP after one to two years
if bleb formation is limited following needling to aid in follow-up seems to range in the low to mid-teen range
improving outflow. Rapid failure following two needling on less than two medications. Patient counseling and
attempts or stents not visible due to excessive tissue selection should be made accordingly with reasonable
carry a poorer prognosis. Surgical open revisions may expectation that bleb needle revision may be necessary
be necessary in such cases. in approximately a third of patients undergoing the
procedure.
5. Literature overview
6. Alternative approaches
The long-term clinical research data for the XEN Gel
Stent is limited due to the relative novelty of the implant. 6.1. Ab externo transconjunctival placement
However, the literature is rapidly accumulating as Sébastien Gagné MD is credited as the first person to
clinicians are gaining more experience with the device. perform an ab externo implantation of XEN Gel Stent
Reported rates of complete and qualified surgical without opening the conjunctiva (transconjunctival
success depend on study population and definitions, implantation). In a yet unpublished series, 25 patients
ranging from 28-80%, and 56-97%, respectively, at at 3 months follow-up visit had IOP of 13.1 ± 3.6 mmHg
12 month follow-up.25-31 Studies report a 29-45% IOP on 0.6 medications. More surgeons are now opting
reduction and 51-95% reduction in medication classes to place the XEN implant using the transconjunctival
after XEN stent implantation.25,26,30,32-34 Most studies technique (Video 1). To describe this approach in brief,
have enrolled or reviewed a mixed study population in the conjunctiva is entered > 7 mm posterior to the
regards to glaucoma diagnosis, prior incisional surgical limbus (Fig. 5A-B). Prior to this, some surgeons choose
history, and performance of concurrent cataract to place a corneal traction suture to aid in exposure and
surgery. Thus far, there is no significant evidence for countertraction. The needle is advanced anteriorly
suggesting a difference in outcomes based on these just under the conjunctiva and staying parallel in this
factors. Few studies have evaluated solo XEN implan- plane (Fig. 5C). Care is taken to avoid blood vessels
tation.29,31,32,34 Most recently, the APEX study group to prevent subconjunctival hemorrhage. At 2.5-2 mm
reported a sustained medicated reduction of IOP at posterior to the limbus, the needle tip enters the sclera
14.9 ± 4.5 mmHg at 12 months and 15.2 ± 4.2 mmHg at and tunneled through the sclera against countertrac-
24 months from a baseline of 21.4 ± 3.6 mmHg.35 tion. At the surgical limbus, the needle approach is
An international multicenter retrospective study steepened to enter the AC parallel to the iris plane. A
comparing trabeculectomy and XEN Gel Stent implanta- gonioscopy lens can be used at this point to confirm
176 V. Vera et al.
Fig. 5. Surgical steps of transconjuntival XEN placement.
needle entry away from the iris and cornea (Fig. 5D). the possibility of retained viscoelastic occluding the
Rotating the injector to a bevel down position during stent in the early postoperative period and associated
deployment may reduce the risk of inadvertent IOP spikes, the latter one which could have detrimental
damage to the soft gel implant with the sharp needle effect in those with advanced optic nerve damage.
edge during removal. The blue slider of the injector is Third, this approach may decrease the likelihood of the
pushed forward until the needle is retracted and the distal stent becoming embedded in the Tenon layer.
implant is deployed (Fig. 5E). As the injector was not An injection of MMC after stent placement is
designed for an external approach, the subconjunctival performed (Fig. 5H), which allows targeting fluid
portion of the implant will be short while the AC portion placement at the distal end of the implant.
is long. To compensate for this, some surgeons suggest Proper stent positioning in the AC may pose a
retracting the injector so that the sleeve is approxi- significant challenge for surgeons not accustomed to an
mately 1.0-1.5 mm away from the scleral surface during external approach. A long and posteriorly placed stent
stent deployment. Blunt forceps may be used to adjust poses a risk for iris occlusion. Conversely, an anteriorly
the stent position by gently grasping from outside placed stent carries a theoretical risk of progressive
the conjunctiva after ensuring adequate conjunctival endothelial cell loss. Fortunately, glaucoma surgeons
mobility. The final positioning of the implant should have become accustomed to this approach, as tube
ideally follow the “1-2-3” rule, as recommended by the shunts are placed through an external needle track.
manufacturer (Fig. 5F). We have found intraoperative gonioscopy helpful to
The ab externo approach has several potential confirm the implant is entering the eye at the proper
benefits over the ab interno approach. First, the location and trajectory.
external placement frees the surgeon from the
ergonomic limitation of placing the implant in the 6.2. Open conjunctival implantation
superonasal quadrant. The surgeon may choose to The pivotal trial that led to the approval of the XEN45
place the stent in the superotemporal quadrant (Fig. required participating surgeons to implant the stent
5G) in the presence of scarring or another XEN stent as an open conjunctival procedure with sponge
in the superonasal quadrant. Second, an external application of MMC.32 Advocates for open implanta-
approach does not require corneal incisions, the use tion report that this approach guarantees sub-Tenon
of viscoelastic or maneuvers in the anterior chamber, implantation and is especially well-suited for African
thus virtually eliminating specific potential complica- American patients with thicker Tenon layers. Anecdotal
tions (e.g. wound leak, lens or endothelial touch, etc.), claims of more trabeculectomy-like blebs with reduced
needling rates have been made. The downside to this Additionally, since the material has an extensive
approach stems from its more invasive nature, with track record for medical use, as well as proven to have
theoretical increased risk of fibrosis and wound leaks. excellent biocompatibility and tolerance, the use of
the gel stent to drain aqueous into the suprachoroi-
dal space, which will require designing an potential
7. Updated injector prototype stent version and injector, could be very
helpful in the armamentarium of the glaucoma surgeon
An updated injector was recently announced. The for the surgical journey of the glaucoma patient.
update features a smaller slider with a travel path 8mm
shorter than its predecessor. Tactile feedback has
also been introduced to allow the surgeon to better 9. Summary
recognize when the needle begins to retract. These
changes were introduced to enhance the ergonomics Trabeculectomy is the time-tested gold-standard
of the delivery system for improved control over stent glaucoma procedure. Dr. John Cairns first described
placement. the modern concept of trabeculectomy in 1968, which
improved AC control compared to prior full-thickness
procedures. Through the ensuing decades, incremental
8. Novel ideas modifications have been made in an effort to improve
the safety and predictability of the procedure. Unfor-
Patens proposing an adjustable XEN version have been tunately, a highly individualized and complex interplay
published, in which the inner diameter of the stent of factors have thus far thwarted surgeons from
could change from 45 to 63 or even 140 microns, this eliminating serious complications.
with the intention to lower achieved IOP after surgical The XEN Gel Stent brings science to the art of glaucoma
stability or to reduce target IOP over time as the surgery by harnessing the principles of fluid dynamics.
disease state progresses. A potential prototype with a Applying the Hagen-Poiseuille equation in the design
modifiable gelatin material or the use of laser to assist of the device has greatly reduced the risk of clinically
internal lumen changes have been suggested. significant hypotony. Furthermore, reduced conjunc-
tival manipulation may help limit proinflammatory
factors predisposing to fibrosis. With proper preoper-
ative, intraoperative, and postoperative management,
we are able to improve the safety of subconjunctival
drainage procedures while maintaining effectiveness.
Like trabeculectomy before it, the surgical technique
and management of XEN is constantly evolving, as
recently seen with the transconjunctival approach,
which may lead to new benefits, as it does not require
the use of viscoelastic, allows for potentially more
accurate placement over Tenon’s capsule, and opens
new locations for placement. The XEN Gel Stent may
further optimize the risk-benefit ratio of subconjuncti-
val drainage surgery and represents an important step
toward the ideal glaucoma surgical procedure.
Fig. 6. Updated injector. The previous injector (left) compared to

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13. An ab externo minimally invasive aqueous
shunt comprised of a novel biomaterial
Leonard Pinchuk1,2, Isabelle Riss3, Juan F. Batlle4, Henny Beckers5, Ingeborg Stalmans6
1
InnFocus, Inc., Miami, FL, USA; 2Ophthalmic Biophysics Center, Bascom Palmer Eye Institute, University of Miami Miller
School of Medicine, Miami, FL, USA; 3Pôle Ophtalmologique de la Clinique Mutualiste, Pessac, Cedex, France; 4Centro
Laser, Santo Domingo, Dominican Republic; 5University Eye Clinic, Maastricht University Medical Center+, Maastricht,
The Netherlands; 6Ophthalmology Department, University Hospitals UZ Leuven, Leuven, Belgium
Abstract
The PRESERFLOTM MicroShunt, formerly called the 6. adverse events were generally transient with no
InnFocus MicroShunt® (MicroShunt) is a minimally long-term, sight-threatening adverse events.
invasive, ab externo glaucoma drainage device used to
shunt aqueous humor from the anterior chamber of the
eye to a filtration bleb formed under the conjunctiva 1. Development of the SIBS-based
and Tenon’s capsule. The invention of a new biomaterial PRESERFLOTM MicroShunt
called poly(styrene-block-isobutylene-block-styrene),
or SIBS, was the enabling factor that led to the success The PRESERFLOTM MicroShunt1 ((MicroShunt, also
of this product. SIBS is ultrastable with virtually no for- discussed in Chapters 3 and 6), formerly called the
eign-body reaction in the body, which results in minimal InnFocus MicroShunt®, is the second of only two
inflammation and fibrous capsule formation in the eye. medical devices that leverages the superb biocompat-
The 70 µm lumen is designed to obtain low intraocular ibility of a unique biomaterial, designed specifically for
pressures without chronic hypotony. long-term implant, called poly(styrene-block-isobu-
This article summarizes the latest implant techniques tylene-block-styrene) or SIBS. The other medical
and five sets of clinical studies, performed outside of device is Boston Scientific’s (Natick, MA, United States)
the United States, which concluded that: TAXUS® coronary-artery stent, where a SIBS matrix
1. Mitomycin C (MMC) was required; impregnated with the antiproliferative drug paclitaxel
2. MMC should be widely applied under the is coated on the stent struts to deliver and release the
conjunctiva/Tenon’s flap; drug in the coronary arteries, as a means of preventing
3. MMC concentration of 0.4 mg/ml was more arterial restenosis.2 TAXUS with its SIBS coating has
effective than 0.2 mg/ml (P = 0.027); been used in the body since 2000.3 Boston Scientific
4. when 0.4 mg/ml MMC was used, the MicroShunt financed a series of companies founded by the lead
was effective in lowering the average intraocular author of this article (Dr. Leonard Pinchuk), who was
pressure (IOP) from baseline by 40-55% for at an inventor of SIBS in medicine, including TAXUS, with
least five years, with a mean IOP below 13 mmHg; the intention of developing novel products from this
5. mean numbers of glaucoma medications unique biomaterial, such as the MicroShunt.
were significantly reduced from baseline and Work on SIBS began in the early 1990s when
sustained for at least five years; and Dr. Pinchuk observed that conventional polyether
Correspondence: Leonard Pinchuk, InnFocus, Inc., A Santen Company, 12415 SW 136 Ave, Ste #3, Miami, FL 33186, USA.

182 L. Pinchuk et al.
urethane implantable biomaterials, such as those Polyisobutylene is a gum, implying that, when
comprising the insulators on pacemaker leads, per- pulled, it elongates without returning to its original
sistently attracted granulocytes as a consequence of shape. Chewing gum is polyisobutylene and this
their slow, unintended biodegradation in the body. elongation behavior is well known to people of all
Macrophages, polymorphonuclear leukocytes, and ages. Gums do not return to baseline when elongated
foreign-body giant cells migrated towards the device because the polymer strands comprising gums are
to either wall off the degrading material or dispose of linear and not tethered to each other; therefore, they
degraded fragments by phagocytosis.2,4 In an effort to slide past each other when elongated, like pulling
stop this degradation, Dr. Pinchuk set out to develop apart a cluster of spaghetti. In order to prevent the
a biostable polymer with no sites for degradation, linear strands from sliding past each other, the strands
i.e., no urethane, ether, ester, carbonate, carbamate, need to be attached or crosslinked, much like how the
amide, etc. linkages, on either the backbone or side rungs on a ladder hold the legs of the ladder together.
groups of the polymer. This premise also precluded There are several methods of crosslinking the strands,
the use of biological polymers, such as crosslinked the most popular being vulcanization with sulfur or
collagen5 or crosslinked hyaluronic acid, as the amide metallic groups. This vulcanization process provides
and/or ester groups in their backbones are susceptible a permanent shape to the crosslinked material and is
to hydrolysis and the material (regardless of the cross- known in polymer chemistry as a thermoset material.
linking content) will embrittle, degrade, and fracture Thermoset materials once formed cannot be melted
over time. or heat processed; silicone rubber and car tires are
Polymers devoid of these aforementioned cleavable examples of thermosets. In addition, the sulfurs and
groups are scarce, with only the fluoropolymers, metals used to form thermosets are often toxic and
silicones, and polyolefins remaining. The fluoropoly- not well tolerated in the body.
mers (e.g., polytetrafluoroethylene [PTFE or Teflon®] A method of forming a crosslink that can be melted
or perfluoroether [PFE]), although extremely inert, are is to provide what are called glassy segments on the
not rubber like, which is important when interfacing end of each linear strand of polyisobutylene. In the
soft tissue; stiff materials when interfacing with presence of heat or solvent, the glassy segments
compliant tissue tend to build up scar tissue or, if in the comingle or codissolve in each other (like attracts like)
anterior chamber of the eye, can damage endothelial and when cooled, or when the solvent is removed,
cells if the rigid device contacts the posterior cornea. the glassy segments coalesce to form microdomains
Silicone rubber (polydimethylsiloxane or PDMS) was which tether the polymer strands together. Once
also eliminated as both silicon and silicone are totally tethered, the strands no longer slide past each other,
foreign to the human body. In addition, the commer- and the material returns to its original shape after
cially available silicones are generally loaded with filler being stretched and relaxed. These elastomeric
and unreacted starting materials that could elute from (rubber-like) materials can be redissolved or reheated
the polymer and, as will be discussed below, could numerous times, such that the glassy segments melt
elicit a foreign-body reaction.6 Polyolefins (e.g., poly- apart and the material is reshaped. This meltable
ethylene and polypropylene) are flexible, but their and reshapable configuration is called a thermoform
flex-fatigue lives are limited as they tend to oxidize in material.
the body to form conjugated double bonds on their Thermoformable materials are advantageous for
backbones, which renders them brittle, causing them certain medical devices, such as glaucoma shunts,
to fragment or erode over time when flexed.7,8 However, as they will assume the shape of the globe without a
there is a small family within the polyolefins that is tendency to return to their original shape, as do the
comprised, in the most part, of dimethyl groups on thermoset materials. An excellent example are the
every second carbon, wherein the dimethyl groups silicone tubes used in large glaucoma valves, where
prevent double-bond formation on the backbone. This the silicone thermoset slowly returns to its extruded
sequence of alternating dimethyl groups characterizes straight configuration; therefore, glaucoma valve
the family of polyolefins knows as the polyisobutylenes. tubes must be tethered to the sclera with a patch graft
An ab externo minimally invasive aqueous shunt comprised of a novel biomaterial 183
Fig. 1. Upper: simplified chemical formula for SIBS showing the blocks of polystyrene, polyisobutylene, and polystyrene (M >> N).
Lower: schematic of microdomains of glassy, meltable polystyrene interconnected with spring-like polyisobutylene.
to avoid this tendency, as well as to prevent erosion is precipitated from the reaction bath and exposed
of the conjunctiva by the silicone tube as it reorients to numerous proprietary cleansing procedures to
itself. SIBS will assume the geometry of the globe with remove any unreacted chemicals or other impurities.
no tendency to straighten; therefore, a patch graft is In its final embodiment, SIBS is totally clean (pure) and
not required. does not contain cleavable groups on its backbone or
To render polyisobutylene a thermoformable its side groups. At the time of writing, there are no
material, the ends of the polyisobutylene need to be other elastomeric materials used in the human body
capped with a meltable glassy polymer; a preferred that can match these claims.10,11
glassy polymer is polystyrene. During the synthesis Sometime around 2003, Dr. Pinchuk introduced
procedure of polyisobutylene, which is performed by SIBS to Dr. Jean-Marie Parel at the University of
living carbo-cationic chemistry, the grown polyisobu- Miami’s Miller School of Medicine, Bascom Palmer Eye
tylene chain is reacted with styrene to form blocks of Institute, Optical Biophysics Center (OBC). Dr. Parel’s
glassy polystyrene on both ends of the polymer.9 The collaborators implanted 3 mm diameter, 1 mm thick
polymer thus formed is called poly (styrene-block- SIBS disks in the corneal stroma, as well as under
isobutylene-block-styrene), or SIBS. The simplified the conjunctiva and Tenon’s capsule, in the eyes of
structure of SIBS is shown in the upper section of New Zealand White rabbits. Similar disks made from
Figure 1, where M is an integer greater than N. The silicone rubber (PDMS) were implanted alongside the
lower section of Figure 1 shows the microdomains SIBS disks as controls. The results of the two-month
where the polystyrenes coalesce, tethering the poly- implants were published by Parel et al.12 and Acosta et
isobutylene strands together. Once SIBS is formed, it al.13 In brief, they found that there were no myofibro-
Fig. 2. Schematic showing the MicroShunt (units in mm) and placement of the MicroShunt in the eye. Note that the MicroShunt distal end
is tucked under Tenon’s capsule and that the bleb is shallow and posterior.
blasts or angiogenesis in the vicinity of the SIBS disks, made the most sense. This rationale for draining to
nor were there integral capsules surrounding the SIBS a bleb rather than Schlemm’s canal or the supracho-
disks. In contrast, the silicone-rubber controls showed roidal space is explained in more detail by Pinchuk et
angiogenesis, myofibroblasts, and significant capsules al.16,17 The potential advantage of the MicroShunt over
attached to the disks. In summary, SIBS was found to trabeculectomy would be the avoidance of cutting
be inert and well tolerated in the rabbit eye. the sclera and suturing the scleral flap with sutures
Based on these favorable observations in the eye, placed under the proper tension to control outflow,
Dr. Pinchuk and Dr. Parel, along with Dr. Francisco a process that requires significant surgical skill. It
Fantes, a glaucoma surgeon, designed an aqueous would also avoid sclerectomy and iridectomy and, if
drainage device without a plate and with a tube lumen required, post-implant suture lysis. In addition, the
diameter sufficiently large to allow passage of sloughed fluid dynamics of the MicroShunt could be controlled
endothelial cells (which are approximately 40-50 µm by the lumen diameter and the length of the device to
in diameter), while at the same time sufficiently minimize hypotony. Lastly, placement of the exit of the
small to prevent hypotony. The lumen diameter was MicroShunt 6 mm posterior to the limbus would direct
approximated from the Hagan-Poiseuille equation, aqueous drainage more posteriorly, which could
and a series of rabbit-eye implants by Arrieta et al.14 eliminate the thinner-walled anterior blebs that can
and Fantes et al.15 confirmed that a lumen diameter occur with trabeculectomy. These potential attributes
of approximately 70 µm would satisfy these require- spurred the development of the MicroShunt.18
ments. It was also decided that draining to a flap (later There were three major iterations of device design
to become a bleb) under the conjunctiva and Tenon’s that were tested first in rabbit eye studies at the
capsule, similar to the gold standard trabeculectomy, University of Miami, Bascom Palmer Eye Institute,
OBC laboratory, and then in pilot feasibility studies 3. three LASIK sponges to apply mitomycin C
over a period of four years, to determine the optimal (MMC; not supplied and concentration is at the
design and implantation technique.13,16 All animal discretion of the surgeon);
studies were authorized by the University of Miami 4. a 1 mm wide triangular knife to incise a shallow
ACUC (Animal Care and Use Committee). Clinical pocket in the sclera; and,
studies were conducted under authorization by the 5. a 25-g needle to form a needle tract under the
proper regulatory agencies in each country. In France, limbus to the anterior chamber.
approval was granted by AFSSAPS (Agence Française The current implant procedure practiced in Europe is
de Sécurité Sanitaire des Produits de Santé) and later shown in Figure 3A and 3B. (The European method of
by ANSM (Agence Nationale de Sécurité du Medicament implantation differs from that in the United States in
et des Produits de Santé). In the Dominican Republic, that a double-stepped knife is used in the United States
approval was granted by CONABIOS (the Dominican to make the pocket and needle tract as a one-stab
Republic National Counsel of Bioethics and Health). incision, which eliminates the need for the 25-G
Local, hospital-based ethics committee approvals were needle). A light pressure patch is generally used the
also obtained, where required. More detailed reviews day after surgery and nightly for five days thereafter.
of these three iterations have been published.16,17 The results of five different studies that helped define
The final design, currently used in the clinic and the design of the MicroShunt, the method of implan-
historically called the InnFocus MicroShunt®, is shown tation, the preferred patient, the proper placement
in Figure 2 along with its placement in the eye. The of MMC, and the optimum concentration of MMC are
MicroShunt consists of an 8.5 mm long SIBS tube with summarized in Table 1.
an outer diameter of 350 µm and a lumen diameter of The safety profile of the MicroShunt can best be
70 µm. Located halfway down the device is a 1.1 mm summarized from the five aforementioned studies by
wingspan planar-fixation member resembling the fins examining the adverse event trends:
on an arrow, which serves: 1. Adverse events from the surgical procedure
1. as a stopper to seal the device in the 1 mm wide occurred 5-15% of the time, usually within one
pocket and prevent leakage around the tube; week of the procedure, and included hyphema,
2. as an anchor to prevent the device from numerical hypotony, shallow chambers,
migrating into the eye; and choroidal detachment, and effusion; all resolved
3. as a mechanism of orienting the device, such spontaneously without surgical intervention
that the bevel in the anterior chamber faces the within one to three months.
cornea and the entrance to the lumen can be 2. Surgical failures — defined as reoperations
cleared if blocked by debris. performed in the operating room, which were
It is noteworthy that the distal end of the MicroShunt generally due to bleb fibrosis and subsequent
is 6 mm posterior to the limbus, thereby generating a bleb revision — included repositioning or
posterior bleb. replacement of the MicroShunt with a new
MicroShunt or a large drainage valve, trabe-
culectomy, or a ciliary body ablation procedure
2. Implantation of the MicroShunt and to reduce aqueous production. These surgical
summaries of results from clinical failures occurred approximately 3-5% of the
time, usually within one year of surgery. Needling
studies
of the bleb, which was generally not performed
The MicroShunt is provided by the manufacturer, in the surgical suite and was not considered
InnFocus, Inc. (Miami, FL, United States), a Santen an adverse event, occurred 2-10% of the time,
company, in a sterile packaged kit, which contains: usually within 9 months.
1. a ruler to measure the site of entry (3 mm from 3. Pressure failures were defined as patients with
the limbus); intraocular pressure (IOP) out of target range
2. a Gentian Violet marking pen to ink the ruler; (target range is IOP > 6 mmHg and ≤ 21 mmHg)
Fig. 3. (A) Implantation of the MicroShunt. Images courtesy of I. Stalmans.

Fig. 3. (B) Implantation of the MicroShunt continued. Images courtesy of I. Stalmans.

Table 1. Summary of five different studies that helped define the MicroShunt, the method of implantation, the preferred patient, and the
placement and concentration of MMC
Who/Where? Professor Isabelle Riss/Bordeaux, France16
Feasibility study to determine implantation methodology, device design, type of
Purpose
patient, and whether MMC is required.
Study 1 MicroShunt was efficacious in patients with POAG, with eyes that were not refractory
to surgery, where the patients failed maximum-tolerated glaucoma medication,
Conclusions
and trabeculectomy was indicated. It was found that MMC was necessary and that
the fin on the MicroShunt needs to be planar and placed in a scleral pocket.
Who/Where? Dr. Juan Batlle et al./Santo Domingo, Dominican Republic1

Feasibility study to determine implantation methodology, safety, and efficacy over
Purpose
time.
Patients with POAG received the MicroShunt, 14 alone and 9 in combination with
Methods cataract surgery. Qualified success ratea (IOP ≤ 14 mmHg and IOP reduction ≥ 20%)
was reported on or off glaucoma medication.
Study 2 Time N Successa IOP (mmHg) Meds/pt

Pre-op 23 n/a 23.8 ± 5.3 2.4 ± 0.9
Results Year 1 23 100% 10.7 ± 2.8 0.3 ± 0.8
Year 2 22 91% 11.9 ± 3.7 0.4 ± 1.0
Year 3 22 95% 10.7 ± 3.5 0.7 ± 1.1
IOP can be sustained in the low teens for at least three years if 0.4 mg/ml MMC is
Conclusions
spread throughout the bleb.
Who/Where? Professor Isabelle Riss/Bordeaux, France2

Feasibility study to determine implantation methodology, MMC placement, safety,
Purpose
and efficacy over time.
Placement of 0.2 or 0.4 mg/ml MMC from LASIK sponges either posteriorly in the
Methods
bleb (Group 1) or throughout the bleb (Group 2).
Time N Success IOP (mmHg) Meds/pt
Study 3 Group 1 (MMC Pre-op 40 N/R 26.0 ± 6.6 2.7 ± 1.3
posterior bleb
only) Year 1 40 N/R 16.5 ± 4.9 0.8 ± 1.1
Group 2 (MMC Pre-op 31 N/R 27.4 ± 6.9 3.1 ± 1.0

everywhere) Year 1 31 N/R 15.1 ± 5.2 1.1 ± 1.3
MMC needs to be spread all over the subconjunctival/Tenon’s flap and not simply
Conclusions
concentrated in the posterior flap.
Who/Where? Multicenter European/Dominican study (Garcia-Feijoo et al.3)

Retroactive pooled analysis to determine if 0.4 mg/ml MMC functions better than
Purpose
0.2 mg/ml MMC.
Patients with POAG received the MicroShunt. Both concentrations of MMC were
Methods
spread over the entire flap using LASIK sponges.
Time N IOP (mmHg) Meds/pt % off meds
Pre-op 58 22.7 ± 4.4 2.4 ± 1.3 n/a
0.2 mg/ml MMC Year 1 55 14.8 ± 5.0 0.7 ± 1.1 64.3
Year 2 50 14.8 ± 4.5 0.8 ± 1.1 59.6
Study 4
Pre-op 67 22.2 ± 4.0 2.1 ± 1.2 n/a
0.4 mg/ml MMC Year 1 59 12.9 ± 3.7 0.3 ± 0.7 84.8
Year 2 53 13.0 ± 3.4 0.2 ± 0.6 85.5
Pre-op IOPs in both groups were not significantly different (P = 0.508); however,
at Years 1 and 2, the IOP between groups was significantly different (P = 0.028
and 0.027, respectively). Similarly, pre-op medications in both groups were not
Conclusions significantly different (P = 0.174); however, at years one and two the difference in
glaucoma medications between the two groups was significantly different (P = 0.017
and 0.001, respectively). The overall conclusion was that 0.4 mg/ml MMC performs
significantly better than 0.2 mg/ml MMC in the patient populations investigated.
Who/Where? Dr. Juan Batlle/Santo Domingo, Dominican Republic.19,4

Purpose This is a continuation of Study 2 above to four and five years.
23 patients with POAG received the MicroShunt, 14 alone and 9 in combination with
Methods cataract surgery. Qualified success ratea (IOP ≤ 14 mmHg and IOP reduction ≥ 20%)
on or off glaucoma medication was reported.
Study 5 Time N Success (%)a IOP (mmHg) Meds/pt
Pre-op 23 n/a 23.8 ± 5.3 2.4 ± 0.9
Results
Year 4 14 87 12.3 ± 3.7 0.5 ± 1.0
Year 5 18 87 11.4 ± 4.9 0.5 ± 1.1
This study suggests that the decrease in IOP and medication can be sustained for at
Conclusions
least five years.
IOP: intraocular pressure; Meds/pt: number of medications per participant; MMC: mitomycin C; N: number of subjects; n/a: not available;
N/R: not reported; POAG: primary open-angle glaucoma
or less than 20% reduction below baseline on tend to be more posterior than traditional blebs
two consecutive, scheduled follow-up visits formed by trabeculectomy. The potential advantage
after three months, that did not achieve target of a posterior bleb is that the conjunctiva and Tenon’s
pressure at their last visit. Pressure failures are thicker; therefore, they should show less tendency
occurred 2-10% of the time in the first year post- to become thin and leak, which can lead to endoph-
operatively and then approximately 1-5% per thalmitis. The downside of a thicker roof of the bleb is
year thereafter. that it does not readily elevate as high with pressure;
4. Success rates, defined as those patients on or the roof is closer to the sclera, which can theoretical-
off medication that were not pressure or surgical ly lead to a higher incidence of bleb failure as the roof
failures, were between 80% and 100% at one to can heal to the sclera. It may be for this shallow-bleb
two years and were similar to those reported for reason or perhaps due to the presence of more Tenon’s
trabeculectomy.23,24 fibroblasts that in the reported studies, the higher
5. There were no long-term, sight-threatening 0.4 mg/mL dose of MMC resulted in better efficacy
adverse events, such as chronic hypotony, vit- outcomes for the MicroShunt than the lower 0.2 mg/
reous hemorrhage, loss of light perception, or mL dose, which may be adequate for trabeculectomy.
hypotony maculopathy in the studies reported At the present time, there is no evidence that 0.4 mg/
above. mL of MMC is more harmful to the patient; in fact, 0.4
mg/mL MMC seems to provide better outcomes in all
parameters measured.
3. Discussion and conclusions SIBS elicits a negligible foreign-body reaction;13
however, some bleb fibrosis has been reported,21
The development of SIBS and subsequently the Micro- which is consistent with surgical procedures (such
Shunt was an educated iterative process that occurred as trabeculectomy) where there is no foreign body
over the course of 20 years.16,17 The process required other than sutures. It is believed that aqueous humor
sophisticated chemistry and engineering, includ- flowing into the bleb contains cytokines that are
ing controlling the foreign-body reaction with SIBS, associated with fibrosis; the extent of fibrosis seems to
designing the device to be atraumatic with a lumen be mitigated with MMC. Therefore, it is not surprising
size that should not trap sloughed cells and still min- that MMC placement and concentration are relevant to
imize hypotony, and developing a design and implant the success of the MicroShunt procedure and, like tra-
procedure that protected the conjunctiva from being beculectomy, needlings and bleb revisions are at times
eroded by the device. The 1.1 mm wingspan fins on required. Needling of blebs is uncomplicated with the
the device are held firmly in the shallow 1.0 mm wide MicroShunt for three reasons:
pocket formed in the sclera, divert aqueous humor into 1. The foreign-body reaction around SIBS is
the lumen of the device, and prevent migration of the minimal; more often than not, bleb fibrosis
device into the eye. Draining to a bleb, as does the gold leads to the roof of the bleb adhering to the
standard trabeculectomy, is important, as this route sclera. Needling the bleb to sever the adhesions
bypasses the high resistances that can be anywhere in between the Tenon’s and sclera reforms the
the drainage path for aqueous humor, i.e., the trabec- bleb, and almost always reestablishes flow
ular meshwork, Schlemm’s canal, the collector chan- through the MicroShunt.
nels, the scleral veins, the episcleral veins, and even 2. SIBS is hydrophobic; therefore, it prevents
further downstream. Drainage of aqueous humor from tissue from growing into or adhering to the
the bleb follows the path of least resistance, which MicroShunt.
could include drainage into the episcleral venous 3. SIBS does not degrade; therefore, it remains
system and/or by percolating through the microcysts25 robust and can be needled without fear of
in the conjunctiva and into the tear film. amputation.
The MicroShunt distal end is approximately 6 mm The MicroShunt is soft with a low modulus and, because
posterior to the limbus and the blebs that are formed of its thermoplastic nature, conforms to the curvature
of the eye. The MicroShunt eventually re-forms into a servatives30 may limit subsequent filtration-treatment
stable, nonirritating and noneroding configuration. effectiveness.
The thermoplastic nature of SIBS can be contrasted The MicroShunt was CE marked on January 9, 2012
to the thermoset nature of silicone-rubber tubes, in Europe and a limited commercial rollout is underway
which tend to straighten in the eye and may erode the in Europe. The MicroShunt is also being tested in
conjunctiva; therefore, silicone-rubber tubes used in Canada, Japan, and Singapore; publications are
large drainage devices often require a patch graft over expected in the near future. Similarly, a US Investiga-
the tube to prevent erosion.26 tional Device Exception (IDE) was granted by the FDA in
In the aforementioned studies, as well as May 2013 and enrollment is complete for a multicenter
others, 27,28 the MicroShunt has demonstrated mean prospective randomized clinical trial of the MicroShunt
IOP reductions of 30-55% from baseline along with compared to primary trabeculectomy in patients who
reductions in mean number of glaucoma medications/ are refractory to glaucoma medication. The primary
patient, with no long-term, sight-threatening adverse endpoint is related to pressure drop from baseline,
events. The current data suggest that spreading 0.4 and the secondary endpoint is related to noninferi-
mg/mL MMC widely in the conjunctival/Tenon’s flap ority in respect to trabeculectomy. It is expected that
helps maintain the mean IOP below 14 mmHg, which the MicroShunt will be commercialized, pending FDA
may be sufficiently low to maintain stable visual fields clearance, in the United States in 2020.
in the majority of glaucoma patients. The advantages
of the MicroShunt procedure include:
1. straightforward procedure without the need for Acknowledgements
special equipment;
2. no dissection of a scleral flap (as performed in The authors wish to acknowledge Ms. Maria Consuelo
trabeculectomy); Varela in the Dominican Republic and Ms. Sophie
3. no need to perform sclerectomy or iridectomy; Albrespy in Bordeaux, France, as clinical coordina-
4. no reliance on subjective suture tension; tors in these studies. Funding for the research and
5. the ability to reposition the MicroShunt if placed development work as well as for the clinical studies
improperly; and was provided by InnFocus, Inc. (Miami, FL, United
6. minimal need for postoperative interventions States), a Santen company. We also acknowledge
(such as suture lysis). the INN 007 team in Europe who contributed to the
The intended use of the MicroShunt is to provide an European multicenter study.21 Editing support was
alternative to primary trabeculectomy. Once its safety provided by Bethany Broughton, MSc, Helios Medical
and efficacy are well established, it is expected that Communications, Cheshire, UK, which was funded by
this device will be studied in patients who are earlier in Santen. Database management and statistics were
the treatment paradigm, as an alternative to long-term provided by Zhengyang Shi from Brightech-Intl, NJ,
glaucoma medication where the drugs and their pre- United States, also funded by Santen.
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4. Pinchuk L. A review of the biostability and carcinogenicity of Poster abstract 1622, WOC 2018.
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stable’ polyurethanes. J Biomater Sci Polym Ed. 1994;6(3):225- the MicroShunt in patients with primary open-angle glaucoma
267. (POAG): 0.2 versus 0.4 mg/mL Mitomycin C (MMC) outcomes.
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8. Goldberg EP, Yalon M, Stacholy J, et al. Biocompatibility of in- spective, comparative trial of EX-PRESS glaucoma filtration
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August 15, 2000. 27. Riss I, Aptel F, Beckers H, et al. Interim 1-year outcomes follow-
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14. Laser trabeculoplasty and micropulse:
evolution from trabecular photocoagulation,
to trabecular photothermolysis, to trabecular
photostimulation
Giorgio Dorin1, Ted S. Acott2, Antonio M. Fea3, John R. Samples2,4
1
ALeyeGN Technologies, Saratoga, CA, USA; 2Casey Eye Institute, Oregon Health & Science University, Portland, OR,
USA; 3Department of Surgical Sciences, Glaucoma Unit, Ocular Clinic, Università degli Studi, Turin, Italy; 4Elson S. Floyd
College of Medicine, Washington State University, Spokane, WA, USA
Abstract
Laser trabeculoplasty (LT), administered as argon understanding of the ways the trabecular meshwork
laser trabeculoplasty (ALT), or as selective laser tra- (TM) can regulate the outflow of aqueous humor (AH)
beculoplasty (SLT), or as micropulse laser trabecu- and IOP homeostasis.
loplasty (MLT), is arguably one of the most valuable
and practiced laser procedures among the clinically Keywords: continuous wave (CW) laser trabeculo-
utilized laser treatments of ocular diseases. LT is used photocoagulation, nanosecond, laser trabeculoplasty,
to lower intraocular pressure (IOP) in patients with laser trabeculo-photothermolysis, micropulse laser
ocular hypertension (OHT) and primary open-angle trabeculo-photostimulation.
glaucoma (POAG). In this chapter, we trace the origins
of LT, its evolution during the past four decades and
its changing role in the clinical practice. This retro- 1. Introduction
spective will help to fully appreciate the conditions
and the rationale for the adoption of the micropulse Glaucoma is a progressive multifactorial optic
laser emission as an additional LT treatment option. neuropathy that currently represents the second
The clinical refinement and the better understand- leading cause of blindness worldwide with over 67
ing of MLT’s mechanism of action has contributed to million people affected and predicted to approach 80
the gradual paradigm shift from the destructive ALT million by the end of the decade.1-3
trabecular photocoagulation to less or nondamaging The goal of current glaucoma treatment is to
IOP-lowering laser techniques (i.e. SLT’s trabecular stop or slow disease progression, characterized by
photothermolysis and MLT’s trabecular photostimu- optic disk cupping and by a distinctive pattern of
lation) that can be administered earlier and repeated permanent visual field loss.4,5 Current glaucoma inter-
PRN (pro re nata) as required in a chronic, progressive ventions (medications, surgery, laser, etc.) achieve
neurodegenerative disease like glaucoma. this goal almost exclusively targeting the reduction
We also outline future directions and new technol- of intraocular pressure (IOP), which is the only known
ogies emerging from LT’s seminal lessons on a better modifiable risk factor and treatable component.
Correspondence: Giorgio Dorin, ALeyeGN Technologies, 12361 Saratoga-Sunnyvale Road, Saratoga, CA 95070, USA.

194 G. Dorin et al.
Tight IOP control relies on patients’ adherence to the wavelengths: 647 nm in krypton laser trabeculoplasty
prescribed medical therapy, but, unfortunately, poor (KLT); 810 nm in diode laser trabeculoplasty (DLT); 568,
patient compliance remains a major factor of disease 577, 595 nm in dye laser trabeculoplasty, etc. They tried
progression often leading to the need of invasive also various treatment protocols, with different burn
surgery. locations and percentages of angle treated, but always
Lasers were first used in the 1970s as a noninvasive pursuing a light to intense photocoagulation visible
microsurgery intended to create microperforations burn endpoint.
in the conventional aqueous humor (AH) outflow DLT was the only exception, due to the intrinsic
structures to lower IOP with laser made gonio- difficulty of obtaining a visible blanching endpoint in
punctures. the TM with the 810 nm diode laser. Luckily, the lower
The attempts of laser-puncture in the anterior 810 nm laser absorption in the TM turned out to be an
chamber angle with a Q-switched ruby laser by Krasnov,6 advantage that resulted in comparable IOP reduction
of argon laser goniotomy by Hager,7 and of argon laser with much lower inflammatory reaction with respect to
trabeculotomy by Worthen and Wickam,8 proved that ALT.11,12
making permanent laser holes into Schlemm’s canal Using a similar endpoint, all studies outcomes
(SC) was very difficult and this idea was eventually reported similar IOP reductions, and this led to
abandoned. The hoped laser-puncture IOP reduction important seminal observations:
was not seen. 1. The type of laser, laser parameters, and treating
However, the follow-up of eyes that underwent argon protocol are not specific factors determining
laser trabeculotomies inspired Ticho and Zauberman’s9 LT’s IOP reduction.
observation of a beneficial reduction of IOP even 2. This strongly suggests common pathways of
though their goal to make a lasting communication action elicited through nonspecific stimuli.
between the anterior chamber and the SC failed. This 3. Comparable IOP reductions are obtained with
resulted in a serendipitous but seminal paradigm-shift intense, light, and even without visible burn
and conceptual change: IOP can be lowered by a laser endpoints.
technique that does not create a lasting patent hole. 4. Complications are proportional to the burn
Since there was no sustained IOP-lowering effect intensity, and, in the absence of burns, effective-
even when a successful hole was created, the surprising ness is proportional to the number of applica-
and unexpected late IOP reduction was somehow tions.
attributed to the healing response of the trabecular 5. TM photocoagulation and photodestruction are
meshwork (TM) to the laser injury. not prerequisite for a useful treatment.
This concept may have been not totally understood 6. Laser photothermal effects cause biomechan-
and accepted when Wise and Witter published their ical responses (i.e. shrinkage due to burns’ scar
first pilot study “Argon laser therapy for open angle tissue contraction pulling open the intertra-
glaucoma”,10 which represented a true milestone: the becular spaces between the photocoagulation
birth of argon laser trabeculoplasty (ALT). ALT had the burns) and concomitant physiologic biochemical
great merit of advancing the thought process from the responses to the indirectly resulting sublethal
original trabecular puncture to a trabecular shrink and thermal stress or biostimulation in the adjacent
pull biomechanical response. ALT, with several burns surrounding still viable TM cells.
placed over the anterior nonfiltering TM (50 burns with 7. The biochemical stress response activates a
50 µm spots spaced in the 180° superior arc) is a proven cellular cascade that modulates biological,
effective treatment to lower IOP, but its photocoagula- metabolic, and gene expression changes;
tion burn endpoint is the main source of complications cytokine secretion; matrix metalloproteinase
and tissue scarring that limit retreatment possibilities, (MMP) induction; and extracellular matrix (ECM)
indications, and utilization. turnover and remodeling to increase AH outflow
Other LT techniques have been tried and facility through the juxtacanalicular trabecular
studied using different continuous wave (CW) laser network (JCTM).
Laser trabeculoplasty and micropulse 195
8. Both biomechanical and biochemical responses 1. immediate necrosis of the TM cells irradiated by
are important and critical to restoring the the laser beam, followed by heat diffusion toward
homeostasis of the TM in regulating AH outflow surrounding cooler tissue to re-equilibrate/decay
and IOP. to baseline temperature, which cause;
2. an adjacent corona of latent necrosis that will
manifest at a later time as an enlarged lesion;
2. LT with visible or no visible endpoint and
3. a larger surrounding corona with an area of heat
In conventional ALT, the treatment endpoint is an spread and decay at nonlethal temperature
intraoperative visible grayish to chalk white tissue stimulating all still viable TM cells that react to
blanching caused by a suprathreshold temperature the indirectly induced nonlethal thermal stress
elevation with photocoagulation of the TM and irre- with a biochemical response that triggers
versible cellular necrosis. Figure 1 illustrates the beneficial cellular cascade.
time-temperature history induced by a suprathreshold This biochemical response does not take place in the
laser photocoagulation burn. TM cells directly targeted, burned, and killed by the
Years of advances in the understanding of the laser, but in the adjacent viable TM cells indirectly
cellular and molecular changes inducible with laser stimulated by the heat re-equilibration process.
irradiation have allowed a better characterization of MLT performed as sub-vis-threshold nondestructive
the photothermal effects of ALT performed as photoco- photostimulation with no visible endpoint (Fig. 3) does
agulation pursuing a visible burn endpoint (Fig. 2) and not cause visible burns, no scars or signs of laser impact
of LT performed as photostimulation without any intra- discernable at any time postoperatively. The sublethal
operative visible burn endpoint (Fig. 3). thermal elevation is directly created in all TM cells
LT performed as photocoagulation with a visible burn targeted but not killed by the laser, with a biochemical
endpoint, such as ALT, KLT, YLT, and also DLT pursuing stress response that triggers the activation of a cellular
the burn endpoint, (Fig. 2) causes: cascade of biological effects in all the viable TM cells.
Fig. 1. Time-temperature history induced by a suprathreshold laser photocoagulation burn.

196 G. Dorin et al.
Fig. 3. MLT performed as sub-vis-threshold

nondestructive photostimulation with no
visible endpoint does not cause visible burns,
no scars or signs of laser impact discernable
at any time postoperatively. The sublethal
thermal elevation is directly created in all TM
cells targeted but not killed by the laser, with a
biochemical stress response that triggers the
activation of a cellular cascade of biological
effects in all the viable TM cells.
7. LT also triggers stem cell division in the “insert”

Fig. 2. LT performed as photocoagulation with a visible burn where the TM inserts under Schwalbe’s line of
endpoint, such as ALT, KLT, YLT, and also DLT pursuing the burn the cornea; these divided stem cells migrate out
endpoint. (a) Immediate necrosis of the TM cells irradiated by
the laser beam, followed by heat diffusion toward surrounding
and repopulate the laser-burn sites over a week
cooler tissue to re-equilibrate/decay to baseline temperature. (b) or so.23
Adjacent corona of latent necrosis that will manifest at a later time There are specific pathways of biomechanical
as an enlarged lesion. (c) Larger surrounding corona with an area
responses and nonspecific pathways of biochemical
of heat spread and decay at nonlethal temperature stimulating all
still viable TM cells that react to the indirectly induced nonlethal responses, all contributing to the reduction of IOP in
thermal stress with a biochemical response that triggers beneficial different times following the LT procedure.
cellular cascade. Selective laser trabeculoplasty (SLT), arguably
the most utilized LT technique in our days, was
Biochemical stress responses to direct or indirect originally designed to lower IOP through a specific
sublethal stimuli in viable TM cells induce biological biomechanical response: the selective photother-
molecular, cellular, and metabolic changes that molysis of pigmented TM cells, evidenced by SLT’s
modulate the aqueous outflow through the TM, including “champagne bubble” visible endpoint. This micro-
changes in gene expression, cytokine secretion, MMP explosion (cavitation) of pigmented cells would
induction, and TM cell and ECM remodeling: reduce the resistance to AH outflow by opening new
1. MMPs increase AH outflow facility and their pathways from the TM toward SC. Histopathological
inhibition decreases facility.13 The constitutively comparisons of human bank eyes after ALT and SLT24,25
secreted inhibitors of the MMPs (TIMPs 1,2, and have documented that SLT produces less morpho-
3) may also play a role. logical disruption of the trabecular beams than ALT,
2. IL-1α or β and TNFα are among the strongest and that this SLT disruption with bubble formation is
stimulators of MMPs, particularly stromelysin energy dose-dependent. The process of lowering SLT
(MMP3).14 treatment energy to reduce TM damage and collateral
3. LT stimulates MMP, including MMP3,15 specifically effects was instrumental to the understanding that
in the JCTM.16 the “champagne bubble” visible endpoint is not a pre-
4. LT mediates its MMP effects via a media-borne requisite for an effective IOP-lowering treatment, but
factor(s), which are IL-1β and TNFα, that are rather the main cause of treatment complications.
secreted into the media over the eight hours SLT can lower IOP without the “champagne bubble”
following LT.17 endpoint, which implies other mechanisms of action
5. This involves signal transduction by protein than the previously thought biomechanical response,
kinase Cµ,18 Erk map kinase,19 p38 map kinase,20 and which is now performed only as a periodical test
and JNK map kinase.21 to establish a lower, less damaging, but still effective
6. IL-1 and TNF act synergistically in the process.22 treatment energy level.
The initial IOP lowering after SLT may be attributed tions and to the overall stimulated area, thus to the
to the biomechanical cavitation response to the pho- number of cells recruited to the process. In the absence
tothermolysis of pigmented TM cells. The long-last- of anatomical and functional laser-induced damage,
ing IOP reduction is now believed to result from the subthreshold photostimulation allows to maximize the
biochemical stress response of nonpigmented TM cells areas and number of cells stimulated and activated to
— adjacent to the sites of cavitation and spared from produce useful biochemical responses. For this reason,
thermolysis by the lack of laser-absorbing pigments — conventional high-intensity/low-density retinal photo-
still viable and indirectly nonlethally stimulated by the
coagulation treatment patterns (Fig. 4) have evolved
surrounding thermo-acoustic stress. into low-intensity/high-density photostimulation
These biological responses induce changes that treatment patterns (Fig. 5) , a seminal paradigm shift
modulate increased AH outflow through the TM, which made possible by the absence of tissue destruction and
include rebalancing of the pathologic gene expression scarring.27,28
profile, cytokine secretion, MMP induction, and TM The very same paradigm shift has been found
remodeling.26 SLT is now preferably performed as a applicable to trabecular laser treatments such as
LT photostimulation procedure avoiding the bubble micropulse diode LT (MDLT), MLT, and SLT, which use a
endpoint. high number of contiguous applications. The efficacy of
the low-intensity/high-density MDLT photostimulation
compared to the traditional high-intensity/low-density
3. Intensity vs density in LT performed ALT photocoagulation in the activation of proinflam-
with visible or without visible endpoint matory cytokines and MMP (stromelysin-1) expression
has been tested in an experimental study at the Casey
The clinical experience with LT performed as a sub- Eye Institute of the Oregon Health & Science University
vis-threshold nondestructive trabecular photostimula- (Portland, OR, USA).
tion procedure with no intraoperative visible endpoint Ex vivo study on human donor eyes supports that
has mirrored the experience gained in years of sub- laser induced biological effects with upregulation of
vis-threshold nondestructive retinal photostimula- MMPs can occur with and without destructive laser
tion treatments with no burn endpoint. In most ocular burns in the TM and that nondestructive low-intensity/
photostimulation treatments, the therapeutically high-density laser applications can be more effective
useful photothermal effects and biological responses in the activation of cellular mechanisms that result in
are confined in the areas targeted and irradiated by increased outflow facility (Fig. 6).
the laser spot, with very limited thermal spread to Stromelysin (MMP-3) can hydrolyze and degrade the
surrounding areas. Unlike conventional threshold pho- excessive ECM in the TM, initiating ECM turnover and
tocoagulation, in which the burn-endpoint applications increasing AH outflow facility.29
must be limited and well separated to avoid large areas This may represent a common mechanism of action
of confluent scars, with subthreshold nondamaging that, to some degrees, is elicited with all LT techniques,
photostimulation the clinical effectiveness has been and possibly with other ocular interventions that result
found to be proportional to the number of applica- in IOP reduction, including trans-scleral CW laser cyclo-
Fig. 4. High-intensity/low-density photocoagulation pattern. Fig. 5. Low-intensity/high-density photostimulation pattern.

198 G. Dorin et al.
Fig. 6. Stromelysin-1 (MMP-3) expression after MDLT low-intensity/high-density photostimulation and ALT high-intensity/low-density
photocoagulation. Image courtesy of John R. Samples, Ted S. Acott, Mary J. Kelley, reproduced from unpublished original work.
Fig. 7. Typical LT treatment patterns normally used with ALT, KLT, and DLT
(left), SLT (center), and MDLT (right). The well-spaced 50 µm diameter burns
conventionally used in thermal ALT, KLT, and DLT photocoagulation (left) are
replaced by confluent large 400 µm diameter laser spots in SLT (center) and
with confluent 300 µm diameter laser spots in MDLT photostimulation (right).
Table 1. Summary of typical LT treatment patterns

ALT, KLT, DLT SLT MDLT
Spot size 50 µm 400 µm 300 µm
Power W & Energy J 300-1000 mW CW 0.4-1.2 mJ 1000 mW 15% duty cycle
Area treated 90 -180° 90-360° 360°
Pulse duration 0.1 s 3 ns 0.2 s
Number of spots 40 -50 50-100 100-140
Endpoint Whitening of the TM Champagne bubbles No visible tissue reaction
ALT: argon laser trabeculoplasty; CW: continuous wave; DLT: diode laser trabeculoplasty; KLT: krypton laser trabeculoplasty;
MDLT: micropulse diode laser trabeculoplasty; SLT: selective laser trabeculoplasty
Fig. 8. Visible and invisible photothermal effects as a function of laser radiant exposure in J/cm2 and tissue pigmentation.
photocoagulation of the ciliary body pars plicata, produces effects that are below the threshold
transscleral micropulse laser cyclophotostimulation of intraoperative visible tissue damage and of a
over the pars plana,51 as well as cataract surgery with latent tissue damage that will manifest after a
ultrasound phacoemulsification. certain time after the treatment; and
Figure 7 and Table 1 illustrate the typical LT treatment 2. a lower threshold of radiant exposure which
patterns normally used with ALT, SLT, and MDLT. The produces effects that are above the threshold of
well-spaced 50 µm diameter burns conventionally activation of biological effects.
used in ALT, KLT, and DLT threshold photocoagula- Can this be done with any laser? Sub-vis-threshold
tion are replaced by confluent large 400 µm diameter LT photostimulation can be certainly also performed
laser spots in SLT photothermolysis and with confluent using a standard CW laser or a Q-Switched Nd:YAG
300 µm diameter laser spots in MDLT photostimulation. laser by properly titrating the laser radiant exposure
(irradiance or power density in watt/cm2 with the CW
lasers and fluence or energy density in joules/cm2 with
4. Sub-vis-threshold LT the Q-Switched Nd:YAG laser) to be set at a median
photostimulation performed with CW or level between the upper and lower thresholds of the
therapeutic window for subvisible photostimulation
with micropulse lasers
treatments.
Sub-vis-threshold LT photostimulation requires the Therefore, why should the micropulse emission be
use of specific laser parameters capable of producing preferred to the standard CW emission for subthresh-
invisible, sublethal photothermal effects that are old photostimulation? The simple answer is that lasers
always below the threshold of tissue damage, but above in the micropulse emission mode provide a finer control
the threshold of activation of biochemical responses. of the induced photothermal effects as well as a wider,
Ideally, the parameters must be set in the middle of and hence safer, therapeutic window with respect
a therapeutic window (Fig. 8), defined as the window to CW emission lasers. This has been elucidated and
between: clinically proven in retinal macular treatments during
1. an upper threshold of radiant exposure which the past two decades.27-28
200 G. Dorin et al.
Fig. 9. (a) CW laser emission with 400 mW power,

50 ms duration, 100% duty cycle.
Fig. 9 (b) Micropulse laser emission with 400

mW power, 50 ms duration, delivering a train
of 25 micropulses. Each micropulse has 0.1 ms
(100 µs) “ON” time, followed by 1.9 ms (1900 µs)
“OFF” inter-pulse time, for a 2.0 ms period, 500
pps repetition rate (1s: 2x10 -3 s = 500 pps) and 5%
duty cycle. The laser emission of 0.1 s every 2.0
ms represents a duty cycle of 5% (0.1 ms: 2.0 ms
x 100).
4.1. What is micropulse? only two controls available in the CW emission mode.
With the conventional CW laser emission (Fig. 9a) A short micropulse “ON” time limits the time for
the surgeon can control the temperature rise for an the laser-induced heat to spread to adjacent tissues,
intended intraoperative endpoint by adjusting the confining the photothermal effect around the area of
laser energy (joules) with: the absorbing chromophore in the targeted cells. A
1. the power (watts); and/or long micropulse “OFF time” interval between pulses
2. the exposure duration (seconds); or allows cooling to take place before the next pulse is
3. both. delivered, minimizing thermal buildup and preventing
In the micropulse emission mode (Fig. 9b), the steady tissue damage.
CW emission is “chopped” into a train of short laser The individual adjustment of power, exposure
pulses, whose pulse-width “ON” time and inter-pulse duration, and duty cycle allows the surgeon an unprec-
“OFF” time are individually adjustable for the intended edented and finer control of:
duty cycle (the ratio ON time / ON+OFF time). The duty 1. the temperature rise;
cycle adds a very powerful and fine third control to the 2. the temperature-time-history; and
laser power and the exposure duration, which are the 3. the expansion of the photothermal effects.
The combination of these controls results in a much 2. insufficient thermal elevation (under-treatment);
wider and safer therapeutic window with respect to and
CW emission lasers. With a wider therapeutic window, 3. excessive thermal elevation (unexpected burn).
treatment risks, including the risk of undertreatment, Figure 10 illustrates the width of the therapeutic win-
are reduced or eliminated, with enhanced confidence dow as a function of the duty cycle of the laser emis-
for the surgeon and comfort for the patient. sion: the CW laser emission is represented as 100%
duty cycle (laser “ON” during all the exposure duration).
4.2. Therapeutic window as a function of the laser Micropulse emission can be set with different duty
emission duty cycle cycles by independently adjusting the pulse “ON” and
A wide therapeutic window is particularly important inter-pulse “OFF” times. The duty cycle settings nor-
when performing sub-vis-threshold treatments mally utilized for sub-vis-threshold treatments are 5%,
without a visible endpoint. The laser photothermal 10%, and 15%, which, as shown in the graph, require
effects in ocular tissue depends on the laser radiant a power that is respectively 15, 6.5, and 4 times higher
exposure and on the tissue pigmentation. Due to the than the power required with 100% duty cycle CW emis-
natural variability of the pigmentation and pigment dis- sion to produce a similar threshold visible tissue effect.
tribution among patients and in a same patient’s eye, In consideration of the ocular tissue pigmentation
a narrow therapeutic window often results in variable variability, the therapeutic window’s upper and lower
and unpredictable photothermal effects: thresholds for safe and effective subvisible photostim-
1. correct thermal elevation; ulation laser treatments are set as:
Fig. 10. Width of the therapeutic window as a function of the duty cycle of the laser emission. Image reproduced from: Kim SY, Sanislo
SR, Dalal R, Kelsoe WE, Blumenkranz MS. The selective effect of micropulse diode laser upon the retina. Association for Research in
Vision and Ophthalmology annual meeting. Fort Lauderdale, Florida, April 21-26, 1996. Abstract 3584. Image courtesy of SR Sanislo
and MS Blumenkranz.
202 G. Dorin et al.
1. upper threshold: 70% of the power needed for a The principles behind the control of photothermal
visible tissue reaction; and effects with micropulse emission can be visualized in
2. lower threshold : 130% of the power needed for Figure 11, showing how different time-temperature
the threshold of activation of biological effects. history profiles can be induced in the TM absorbing
The therapeutic window with 810 nm micropulse laser cells using different duty cycle settings.
at 5% duty cycle is 15 times wider than with CW laser With shorter pulse ‘‘ON’’ time, less heat can
(100% duty cycle), allowing effective and safe sub-vis- spread toward adjacent cooler tissue during the laser
threshold laser photostimulation treatments also in the emission, and the thermal effect is kept confined
presence of pronounced pigment variability. around the absorbing melanosomes. The longer the
cooling ‘‘OFF’’ time between pulses, the more thermal
relaxation with re-equilibration toward baseline
5. Sub-vis-threshold MDLT temperature can occur. When the inter-pulse ‘‘OFF’’
photostimulation time is adequately long, each micropulse thermal
rise can return to baseline temperature, creating
MDLT photostimulation represents the evolution of DLT a time-temperature history of sequential separate
photocoagulation performed with a CW 810 nm diode thermal ‘‘elevations’’ without cumulative thermal
laser. Remarkably, DLT was found as effective as ALT rise.
even without the visible burn endpoint,11 and, conse- Theoretically, each micropulse that can elevate the
quently, with a much lower inflammatory response.12 temperature of the cells by only a few degrees cannot
MDLT is a 300 µ diameter spot, low-irradiance pho- cause coagulation necrosis and can only denature
tostimulation protocol that lowers IOP without visible a very small fraction of proteins. In the absence of
destructive endpoint, thus minimizing or eliminating quick biologic repair mechanisms, each subsequent
collateral cell damage. MDLT utilizes the same 810-nm micropulse cumulatively adds to the fraction of
diode laser used for DLT, but in its micropulse emission denatured proteins, gradually reaching the intended
mode at 15% duty cycle. In the micropulse mode, a threshold of sublethal cellular injury in accordance
train of repetitive short pulses gives the surgeon the with the N-1/4 damage additivity formulation. 30
fine control of the laser-induced thermal elevation in Cumulative limited cellular protein denaturation
order to produce sublethal photothermal effects and has been for years the basis of subthreshold diode
induce biological response in the TM cells without any laser micropulse photostimulation therapy clinically
discernable cellular damage. used for the treatment of various retinal disorders.27,31
Fig. 11. Principles behind the control of pho-

tothermal effects with micropulse emission.
Different time-temperature history profiles
(dark curves) can be induced in the TM
absorbing cells using different duty cycle
settings (light grey pulses).
Fig. 12. Summary of MDLT

technique.
MDLT is typically performed as summarized in Figure which was renamed MLT, with no indication of laser
12 and Table 2, delivering 65 (or 130) confluent 300 µm type or wavelength to include 532 nm and 577 nm in
diameter invisible laser applications covering the whole addition to the original 810 nm diode laser wavelength.
height of the TM over a 180° (or 360°) angle. MLT with a 532 nm green or a 577 nm yellow laser
Due to the combination of the low absorption of in micropulse emission mode is performed using
the 810-nm laser wavelength by the TM and the low the same technique shown in Figure 12 for MDLT but,
irradiance over the relatively large 300 µm spot, MDLT obviously, lowering the laser power as appropriate by
interacts and thermally affects superficial and deeper the respective higher absorption coefficient of each-
TM-pigmented cells without producing visible changes, wavelength in order to produce the same photother-
tissue blanching, or bubble formation. The treatment is mal effects with no visible tissue reaction endpoint as
invisible to the surgeon and uneventful for the patient: in MDLT.
no dazzling laser flashes since the 810 nm infrared
(IR) wavelength is invisible to the patient’s eye, which 5.2. Clinical outcomes reported with MDLT
remains quiet with negligible flare and postoperative and MLT
inflammation, no IOP spikes, no pain, and no need for MDLT and MLT were introduced much later with
postoperative steroid therapy. respect to ALT and SLT and have been somehow under-
estimated during the LT renaissance prompted by SLT.
5.1. MDLT and MLT This may explain why there is only a limited body of
MDLT was the first trabecular treatment performed with efficacy and safety studies. Nevertheless, there are
a laser in the micropulse emission mode: the IRIDEX studies establishing both MDLT and MLT as safe and
OcuLight SLx 810 nm diode laser, which, at the time, effective treatments.
was the only ophthalmic laser with micropulse emission In a randomized pilot study conducted by Ingvoldstat
capability. However, when 532 nm green lasers and 577 et al. at the University of Missouri Kansas City, 32 MDLT
nm yellow lasers became available with both CW and and ALT showed an equal IOP-lowering effect at three
micropulse emission, they have been immediately months. IOP reduction from baseline was statistically
utilized to perform micropulse laser trabeculoplasty, significant for both arms of the study. At 1-hour from
204 G. Dorin et al.
Table 2. CW and pulsed laser trabeculoplasty treatment parameters within the range considered typical for average patients
Characteristics and CW-LT Pulsed-LT

Units
parameter ALT a,b,c
DLT a,b,c
SLTb,c MDLTd,e,f EMDLT50
Argon Diode laser in
Q-switched FD Micropulse Micropulse
Type of laser -/- (or CW FD CW mode
Nd:YAG laser diode laser diode laser
Nd:YAG) laser
Laser wavelength 488/514 810 532 810 810 nm
nm
(or 532)
Contact goniolens Goldman Ritch Latina MLT no goniolens
-/- 3-mirror lens trabeculoplasty laser goniolens laser goniolens Trans-scleral
(laser magnification) (1.08x) (0.71x) (1.0x) (1.0x) contact probe
(Spot diameter in air)
(50) (75) (400) (300 - 200)
Spot diameter at µm
54 53 400 300 - 200 600 µm
tissue
Laser power W 0.4-0.7 0.6-1.0 200-400 x103 2 1.5 W
Laser irradiance W/cm2 20-36 x 103 30-50 x 103 160-320 x 106 2.83 – 6.37 x 103 530 W/cm2
0.5 x 10 -3
Laser pulse length s 0.1 0.1-0.2 3 x 10 -9 300 x 10 -6
500 x 10 -6
Exposure duration s 0.1 s 0.1 - 0.2 s 3 x 10 -9 s 0.2 s 30 s

# 1 1 1 100 18,750
# of laser pulses
% 100% 100% 100% 15% 31.25%
Duty factor 0.3 ms ON + 1.7 ms OFF 0.5 ms ON + 1.1 ms OFF
Laser energy per 0.6 x 10 /pulse

-3
pulse and per J 40-70 x 10 -3 60-200 x 10 -3 0.6-1.2 x 10 -3 60 x 10 -3/ 7.5 x 10 -3 J

application site application
Laser fluence per
J/cm2 2.0-3.6 x 103 3.0-10 x 103 0.5-1.0 0.85 – 1.91 2.65 J/cm2
pulse
Number of laser 50 (or 100) 50 (100) 50 (or 100) 66-100 (132-200) 18,750 µ pulses
placements # spaced over spaced over confluent over confluent over in 30 s on 180°
over the TM 180° (or 360°) 180° (360°) 180° or 360° 180° (360°) superior TM
Treated fraction
(%) of the TM -/- 6.5-13% 6.5-13% 50% (or 100%) 50% or 100% 50%
circumference
Total energy per eye J 2.0-7.0 3.0-20.0 30 – 120 x 10 -3 3.96 - 12.0 140.63 J
TM blanching
Light grayish to Bubbles to no
to No visible tissue No visible tissue
Treatment endpoint -/- no visible tissue visible tissue
bubble reaction reaction
reaction reaction
(intense)
ALT: argon laser trabeculoplasty; CW: continuous wave; DLT: diode laser trabeculoplasty; EMDLT: ab externo micropulse diode laser trabeculoplasty; KLT:
krypton laser trabeculoplasty; MDLT: micropulse diode laser trabeculoplasty; SLT: selective laser trabeculoplasty
a
American Academy of Ophthalmology. Committee on Ophthalmic Procedures Assessment. Laser trabeculoplasty for primary open-angle glaucoma.
Ophthalmology. 1996;103(10):1706-1712.
b
Park CH, Latina MA, Schuman JS. Developments in laser trabeculoplasty. Ophthalmic Surg Lasers. 2000;30(4):315-322.
c
Olivier MMG. Glaucoma laser treatment: where are we now? Tec Ophthalmol. 2004; 2(3):118-123.
d
Ingvoldstat DD, Krishna R, Willoughby L. Micropulse diode laser trabeculoplasty versus argon laser trabeculoplasty in the treatment of open angle
glaucoma. Invest Ophthalmol Vis Sci. 2005;46:ARVO E-Abstract 123.
e
Fea AM, Bosone A, Rolle T, Brogliatti B, Grignolo FM. Micropulse diode laser trabeculoplasty (MDLT): A phase II clinical study with 12 months follow-up.
Clin Ophthalmol. 2008;2(2):247-252.
f
Fea AM, Dorin G. Laser treatment of glaucoma: evolution of laser trabeculoplasty techniques. Tec Ophthalmol. 2008;6:45-52.
treatment, cell and flare reaction at ‘‘trace-1+’’ level = 25). There was no statistically significant difference
was found in 10/11 (91%) of the ALT eyes and in 2/10 in IOP reduction between the SLT and MLT groups at
(20%) of the MDLT eyes. both 4-6 weeks and 8-16 weeks post-treatment. Both
In a 1-year prospective clinical trial at the University lasers were safe, but MLT was more comfortable for
of Turin-Italy, Fea et al.33 looked at the 12-month most patients, mostly because of the absence of the
efficacy of treating the inferior 180° of the TM with disturbing intense glare of SLT’s 532 nm dazzling green
MDLT using 100 confluent applications at 2.0 W with laser beam. Additionally, there was a trend towards
15% duty cycle. The study showed that at 12 months, earlier IOP reduction in the MLT group at post-treat-
75% of the eyes treated with MDLT for uncontrolled ment week 1 follow-up visit, but this was not statisti-
open-angle glaucoma (OAG) despite maximally cally significant.
tolerable medication treatment reached their target Abramowitz et al.36 went on to compare MLT with
pressure. IOP was below 22 mmHg and at least 3 SLT. This study group used much more accurate
mmHg lower from pretreatment baseline. The mean treatment parameters, with each group receiving a
percentage of IOP reduction was 22.1%. Anterior full 360° treatment. Patients were randomly selected
chamber reaction was measured with a flare meter: for either the MLT or SLT group and followed for
no significant changes were observed after treatment, a 52-week period. IOP was lowered to ≥ 3 mmHg
except for one patient with a pigmented meshwork from baseline among 37.0% of the MLT patients
who also experienced an IOP spike (34 mmHg), which and 36.0% of patients in the SLT group at 24–52
was medically controlled. At one year, no anterior weeks. Of the MLT patients, 29.6% experienced a
synechiae were detected. 20% or greater decrease from baseline, while 36.0%
In a prospective randomized trial comparing ALT of the SLT patients achieved the same reduction
and MLT performed by Detry-Morel et al., 34 patients (P = 0.77). The study group also found that patients in
were randomly selected to treatment with ALT or MLT the MLT group reported significantly less intraopera-
and followed for three months. Both groups showed tive and postoperative pain and discomfort (P = 0.005).
significant lowering in IOP, but the ALT group was sig- Lee et al.37 investigated the safety and efficacy of
nificantly lower than the MLT group. The MLT group did performing MLT with the 577 nm micropulse yellow
not have any adverse events and no pain was reported, laser in the treatment of 48 subjects with OAG. The
which was significantly better than the ALT group. The mean number of MLT applications was 120.5 ± 2.0
flaw in the study is that the number of applications in confluent over 360° TM using a mean power of 1.0
the MLT treatment protocol were significantly lower W per application. Only 7.5% had a mild, self-limit-
than what is currently recommended for an effective ing anterior uveitis post-laser with no change in the
low-intensity/high-density photostimulation. Patients Snellen visual acuity at 6 months (Ps > 0.5). The IOP
treated with MLT received only 66 spots, which is and number of medications were significantly reduced
about half of the 130 confluent 300 µm dia. spots at all time intervals following MLT compared to the
contiguously applied over the entire 360° TM that are pre-MLT level (Ps < 0.0001). At 1 month, 35/48 subjects
currently used in the clinical practice. The merit of the had an IOP reduction ≥ 20%, representing a 72.9%
study is to support the notion that the high-intensity MLT success rate, with a mean IOP reduction of 23.8%
burn endpoint of ALT photocoagulation is not prereq- from pre-MLT levels among all treated subjects. At 6
uisite for the activation of LT’s beneficial biochemical months, IOP was reduced by 19.5% in addition to a
response, but the main cause of treatment discomfort 21.4% reduction in medication use compared to pre-
and complication, while the effectiveness of low-inten- treatment levels. During the first 6 months only 2.1 %
sity photostimulation is proportional to the number required a repeated MLT. MLT was effective in reducing
and density of the applications IOP and medications in OAG with minimal post-laser
Chadha et al.35 conducted a randomized, prospective inflammation and low failure rate at 6 months following
study with 48 patients with OAG that needed laser. None of the eyes experienced IOP spikes after
additional IOP reduction. Patients were randomly MLT.
assigned to receive 360° SLT (N = 23) or 577 nm MLT (N
206 G. Dorin et al.
6. Discussion outcomes are quite consistent, regardless the type of

LT technique utilized. This points toward the likelihood
Trabecular laser photocoagulation (ALT, KLT, DLT, etc.), that all types of LT create a photostimulation which
trabecular laser photothermolysis (SLT), and trabecular activates a common mechanism of action responsible
laser photostimulation (MDLT and MLT) appear to be for the similar IOP lowering effect.38-40
equally effective in lowering IOP. They differ in the A biomechanical theory and a biochemical theory
amount of iatrogenic tissue damage, retreatment are both considered important and synergistic to the
possibility, collateral complications, and patient homeostasis of the TM in regulating AH outflow and IOP.
comfort. Their efficacy and success rate seem to be Numerous studies provide the framework for a
more dependent on patients’ factors (race, age, pig- hypothesis on a mechanism based upon the transcrip-
mentation, preoperative IOP, stage of glaucoma, and tional activation of trabecular MMPs to modulate the
fellow eye response to laser) than on the LT technique/ juxtacanalicular extracellular matrix (ECM) turnover and
protocol utilized. biosynthesis, with beneficial effects on the chronically
These observations strongly suggest that all forms reduced proteoglycan turnover.41
of LT may share at least a common mechanism of LT induces trabecular cell division and change in gly-
action, which is likely a cellular cascade initiated by cosaminoglycan (GAG) production profiles within the
the activation of cytokine expression with subsequent first 48 hours following treatment.42-44 By 1 or 2 weeks
upregulation of MMPs (MMP-3). post-LT, the cells that divided within the first 48 hours
This activation could not occur in TM cells directly have migrated from the trabecular insert into the
targeted by the laser and destroyed by coagulation or TM and are found surrounding the LT burn sites.45 By
thermolysis, but could only take place in viable cells, 10 days post-LT, restoration to a more normal GAG bio-
stimulated but not killed, by an indirectly (ALT, SLT) synthesis profile has also occurred;43 this relies heavily
or directly (MDLT, MLT) induced nonlethal photother- on transcriptional activation mechanisms to modulate
mal or photoacoustic stress. The stimulation of the ECM turnover and biosynthesis.41, 46
biochemical activation with a modest and nonlethal LT treatment induces a rapid increase in the
thermal rise (i.e. 7-10°C) and/or acoustic cavitation is: messenger RNA (mRNA) levels of the trabecular
1. directly produced with the low-intensity/ MMPs and their TIMPs, followed by an increase in the
high-density application of low-irradiance laser expression of these proteins.46-48
micropulses in MDLT and MLT; and The induction of cell division and metalloproteinas-
2. indirectly elicited in nontargeted TM cells by the es expression occurs for the full 360° of the meshwork,
thermal spread from the high temperature of the whether 360° or only 180° are laser treated.48 This
well-spaced burn endpoints in ALT, KLT, and DLT supports the hypothesis that medium-borne factor(s),
or in nonpigmented TM cells adjacent to the sites likely cytokines, are responsible for triggering these
of ‘‘cavitation microexplosion’’ of pigmented TM responses.17
cells in SLT’s photothermolysis. Furthermore, the understanding that direct TM
These considerations support the hypothesis that all tissue targeting and destruction, either by photocoag-
types of LT work through at least a common mechanism ulation or by photothermolysis, is not prerequisite for
of action stimulated by a sublethal stress response, a useful IOP-lowering treatment, has already inspired
and consequently offer a reasonable explanation to the evaluation of novel nongonioscopic laser delivery
the comparable IOP-lowering outcomes in responding approaches that could simplify and even improve the
eyes. efficiency of stimulating trabeculoplasty-like responses
LT is now advocated as a possible first-line therapy and the effectiveness of achieving trabeculoplas-
for eyes with OAG and OHT. ty-comparable IOP reductions.
LT ameliorates the pathologically increased
resistance to the outflow of AH by mechanisms that 6.1. Future directions: trans-scleral LT
are still not completely understood. LT clinical efficacy Until recently, all LT procedures were performed
in lowering IOP is well-established and the clinical trans-corneally, directing and focusing the laser
beam over the TM through a gonioscopy lens. Unfor- junction while pointing at the underlying convention-
tunately, visualization of the TM and of the angle with al outflow structures: TM, SC, and collector channels.
a gonioscopy lens requires enough angle width and They used micropulse laser settings of 0.5 ms “ON”
delivering the laser beam under gonioscopic guidance time, 1.1 ms “OFF” time, thus 1.6 ms period, 31.25%
requires training, skills, and experience, which may duty cycle, and 625 pps repetition rate. Care was used
represent a challenge. to complete the sliding of the probe over the superior
In prevision of an increased role of LT in the 180° arc in 30 s, delivering a train of 18,750 repetitive
management of glaucoma patients, and in consid- micropulses. This 30 s laser treatment provided a 14%
eration of its huge benefits in blunting IOP diurnal IOP reduction until 3 months of follow-up, with no
variation and in relieving patient’s compliance issues (a postoperative IOP spikes and no visual acuity decline.
common problem in glaucoma medical therapy), new The authors described this trans-scleral laser sublethal
less invasive or noninvasive techniques are currently photostimulation ab externo treatment as a practical
under development and in clinical evaluation for nongonioscopic alternative to the standard ab-interno
the purpose of achieving LT-comparable IOP-lower- LT, easy and quick to perform, with minimum intraop-
ing responses with easier to perform laser delivery erative discomfort, and no postoperative IOP spike. All
approaches. the details of EMDLT laser parameters can be found in
Clinicians performing sub-visible-threshold Table 2, where EMDLT is compared to ALT, DLT, SLT, and
trabecular photostimulation realized that gonioscop- MDLT.
ically pinpointing TM cells to elicit nonspecific and The above two innovative trans-scleral nonde-
invisible effects was a tedious and unnecessary effort structive laser photostimulation interventions are just
and decided to bypass the traditional gonioscopic logical developments derived from the understand-
delivery by directing the laser beam ab externo ing that photocoagulation or photodestruction of TM
trans-sclerally.49,50 cells is a redundant nonprerequisite and nonstrictly
Geffen et al.49 have described their ab externo significant stimulus for the activation of common
approach to perform SLT without a gonioscopy lens. biological pathways to IOP reduction and restored
The 532 nm Q-switch Nd:YAG laser energy is applied homeostasis.
trans-sclerally over the perilimbal region to reach the Another example is micropulse trans-scleral laser
conventional outflow-path structures through about cyclophotocoagulation (MP-TSCPC), delivered with a
1 mm penetration depth without specifically targeting handpiece manually slid over the pars plana. Depending
and focusing the TM. The intermediate-term results on the surgeon’s sliding speed, MP-TSCPC can be a
report an IOP reduction comparable to conventional minimally destructive photocoagulation or a nonde-
SLT for one year, without lens-related corneal compli- structive photostimulation, which has been found
cations, such as iatrogenic corneal lesions, superficial to be an efficient noninvasive glaucoma treatment
punctate keratopathy (SPK), infections, and ocular that achieves sustained IOP reduction and reduced
discomfort associated with the use of the gonioscopy need for ocular antihypertensive medications for up to
lens. This novel technique simplifies and shortens the 15 months.51
administration of the LT procedure. This notion may pave the road for the development
Aquino and Chew of the National University of more practical and gentler laser interventions that
Hospital of Singapore, have presented the results do not require the use of a gonioscopy lens, are easy to
of their prospective case series pilot study treating administer, and are fast to perform with the least intra-
patients with POAG and IOP ≥ 22 mmHg with their operative discomfort and postoperative complications.
original ab externo micropulse diode laser trabecu- A safe, effective, repeatable pro re nata (PRN) and
loplasty (EMDLT) at the 13th Congress of the European nondestructive trabecular laser photostimulation
Glaucoma Society (May 2018, Florence, Italy).50 The treatment could provide a cost-effective primary
810 nm IR laser energy is applied through a customized antiglaucomatous therapy, with the added benefit
indenting probe that is manually slid at constant of blunting diurnal IOP variations52 and alleviating
speed over the superior 180° arc of the scleral-corneal patient’s compliance problems.
208 G. Dorin et al.
7. Conclusions
and patient comfort, with no discernable iatrogenic
MDLT and MLT are LT techniques that use micropulse damage to the TM, and with the lowest incidence of
laser irradiation to intentionally avoid any visible intraoperative and postoperative complications and
treatment endpoint and inherent iatrogenic damage. side effects.
Visible endpoints such as the photocoagulation They are repeatable PRNand their wide therapeutic
“burn” of ALT, KLT, DLT, etc. or the photothermolysis window provides consistent invisible photostimula-
“champagne bubble” of SLT are not prerequisites for tion for the safe and effective bioactivation of cellular
a useful IOP-lowering treatment, are redundant, and responses with transcriptional mechanisms that
constitute the main cause of treatment complications. modulate ECM turnover and biosynthesis even in eyes
MDLT and MLT are subthreshold laser trabecular with pronounced pigmentation variability.
photostimulation treatments performed to induce MDLT and MLT are administered using multi-pur-
biochemical responses in the targeted, but not lethally pose ophthalmic lasers with both CW and micropulse
injured, TM cells. They have shown IOP-lowering efficacy emission capabilities, and do not require the acquisition
comparable to ALT and SLT, with excellent safety profile of single-purpose laser systems.
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(SLT) vs. 577 nm Micropulse Laser Trabeculoplasty (MLT) in Eyes 50. Aquino MC, Chew PTK. External micropulse diode laser tra-
with Open-Angle Glaucoma. American Glaucoma Society 25th beculoplasty (EMDLT) for primary open-angle glaucoma. 13th
Annual Meeting Abstract # 90. European Glaucoma Society Congress, Florence, Italy, 19-22
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DA, Lamba T. Selective laser trabeculoplasty vs micropulse 51. Zaaron K, Abdelmassih Y, Arej N, Tomey K, Khoueir Z. Outcomes
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37. Lee JW, Yau GS, Yick DW, Yuen CY. Micropulse laser trabecu- doi:10.1097/IJG.0000000000001174
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15. Cyclophotocoagulation
Michael Giovingo1,2, Shyam Patel1, Shweta Chaudhary1, Amar Mannina1, Thomas Patrianakos1
Division of Ophthalmology, Cook County Health, Chicago, IL, USA; 2Department of Ophthalmology, Northwestern
1
University, Chicago, IL, USA
Purpose: To discuss cyclophotocoagulation as a treat- Currently, the only modifiable risk factor in the
ment for glaucoma and review recent innovations in the treatment of glaucoma is intraocular pressure (IOP).
technology. Over time, multiple targets for lowering IOP have
Summary: Cyclophotocoagulation is a procedure that been used to slow the progression of glaucoma. Since
lowers intraocular pressure by thermally damaging the the 1930s, cyclodestruction has been employed to
nonpigmented ciliary epithelium, which is responsible decrease aqueous production.1 Historically, multiple
for producing aqueous humor. Historically, it was viewed methods have been used to damage the ciliary body
as a last line therapy for end-stage disease due to diffi- and subsequently decrease aqueous production:
culty titrating results, post-procedure inflammation, and cryotherapy, diathermy, ultrasound, surgical excision,
risk of phthisis bulbi. Traditional cyclophotocoagulation and laser.2 Out of these different methods, cyclophoto-
still has a significant role in glaucoma treatment as newer coagulation with a thermal diode laser emerged as the
techniques have improved the side effect profile. Tech- predominant modality. It allows for a quick, effective,
nologic advances, including endoscopic application and and technically easy procedure to decrease aqueous
micropulse application of the laser, have also broadened production. The procedure works well in lowering IOP,
the scope of cyclophotocoagulation. Endocyclophoto- but is highly inflammatory and carries a risk of inducing
coagulation allows for direct application of the thermal phthisis, which is devastating.3 Newer probe models
energy to the ciliary body, which decreases collateral have emerged, which include a fiber optic probe that
damage and subsequent postoperative inflammation. helps identify the ciliary body and ensure proper probe
Micropulse technology is still applied in a trans-scleral placement.
approach, but also is minimally inflammatory. Recent As the technology advanced, the laser was combined
studies also indicate that micropulse cyclophotocoag- with endoscopic technology so that the same laser
ulation may have multiple mechanisms of action which could be directed specifically at the ciliary body through
allow for a more physiologic treatment. Overall, cyclo- an internal approach. This technique, known as endo-
photocoagulation has been a mainstay in glaucoma cyclophotocoagulation (ECP), causes less collateral
treatment. Newer treatment parameters and technol- damage but can still cause a significant amount of
ogies have allowed for improved outcomes, better side inflammation.4 ECP must also be performed on a pseu-
effect profiles, and new mechanisms of action. dophakic or aphakic patient, or in combination with
cataract surgery.5 The other downside to the endoscopic
Keywords: continuous wave cyclophotocoagulation approach is that it is intraocular, so it carries a relatively
(CWCPC), endocyclophotocoagulation (ECP), glaucoma, higher risk of intraocular infection in comparison to
micropulse cyclophotocoagulation (MPCPC), trans-scler- extraocular surgery. Due to the infection risk, it must be
al cyclophotocoagulation (TSCPC) performed in an operating room setting.
Correspondence: Michael C. Giovingo, MD, 100 E. Huron, Suite 1000, Chicago, IL 60611, USA.

212 M. Giovingo et al.
Recently, a new development in micropulse laser CWCPC is a highly successful procedure in terms of
technology has changed our view on trans-scler- pressure lowering, but due to its destructive nature,
al cyclodiode laser.6 This new method of delivering it also carries significant risks.3 Complications range
diode laser to the ciliary body, micropulse cyclo- from pain and prolonged inflammation all the way to
photocoagulation (MPCPC), is still done in a trans- phthisis. In order to minimize complications, clinicians
scleral fashion, but has significantly less inflammation have tried varying techniques by changing the power
than previous methods. The laser beam is delivered and duration of each application.
in a continuous fashion but is split into short bursts
of energy. These short bursts allow for a significant 2.1. Procedure
amount of energy to be delivered to the tissue without CWCPC is performed with a G-Probe (IRIDEX
the significant increase in tissue temperature seen with Corporation, Mountain View, CA, USA) (Fig. 1) in a
both traditional trans-scleral cyclodiode laser and ECP. trans-scleral fashion. The clinician places the leading
Early studies indicated that the mechanism of action edge of the probe at the limbus and holds it in straight
for lowering IOP with MPCPC appear to be multifac- up and down (Fig. 2, Video 1). Individual laser spots are
torial. There is some ciliary body destruction, along then placed around the limbus (Fig. 3). The clinician can
with a possible increase in outflow via the uveoscleral vary the power and time of delivery for each spot. The
pathway and a trabeculoplasty-like effect.6 3 o’clock and 9 o’clock positions are to be avoided to
As glaucoma intervention advances, the main goal is spare the long ciliary nerves, as treating those areas
to achieve a blebless, safe method for lowering IOP. Over would induce significant pain. CWCPC can be performed
the last ten to twenty years, technology has advanced in either a clinic or in an operating room setting. The
drastically in performing cyclophotocoagulation, procedure causes significant pain, so it should always
developing multiple different treatment modalities. be performed with either a retrobulbar block, systemic
Each of these modalities has a different efficacy and anesthesia, or a combination of both.
safety profile, allowing treatment to be tailored to each There is some debate regarding the most effective
individual patient. Overall, cyclophotocoagulation is and safe method for delivery. Some advocate for the
one of the mainstays in glaucoma intervention. standard duration (SD) technique, where higher powers
are used with a shorter duration. The clinician titrates
the power to hear an audible “pop” that signifies tissue
2. Continuous wave rupture, subsequently titrating the power down until
cyclophotocoagulation the “pop” disappears or is barely audible. Powers range
from 1500 to 2300 mW with a duration of 2000 ms,
Standard cycophotocoagulation or continuous wave resulting in a delivery of 3-4 J per spot. Others advocate
cyclophotocoagulation (CWCPC) is performed with a for a long duration (LD) or “slow burn” technique, where
diode laser at 810 nm. The diode laser is preferred over lower powers are used for a longer duration. When
other types of laser for this procedure due to the fact employing this technique, “pops” may or may not occur,
that the melanin absorbs energy at this wavelength, but the physician maintains the same power settings
directing the power to the ciliary body epithelium and throughout the entirety of the procedure.
decreasing absorption in surrounding tissues.2 The
goal of the procedure is to cause thermal injury at the 2.2. Improving outcomes
cellular level within the ciliary body, thus decreasing Iridex Corporation has released a new probe, the
aqueous production. G-Probe Illuminate (Fig. 4), intended to guide probe
Fig. 1. G-Probe used for

CWCPC.
Cyclophotocoagulation 213
Fig. 2. Proper placement at the limbus of a G-Probe for CWPC.

Image courtesy of Iridex Corp.
Fig. 4. G-Probe Illuminate. Image courtesy of Iridex Corp. Fig. 3. CWCPC laser spot placement. Image courtesy of Iridex Corp.
Fig. 5. G-Probe Illuminate being used to guide placement of the probe over the ciliary body. Image courtesy of Iridex Corp.
placement. The original G-Probe is held at the limbus the probe position until they do receive feedback that
(Fig. 2), which standardizes the laser delivery at 1.2 the probe is over the ciliary body. Although research
mm posterior to the limbus. This procedure works into the outcomes of this procedure is limited, it can,
very well but does not account for anatomy that in theory, improve outcomes by making sure the laser
deviates from average. The G-Probe Illuminate has is delivered to the intended tissue.
a fiber optic light in addition to the laser probe. The
clinician places the probe at the limbus in a similar 2.3. Clinical outcomes
fashion to the procedure for the G-Probe. If 360° Studies have demonstrated an ocular antihyperten-
transillumination is seen, the probe is accurately sive effect of CWCPC ranging from 12.3 to 66.0%.7 Eyes
placed over the ciliary body (Fig. 5, Video 2). attaining an IOP of 21 mmHg or less vary from 54.0
If no transillumination is seen, the clinician can vary to 92.7%.8 The amount of energy used for treatment
seems to correlate with treatment success without age groups18 Grueb et al. looked at prior surgery as
leading to a higher complication or vision loss rate.9-11 a predictor of CWCPC success in pseudoexfoliation
There is a direct linear correlation between the total glaucoma. They found that the success rate was
amount of energy applied to the ciliary body and higher when CWCPC was performed as a primary
surgical success (Table 1).9 procedure.19
Noureddin et al.10 evaluated the IOP-lowering ability, Many clinicians use CWCPC in the treatment of
retreatment rate, and complications of CWCPC using refractory glaucoma after incisional surgery has
a higher power setting of 126 J per session. The use failed, so it is very important to understand the
of higher power settings resulted in a sustained lower clinical outcomes in this scenario. Since the Tube
IOP (below 21 mmHg) in 72.2%, less need for re-treat- versus Trabeculectomy Study, 20 more clinicians
ment (25%), and no irreversible complications. They have employed tube shunts in patients as the
also found that the mean IOP reduction was strongly incisional surgery of choice. When a tube shunt
correlated with the number of laser burns. On the fails to adequately control IOP, limited treatment
other hand, there are several studies that could not options remain. These options include a second
find a direct correlation between energy delivered tube shunt placement, 21 revision of the existing
and treatment success.12,13 tube shunt, or a cyclodestructive procedure.21-23
Many groups have studied patient demographics Semchyshyn et al. assessed the efficacy of supplemen-
and history to identify factors predictive of success. tal CWCPC in 21 eyes with uncontrolled IOP despite
Pretreatment IOP level, 2 patient age, types of refractory maximally tolerated glaucoma medications after
glaucoma, history of previous surgery, male sex, and tube-shunt placement.22 IOP was successfully lowered
pigmentation are also reported to have an influence in 71.5% of the cases with an overall favorable safety
on the treatment results.10,14-17 Schlote et al. found that profile. Other studies have also shown high success
treatment success depends on the type of glaucoma. in terms of pressure lowering, but also reported a
A high success rate was achieved in primary high complication rate.23 Ness et al. showed a mean
open-angle glaucoma (POAG) (89.5%), neovascular IOP decrease from 28.6 to 14.7 mmHg in eyes with
glaucoma (NVG) (86.7%), and inflammatory glaucoma previous tube-shunt surgery. This study did, however,
(75.0%), whereas relatively poor results were found have a high complication rate: hypotony (12.5%),
in congenital or juvenile glaucoma (62.5%), traumatic loss of two or more lines of visual acuity (VA) from
glaucoma (57.1%), and aphakic glaucoma (57.1%).15 baseline (56.3%), and loss of light perception (15.6%)
Success rate increased with age and decreased with were observed.23 When interpreting these results, the
history of previous surgery. Kramp et al. also found clinician needs to understand that, generally, eyes that
a higher success rate in POAG when compared to have failed a tube shunt have end-stage disease and
secondary glaucomas and in patients in the older thus have a high risk of vision loss with any treatment.
Table 1. Summary of IOP response and CWCPC parameters
Mean IOP Mean IOP Overall Mean energy/

Number of IOP %
Study/Location pretreatment (mmHG) end success rate treatment
eyes reduction
(mmHg) of follow-up (%) episode (J)
Ramli et al./Singapore, 201224 90 41.8 17.8 57.4 54 N/A

Osman et al./Saudi Arabia, 35 35.1 18.8 46.4 62.8 24-40
201025
Rotchford et al./ UK, 201026 49 28.0 15.3 45.4 89.8 57.6
Kaushik et al./India, 2008 27
66 36.4 15.6 57.1 78.8 87.8
Ansari and Gandhewar et al./ 74 40.3 21.1 43.0 82.0 80.0
UK, 200728
Vermon et al./ UK, 200629 42 31.4 15.6 50.3 88.1 56.0
Murphy et al./UK, 2003 30
263 40.7 17.7 52.6 79.5 104.1
2.3.1. Clinical outcomes of SD and LD CWCPC the one-month follow-up in the longer duration group
Alzuhairy et al. performed a study comparing SD and LD suggests that the LD technique may result in greater
CWCPC (Table 2). They found that the mean reduction ciliary body inflammation in the early postoperative
in IOP following treatment after 1 year was 16.8 ± 13.1 period. This difference in inflammation, however, was
mmHg in the SD group and 18.7 ± 14.9 mmHg in the not seen at the one-year follow-up. It should be kept in
LD group. This difference in mean reduction in IOP mind that these results are from patients with highly
was not statistically significant (P = 0.505). There was variable surgical history and types of glaucoma.
a statistically significant reduction in the number of
topical hypotensive medications for both groups. The 2.4. Complications
difference in the decrease in VA between groups was The documented complications after CWCPC include
not statistically significant (P = 0.075).31 pain, uveitis, IOP spikes, pigment dispersion, pupil
The significantly greater degree of inflammation at irregularities, hyphema, vitreous hemorrhage,
Table 2. Summary of SD and LD CWCPC Comparison
Number of medications Hyphema Hypotony

Group VA (median) IOP (mean)
(mean) (%) (%)
LD
Preop 2.03 36.2 2.9 0 0
1 month 2.1 16.2 1.8 0 4
6 months 2.2 17.2 1.7 1 3
1 year 2.3 17.4 1.6 0 2
SD
Preop 1.87 33.5 2.5 1 0
1 month 1.86 16.9 1.8 2 4
6 months 1.86 18.4 1.5 1 2
1 year 1.95 16.7 1.3 1 3
IOP: intraocular pressure; VA: visual acuity
Table 3. Summary of study outcomes and rates of serious complications for CWCPC
Mean IOP Mean IOP Mean energy

% POAG Phthisis
Study % NVG pretreatment postop per treatment Hypotony (%)
and CACG (%)
(mmHg) (mmHg) episodes (J)
Gupta and Agarwal7 11.5 11.5 44.7 15.2 120.0-160.0 N/A 1.9
Noureddin et al. 10
16.6 19.4 35.8 19.1 121.5 2.7 0
Murphy et al.30 46.4 18.6 40.7 17.7 104.1 9.5 5.3
Iliev and Gerber 14
61.1 12.2 37.7 15.3 86.8 17.6 9.9
Egbert et al. 32
0 100 29.3 25.7 45.0-62.5 0 0
Yildirim et al.33 100 0 43.4 18.7 48.0-60.0 9.1 0
Nabili and Kirkness 34
100 0 34.4 18.2 60.0 25.0 5.0
Pokroy et al. 35
37.9 62.1 29.0 19.5 53.8 5.1 0
Vernon et al. 29
11.9 21.4 31.4 15.6 56.0 0 0
Scholte et al.36 16.1 20.4 30.6 20.6 47 0 0
Pucci et al. 37
12.5 52.5 30.4 20.3 43.6 0 0
Frezzotti et al. 38
21.8 36.2 29.9 20.8 36.7 0 0
CACG: chronic angle-closure glaucoma; IOP: intraocular pressure; NVG: neovascular glaucoma; POAG: primary open-angle glaucoma
cataract progression, lens subluxation, malignant serious complications; and second, that many of these
glaucoma, necrotizing scleritis, vision loss, sympathetic eyes have end-stage disease, so vision loss may be
ophthalmia, hypotony, and phthisis. As stated due to the disease process rather than the procedure.
previously, interpreting the complication results in all The clinician needs to consider the risk of treatment vs
studies is difficult given the high degree of complexity observation when determining what is best for each
seen in most eyes that undergo CWCPC. Was the com- patient. The literature does present some information
plication a result of the CWCPC, the disease itself, or on lowering the rate of complications, with more
other surgical interventions? favorable outcomes being associated with lower energy
Of all of the possible complications, the most settings (less than 60 J total energy per treatment).
feared is phthisis. This occurs when the ciliary body is
destroyed to a degree that it does not produce enough
fluid to maintain IOP, leading to profound vision loss. 3. ECP
A literature review (Table 3) reveals that, luckily, this
complication does not occur at a high rate. Vernon et ECP is a safe and effective procedure commonly per-
al. showed protocols with less than 60 J of energy per formed in conjunction with phacoemulsification to
treatment session were free of hypotony and phthisis.29 lower IOP and reduce the use of IOP-lowering med-
Above 60 J of energy per treatment session revealed ications. Although first used in the treatment of
rates of persistent hypotony ranging from 0 to 25%, refractory glaucoma, it has emerged as an alternative
and phthisis bulbi ranging from 0 to 9.9%. Murphy et adjunct surgical procedure in the class of minimally
al. investigated the predictive factors for developing invasive glaucoma surgeries (MIGS), with a particular-
hypotony and found the only associated factors were ly promising role in the treatment of chronic angle-
high pretreatment IOP and high mean treatment energy closure glaucoma.
per episode.30 In contrast to “blind” trans-scleral cyclodestructive
Other serious complications include vision loss and procedures, ECP offers direct visualization of and precise
sympathetic ophthalmia. Murphy et al. reported that ablation of ciliary epithelium. This precision, combined
VA remained the same in 74.6% of patients at 6 months with the lower cumulative energy delivery, decreases
following CWCPC treatment.30 The rate of sympathetic the risk in ECP-treated eyes of some of the serious com-
ophthalmia is unknown due to its extremely low rate of plications that can be seen with cyclophotocoagulation
occurrence.39 performed in a trans-scleral fashion: injury to sclera,
More recent studies have looked at the use of CWCPC hypotony, and phthisis.4 Histological examination of
in patients who have better VA than was seen in older eyes treated with ECP has shown ciliary body disrup-
studies. Ansari and Gandhewar examined CWCPC tion with less neighboring tissue disruption when com-
in patients with 6/36 vision or better. They studied pared with other cyclodestructive procedures (Fig. 6).42
23 eyes with “good” VA and 20 maintained prelaser VA. Lin et al. observed reperfusion of vascular crypts in
Of the three eyes that had worse VA, two were due to ECP-treated ciliary epithelium in a rabbit model at
progression of cataract and one was due to progression one week and one month. Their group saw no reper-
of optic neuropathy and chronic iritis.28 Wilensky and fusion in the rabbit model treated with trans-scleral
Kammer also studied patients with “ambulatory” vision. CWCPC. Taken together, these findings give insight into
They performed a retrospective study of 21 eyes with the underlying mechanism that decreases the risk of
VA 20/80 or better. Of the 21 eyes, 17 had vision within severe complications that can be seen with trans-scler-
one line of their preoperative vision. Of the four eyes al CWCPC.43,44
with vision change, one showed improvement while
three eyes deteriorated.40 Visual loss was unrelated to 3.1. Procedure
total treatment dose, initial VA, or initial IOP level. ECP is performed using a two-unit system: the
Overall, the complication rates after CWCPC are quite three-component endoscope (Fig. 7) (diode laser, light
low. Two main things need to be taken into consider- source, and camera) and the high-definition console
ation; first, that all invasive glaucoma procedures have for viewing (Fig. 8). Housed within a single 18-g or 20-g
Fig. 6. Histologic comparison. (a) Ciliary body treated with trans-scleral CWCPC showing separation of the non-pigmented and pigmented
ciliary epithelium (wavy arrow), pigment clumping (arrowheads), coagulative necrosis of the underlying ciliary stroma (asterisk), and archi-
tectural destruction of the treated tissue (straight arrows). (b) Ciliary body treated with ECP showing loss of the lacy appearance of the
ciliary processes (asterisk) with destruction of the nonpigmented epithelium and clumping of the pigmented epithelium (arrowheads).
Image courtesy of BVI Medical.
a b c
Fig. 7. The ECP probe and its various components. (a) Curved and straight probe. (b) Internal structure of the probe. (c) Application surface
on the bottom of the probe with light source, laser source, and imaging recorder. Image courtesy of BVI Medical.
Fig. 8. Endo Optics E2 Laser and Endoscopy System. Image courtesy of BVI Medical.
probe is an 810 nm diode laser, 175 lux illuminating light The pars plana approach is more technically chal-
source, and camera with 1-30 mm depth of focus and lenging and time-consuming, as it must be preceded by
110° field of view (Endo Optiks, Little Silver, NJ, USA). anterior vitrectomy. Pars plana ECP can be performed
The diode laser has up to 2 watts of power output that on pseudophakic and aphakic eyes. Due to its potential
can be either pulsed or used continuously. The power is to violate the lens capsule and induce traumatic cata-
titrated on a per patient basis. ract, it is contraindicated in phakic eyes. Pars plana is
ECP is performed by two routes: via clear corneal believed to have greater efficacy due to complete visi-
incision (limbal approach) or alternatively through the bility of the ciliary epithelium.
pars plana. The limbal approach is performed with Most clinicians place patients on a third or fourth
a clear cornea self-sealing 3.2 mm incision placed generation fluoroquinolone, as well as a slow taper
through the peripheral cornea. Cohesive viscoelastic is of prednisolone acetate 1% individualized per patient
used to separate the iris from the implant or empty bag examination. Glaucoma medications are titrated up
following phacoemulsification. The 20-g probe is then or down as needed based upon the patients’ post-
positioned between the anterior lens capsule and iris operative IOP. Follow-up generally mimics standard
with direct application until whitening and shrinkage follow-up of a cataract surgery unless clinical exam
of ciliary processes takes place (Fig. 9, Video 3). Care dictates otherwise.
is taken to avoid excessive treatment, which will result
in audible “popping” of ciliary tissue leading to inflam- 3.2. Clinical outcomes
mation and breakdown of the blood-aqueous barrier.45 The use of an intraocular endoscope was first performed
Laser settings are adjustable, generally in a range of in 1992 by Uram using vitreoretinal and anterior
200-300 mw. Treatment is applied to a certain number segment applications in the treatment of NVG.47 Among
of degrees of the ciliary ring alternatively described in the earliest papers published regarding ECP, Dr. Martin
clock hours. Uram reported a series of 10 patients with NVG with
Variations include one vs two clear cornea incisions, IOPs ranging from 36 to 62 mmHg (mean: 43.6 mmHg)
the total degree of application delivered (180° vs treated with ECP via pars plana approach. Postopera-
270-360°), and whether it used in conjunction with tive IOP ranged from 3 to 27 mmHg (mean: 15.3 mmHg).
phacoemulsification and cataract extraction. In a ret- Postoperative complications included hypotony in two
rospective consecutive case review, Kahook reported eyes that had chronic retinal detachments.48
that phacoemulsification with ECP improved efficacy The majority of early data published regarding the
with a two-incision 270-360° application.46 Following efficacy and clinical outcomes of ECP was skewed
ciliary body treatment, removal of all viscoelastic agent towards patients that had undergone prior glaucoma
must be performed to prevent postoperative IOP spike. surgery or had failed maximum medical therapy. Chen
a b c
Fig. 9. Application of ECP to the ciliary processes. (a) Positioning probe in the sulcus. (b) Laser application to the ciliary processes.
(c) Whitening of the ciliary processes, indicating adequate treatment. Image courtesy of BVI Medical.
et al. reported in 1997 a retrospective review of 68 eyes ative VA showed no statistical change in the ECP group,
of 68 patients who underwent ECP for refractory while a slight worsening of VA in the Ahmed Valve group
glaucoma. The underlying diagnosis for study partici- was observed. Complications in the ECP group included
pants included: POAG (16), congenital/developmental choroidal detachment in 1 eye (2.94%), hyphema in 6
(12), chronic angle-closure (11), aphakic/pseudophakic eyes (17.64%), corneal graft failure in 1 eye (2.94%),
(10), uveitic (10), pseudoexfoliative/pigmentary (5), NVG retinal detachment in 1 eye (2.94%), fibrin deposits in
(2), and angle-recession (2) glaucomas. Thirty-three 4 eyes (11.76%), hypotony in 1 eye (2.94%), and phthisis
eyes were pseudophakic (21 posterior chamber and bulbi in 1 eye (2.94%).50
12 anterior chamber intraocular lenses), 14 were The earliest use of ECP with phacoemulsification
aphakic, and 21 were phakic. All patients had failed was reported in 1995 by Uram. In this study, ten eyes
maximally tolerated medical therapy with the exception of ten people with uncontrolled glaucoma and cataract
of the phacoemulsification ECP group (12), and most underwent combined ECP and phacoemulsification.
had a history of one or more unsuccessful glaucoma Preoperative mean IOP was 31.4 mmHg and postoper-
surgeries. Of the 68 eyes, 56 underwent ECP via a limbal ative mean IOP was 13.5 mmHg. Clinically significant
approach (of which 12 were combined with cataract complications included transient vitreous detachment
extraction) and 12 performed by pars plana incision. in one eye.61
In 60 eyes, laser treatment was performed on 180-360° Following the trend of cataract plus MIGS, ECP has
(mean, 293° ± 68°) and the remaining 8 had less than found a new place in the armamentarium of glaucoma
180° treatment. Results were measured in a follow-up specialists as a viable adjunct to cataract extraction in
period of 12.9 months: mean IOP decreased from eyes with medically controlled open-angle glaucoma.
27.7 ± 10.3 mmHg preoperatively to 17.0 ± 6.7 mmHg In a prospective, nonrandomized, matched-control
at the final postoperative visit (P < 0.0001). Sixty-one study, Francis et al. compared 80 eyes treated with ECP
eyes achieved IOP ≤ 21 mmHg. Mean antihypertensive and phacoemulsification to 80 eyes that underwent
medications reduced from 3.0 ± 1.3 preoperatively to phacoemulsification alone. Patients included in the
2.0 ± 1.3 at the last postoperative visit (P < 0.0001). Best study had moderate POAG without previous glaucoma
corrected VA was stable or improved in 64 eyes, and procedures with the exception of trabeculoplasty. ECP
4 lost 2 or more lines. Complications included fibrin was performed following posterior chamber intraocular
exudate in 16 eyes (24%), hyphema in 8 eyes (12%), lens insertion with laser applied to 270-360° in the
cystoid macular edema (CME) in 7 eyes (10%), and study group. Preoperative IOP was 18.1 ± 3.0 mmHg
choroidal detachment in 3 eyes (4%).49 in the study group, and 18.2 ± 3.0 mmHg in the control
Comparison of ECP to Ahmed drainage device group. Mean preoperative medications were 1.5 ± 0.8 in
placement was reported in 2004 by Lima et al. in a the study group and 2.4 +/-1.0 in the control group. At
prospective comparative study with mean follow-up 1 and 2 years, the mean IOPs of the study group were
of 19 months. The study population comprised 68 16.0 ± 2.8 mmHg and 16.0 ± 3.3 mmHg, respectively.
eyes of 68 patients with refractory glaucoma. Eyes The number of glaucoma medications decreased from
were pseudophakic, with an IOP ≥ 35 mmHg, and had 1.5 ± 0.8 to 0.4 ± 0.7 (1 year and 2 years). In the control
undergone at least one previous trabeculectomy with group (n = 80), the mean IOPs at 1 and 2 years were
antimetabolite. VA was required to be light perception 17.5 ± 3.6 mmHg and 17.3 ± 3.2 mmHg, respectively.
or better. ECP treatment was performed using a pars The mean number of glaucoma medications was 2.4
plana approach with 210° treatment to the ciliary ± 1.0 preoperatively, and 1.8 ± 1.2 and 2.0 ± 1.0 at 1 and
body. Preoperative IOP was 41.32 ± 3.03 mmHg for the 2 years, respectively.52 Many additional reviews and
Ahmed group and 41.61 ± 3.42 mmHg for the ECP group comparative studies have been published in recent
(P = 0.5). At 24-months post-procedure, mean IOP was years depicting the utility of ECP in combination with
14.73 ± 6.44 mmHg for the Ahmed group and 14.07 phacoemulsification (Table 4).
± 7.21 mmHg for the ECP group (P < 0.001 for each group A new front currently being investigated is definitive
in comparison to the pre-procedure pressure). Preoper- treatment of angle-closure glaucoma and plateau iris
ative VA was similar between the two groups. Postoper- syndrome (PIS) with ECP. PIS has largely been treated
pharmacologically with pilocarpine or by laser periph- quadrants despite lens extraction.54 These results and
eral iridoplasty. Both treatments have their limitations, those of similar studies show a promising role for ECP
as neither eliminates the anatomical abnormality of an as a potential definitive treatment for chronic angle
anteriorly positioned pars plicata. In 2017, Hollander closure and particularly PIS.
et al. evaluated nine eyes of six patients with PIS diag-
nosed by dark room provocative testing that had 3.3. Complications
undergone ECP with cataract extraction, with evalua- The ECP Collaborative Study group retrospective-
tion of angles pre- and postoperatively by ultrasound ly reviewed 5,824 cases of ECP followed postoper-
biomicroscopy (UBM). Following ECP (120-360° treat- atively for a mean of 5.2 years showing the following
ment), UBM showed that angles treated with ECP were complications: IOP spike (14.5%), hemorrhage (3.8%),
open with corresponding flattened ciliary processes, serous choroidal effusion (0.36%), retinal detachment
while the untreated angles remained occludable in (0.27%), and hypotony or phthisis (0.12%). More
Table 4. Recently published results of phacoemulsification cataract extraction with ECP literature with the addition of ECP postoperative
complications. Adapted review from Wen Sun et al.53
Final Mean no. of

No. of Mean
mean reduction Study
First eyes in baseline Postoperative complications
Study type reduction in length
author phaco-ECP IOP phaco-ECP group
in IOP, medication (months)
group (mmHg)
mmHg (%) (%)
Roberts Retrospective 91 16.6 3.3. (19.9) 0.4 (21.3) 12 Not reported
2016
Siegel Retrospective 261 17.2 2.6 (15.1) 1.1 (84.6) 36 Additional glaucoma surgery: 7
2015 CME: 4
Retinal detachment: 2
Required penetrating keratoplasty: 1
Morales Retrospective 104 17.0 2.3 (13.5) Not 12 Fibrin exudate: 4
2015 reported Postop IOP spike > 30 mmHg: 8
Corneal decompensation: 3
Francis Prospective 80 18.1 2.1 (11.6) 1.1 (73.3) 24 Hyphema: 2
2014
Clement Retrospective 63 21.1 5.0 (23.7) 1.2 (45.8) 12 Fibrinous uveitis: 7
2013 IOP spike: 2
Chronic IOP elevation: 5
CME: 2
Corneal decompensation: 2
HSV keratitis recurrence: 1
PVD: 1
Corneal astigmatism: 1
Lindfield Retrospective 56 21.5 7.1 (33.0) -0.1 24 Steroid-associated IOP elevation: 1
2012 (-5.1) Vitreous in anterior chamber with
peaked pupil: 1
Anterior uveitis: 3
Lima Retrospective 368 23.1 10.9 (47.2) 0.4 (25.7) 24 Immediate postop IOP spike: 53
2010 CME: 16
Transient hypotony: 8
Fibrin exudate: 26
Kahook Retrospective 40 24.5 11.2 (45.7) 2.0 (79.7) 6 No complications
2007
Gayton Prospective 58 24.9 8.9 (35.7) 0.6 (30.0) 24 Postop IOP spike: 5
1999 Postop inflammation: 1
CME: cystoid macular edema; HSV: herpes simplex virus; IOP: intraocular pressure; PVD: posterior vitreous detachment
commonly, ECP is being used as an adjunct to cataract may be performed as a standalone procedure, either in
extraction in eyes with moderately controlled the operating room or in a minor procedure room in the
glaucoma and offers an excellent safety profile. Of clinic.
those listed in Table 3, no hypotony or phthisis occurred For MPCPC, the MP3 probe is used. The probe contains
when treating controlled glaucoma with phacoemulsi- a quartz fiber optic cable 600 μm in diameter, with the
fication and ECP. tip protruding 0.7 mm from the hand piece (Fig. 11). It
is designed so that the fiber optic tip is positioned
3 mm posterior to the edge of the probe. The standard
4. MPCPC MPCPC settings are 2000 mW of 810 nm infrared diode
laser on micropulse mode, delivered between 160-360
Recently, a new development in micropulse laser tech- seconds over 360° (Video 4). It has a duty cycle of
nology has changed our view on trans-scleral cyclodiode 31.3%, composed of repetitive short pulses of energy
laser. This method of delivering diode laser to the ciliary separated by periods of rest. The duty cycle delivers
body, MPCPC, is done in a trans-scleral fashion, but has
significantly less inflammation than previous
methods.41 The laser beam is delivered in a continuous
fashion, but it is split into short bursts of energy. These
short bursts allow for a significant amount of energy
to be delivered to the tissue without the significant
increase in tissue temperature seen with both tradi-
tional trans-scleral cyclodiode laser and ECP, and this
has been supported on histopathology (Fig. 10).42 Early
studies indicate that the mechanism of action for low-
ering IOP with this method appears to be multifactorial.
There is some ciliary body destruction, an increase in
uveoscleral outflow, and a trabeculoplasty-like effect,
which increases conventional outflow as well.
Micropulse technology presents us with a way to
combat elevated pressure in glaucoma. The procedure
is safe, less inflammatory, repeatable, and extraocular.
Another advantage offered by this technique is that it
Fig. 10. Histopathology of human cadaver eyes after (a) CWCPC and Fig. 11. The G-Probe and the MP3 probe. Image courtesy of Iridex
(b) MPCPC. The circled areas indicate coagulative tissue necrosis.42 Corp.
Fig. 12. Graph depicting the on and off pulse of that occurs with
MPCPC.
Fig. 14. Technique for MPCPC with avoidance of the 3 and 9 o’clock
positions.
Sparing these positions also helps prevent anterior

segment ischemia. The current probe presents some
difficulties for proper positioning, and thus, delivering
proper treatment. The posterior position allows for
less damage to the limbal stem cells and pupillary
fibers. When improperly positioned, complications will
increase while successful outcomes will decrease.
Similar to TSCPC, MPCPC can be done in the
operating room as well as in a minor procedure room
in the clinic. Given that the procedure can be quite
painful, if performed in any setting without systemic
Fig. 13. MP3 probe being applied to the eye for MPCPC. MPCPC. anesthesia, a retrobulbar or peribulbar block is
Image courtesy of Iridex Corp. crucial. A coupling agent should be used to ensure
adequate contact between the probe and the globe,
0.5 ms of laser in an active phase followed by 1.1 ms as “dry” application of the laser leads to significantly
of rest (Fig. 12). MPCPC is delivered in a sliding motion, lower power output (Table 5). Topical lidocaine gel or
with constant contact and firm pressure applied to the tetracaine can be used as a coupling agent depending
sclera. The MPCPC has a 600 μm fiber optic cable within on surgeon preference, as our group found that there is
the probe, which is positioned to lie 4-5 mm posterior no difference with laser probe output between the two.
to the limbus when the clinician places the leading The pain from the procedure is generally limited to the
edge 2 mm posterior to the limbus (Fig. 13). Preliminary time of laser application and it usually dissipates rapidly
data from our institution, Stroger Hospital (Chicago, IL, after the procedure is completed. Given the low level of
USA), show that the highest power output is obtained postoperative pain, if systemic anesthesia is used, the
when the MP3 probe is held at 90° to the ocular surface procedure can be performed without any type of block.
with direct contact and a moist contact media. Similar The procedure is brief, so, if propofol is used, the patient
to trans-scleral cyclophotocoagulation (TSCPC), the 3 can be completely anesthetized and not awake until the
o’clock and 9 o’clock positions are not treated to avoid procedure has been completed. This approach allows
the long ciliary nerves and decrease pain (Fig. 14). for multiple benefits: decreased risk from block compli-
Table 5. Probe output data in various media and at different angles from our institution (Cook County Health, Chicago, IL, USA)
90° Probe angle 45° Probe angle
Trial Tetracaine eye Tetracaine eye
No substrate Lidocaine gel No substrate Lidocaine gel
drop drop
Mean power 360.4 621.4 620.7 321.9 602.3 590.7
output
Standard 16.7 10.6 20.7 22.3 15.4 25.1
deviation
Table 6. Post MPCPC results from Tan et al.43 Table 7. Data from Aquino et al.44
12 months MPCPC (n = 24) CWCPC (n = 24)
Prelaser P-value P-value
postlaser IOP IOP
IOP (mmHg) 40.1 + 16.8 24.7 + 10.8 <0.001 Preoperative 36.5 35.0 0.50
IOP reduction 1 day 21.5 27.0 0.21
from baseline N/A 38.4% <0.001 1 week 16.5 21.0 0.80
(%)
1 month 22.5 22.0 0.85
Medications 2.1 + 1.1 1.3 + 1.0 <0.001
3 months 20.0 20.5 0.98
Overall success* N/A 80% (32/40 eyes) N/A
6 months 20.0 18.5 0.98
NVG success*
N/A 50% (6/12 eyes) N/A 12 months 18.0 20.0 0.63
rate
18 months 20.0 19 0.70
*Success is defined as maintaining IOP < 21 mmHg or achieving
a reduction in IOP of 30% with or without antihypertensive P-value adjusted for NVG via robust linear regression to compare
medications. IOP: intraocular pressure; N/A: not applicable; NVG: between MPCPC and CWCPC. IOP represented as a median. IOP:
neovascular glaucoma intraocular pressure
cations, no need for an eye patch, and ability to restart The P-values at all time points were < 0.001 and no
glaucoma drops immediately. The postoperative pain cases of hypotony were recorded. In addition, the mean
is minimal and typically managed with acetaminophen. number of IOP lowering medications dropped from
The other added benefit is induced amnesia so that the 2.1 ± 1.1 to 1.3 ± 1.0. VA through the Snellen chart
patients do not remember the experience, which may showed improvement in 4/40 patients, and no change
be of benefit if the patient needs a repeat treatment. in 36/40 patients. No patients had a decrease in VA. The
success rate was 80% at final follow-up (mean: 16.3
4.1. Clinical results months). The group with the lowest success rate was
One of the earliest studies to examine the clinical NVG. It should be noted that success could be achieved
outcomes of MPCPC from an isolated perspective was with glaucoma medications and with re-treatment with
from the National University Hospital in Chennai, India CWCPC.
and the Singapore National Eye Centre.43 Using 2000 mW In 2015, Aquino et al.44 explored the outcome
at 810 nm IR in micropulse mode, the IOP of 40 eyes from differences between MPCPC and CWCPC techniques in
38 patients was tracked over the course of an average patients with refractory glaucoma. In this randomized
of 16.3 months. In addition to IOP, the success rate of control trial, 24 eyes were randomly assigned to each
patients was analyzed by quantifying the percentage procedure under the same inclusion criteria as above
of patients that achieved a steady IOP < 21 mmHg or (IOP > 21 and VA < 6/60). IOP changes at the same time
> 30% reduction from baseline (Table 6). A failure to points in the 2010 Tan et al. study43 were recorded, as well
reach this standard on two consecutive visits after the as VA, hypotony, number of IOP-reducing medications,
one-month mark constituted a need for retreatment. pain, and success rate (> 30% reduction in IOP). The
Finally, this study investigated the change in number of baseline IOP in each group was statistically similar
IOP-lowering medications, cases of hypotony (IOP < 6 between the two groups, while the success rates at one
mmHg), changes in VA, and reports of pain. year differed. The MPCPC group had a 75% success rate
(18/24), while the CWCPC group achieved this mark at Given the short amount of time MPCPC has been
29% (7/24), P < 0.01. However, at the final follow-up (18 available, new studies are coming out daily. Over the last
months), the MPCPC group fell to 12 patients meeting few years, many studies have been presented at inter-
the primary outcome vs 7 patients in the CWCPC cohort national meetings focused on various aspects of MPCPC
(P = 0.13). (Table 8). A multitude of different factors were analyzed
A key measure from the study came from hypotony but an overlying theme remained: the procedure has a
results. As previously discussed, hypotony is a feared high success rate and a low complication rate. These
complication of any cyclodestructive procedure and studies also reaffirmed that the procedure works best in
has a high rate of occurrence with CWCPC. No MPCPC POAG and has its poorest success rate with aggressive
patients had hypotony at any postoperative visit, while secondary glaucoma, such as NVG. Patel et al. found
five patients from the CWCPC cohort did, four of which that of 42/54 (77%) patients had 3-month success
had NVG. It is important to note that the subtype of with MPCPC.47 Success was defined as 8 ≤ IOP ≤21 or
glaucoma was not matched in this study, and that the IOP reduction > 20%. When comparing success rates
CWCPC cohort had 12 NVG patients, while the MPCPC with patients who had undergone MPCPC and CWCPC,
treatment group had 7 NVG patients. A linear regression both cohorts had comparable success rates at three
analysis was undertaken to stratify the IOP outcomes in months, with fewer complications seen in patients
each group while taking the differential NVG numbers who underwent MPCPC. More recently, Sarrafpour
into account (Table 7). As shown, there were no et al. reported at ARVO 2018 that there was a larger
significant IOP differences between the two groups at percent decrease in IOP without an increase in com-
any point postoperatively after this adjustment. The plications.48 This brought up the thought that power
importance of the NVG etiology was highlighted in selection should possibly be varied according to pre-
re-treatments, as four NVG patients underwent three operative pressure. For traditional baseline purposes,
MPCPC procedures, all of which were refractory to IOP results from incisional glaucoma procedures provide
reduction. The number of IOP-lowering medications at some long-term, high-volume data for reference when
the 18-month follow-up was equally reduced (from two considering micropulse technology. As opposed to
to one). MPCPC, trabeculectomies and tube shunts have been
A study from Wills Eye Hospital supported the explored for many more years. Gedde et al.60 presented
potential efficacy of MPCPC from a short-term a multicenter analysis of the two procedures with
perspective.45 Using the same technique (31.3% duty five-year data that has had a major impact on modern
cycle) as the groups from India and Singapore, and a clinical glaucoma management. The study included 212
success criteria of 6 < IOP < 21 and > 20% improvement patients from 17 clinical centers and the results were
from baseline, they found a 73.7% success rate after the similar to those in the MPCPC studies presented above:
initial treatment and 90% success after any necessary IOP reduction, VA, number of glaucoma medications,
re-treatments. Final follow-up was only at 60 days, yet success rates, and rate of reoperation. At the 5-year
a mean 40% IOP reduction was measured within this follow-up mark, IOP reduction was 41.4% in the tube
relatively short period of time. group and 49.5% in the trabeculectomy group. When
Similar short-term data was supported by Radcliffe drawn in comparison to the largest micropulse group
et al.46 during the 2015 American Glaucoma Society from Tan et al.3 (40 eyes), those individuals presented
annual meeting. Of 42 eyes operated on, an average with a 38.6% IOP reduction. Clearly, the measure
IOP reduction of 38.1% was seen by the 3-month mark, is relatively consistent between the invasive and
with no complications of hypotony, macular edema, or noninvasive cohorts. However, a significant disparity in
phthisis bulbi at any point. They argue that, by way of failure rates was apparent. Outlined by Gedde as an IOP
a cooling period, the collateral damage to the ciliary > 21 mmHg on two consecutive visits, IOP < 5 mmHg,
body is decreased and that the uveoscleral outflow may or a need for reoperation, 33% of the tube shunt and
actually increase by the heating mechanism of MPCPC. 50% of the trabeculectomy patients who remained at
In turn, the amount of postoperative inflammation is 5-year follow-up failed. The most common reason for
drastically decreased. failure was a lack of IOP reduction, albeit the trabe-
Table 8. Recent data from various meetings on MPCPC

Therapy Pre-IOP Post-IOP
Author N (eyes) Success rate Comments and complications
time (s) (mmHg) (mmHg)
Patel et al. 11 160 29.1 17.9 POAG75% Hyphema (1/11)
ARVO Poster 2016 49 SOAG 41.6% Retrobulbar hemorrhage (1/11)
Subconjunctival hemorrhage
(2/11)
Ayyala et al. 237 160 22.39 17.29 78% Pain (37%)
AGS Poster 201750 Inflammation (41%)
Nguyen et al. 95 180 25.1 17.4 AC at 1 week
AGS Poster 201751 No AC at 12 months
Massis et al. 40 160 24 17 66% UBM and AS-OCT reveal no
AGS Poster 201752 anatomic changes
Werner et al. 33 160 50 22 50% CME or AC inflammation (0)
AGS Poster 201753 VA loss (1)
hypotony (1)
Shazaly et al. 34 180 29.2 16.6 MP-TSCPC retreatment (5)
AGS Poster 201754
Radhakrishnan et al. 166 160-320 22 16.7 57.80% Multicenter review
AGS Poster 201755 Mydriasis (18)
SPK (11)
Fibrinous AC (5) CME (4)
AC tap (3)
Williams et al. 81 120-320 31.9 15.1 85% Early hypotony (5) Late
AGS Poster 201756 hypotony (4) Prolonged AC
inflammation (25) VA loss (8)
Toeteberg-Harms et al. 34 29 21 MPCPC more rapid IOP decline
AGS Poster 201757 at 1 month follow-up
Lee et al. 36 180 28.4/34.28 18.62/23.00 74.07%/33.33% 66.67% pediatric patients
AGS Poster 201758 needed additional surgery
Emanuel et al. 84 27.7 11.1 5 patients required additional

AGS Poster 201759 surgery; hypotony, IOP spike,
hyphema,
serous choroidal detachment,
and persistent inflammation
Patel et al. 54 160-200 26.54 15.59 77% Mydriasis (9/54, 16.6%)
ARVO Poster 201747 Retrobulbar hemorrhage (1/54,
1.8%)
Hyphema (1/54, 1.8%)
PKP dehiscence (1/54, 1.8%)
Sarrafpour et al. 71 eyes 200s with 38.3 (2500mW) 16.3 77.5% of No cystoids, macular edema, or
ARVO Poster 2018 48 varying 23.2 (2400mW) (2500mW) patients phthisis seen
power 26.0 11.3 received at least
(2250mW) (2400mW) a 20% reduction
21.6 12.7 from baseline
(2000mW) (2250mW)
15.6
(2000mW)
*Success rate: postoperative IOP < 21 mmHg or > 20-30% drop in IOP (depending on the individual study). AC: anterior chamber; AGS:
American Glaucoma Society; ARVO: Association for Research in Vision and Ophthalmology; AS-OCT: anterior segment optical coherence
tomography; CME: cystoids macular edema; PKP: penetrating keratoplasty; POAG: primary open-angle glaucoma; SOAG: secondary
open-angle glaucoma UBM: ultrasound biomicroscopy; VA: visual acuity
culectomy group had a large number of hypotony cases rounds of therapy. The Radcliffe et al.46 study from New
as well. Compared to the MPCPC group that succeeded York University supports the aforementioned results
at an 80% clip under similar metric standards after only within the short-term context of three-month post-
18 months of follow-up, it is easy to see the advan- procedure. Of the 42 eyes studied, there were zero
tageous nature of the noninvasive procedure in this reported cases of hypotony, macular edema, and
modality. phthisis bulbi. Just one eye experienced a VA decrease
of > 2 lines from progression of a pre-existing cataract.
4.2. Complications This study argues that the IOP reduction is in line with
The 2010 study by Tan et al.43 reported no incidences that of the traditional CWCPC, but that the short-term
of hypotony or VA deterioration from baseline. During inflammatory complications are far less with the
the MPCPC procedure itself, 12 cases reported pain but MPCPC technique.
only 2 of those cases required additional peribulbar In the Patel et al. study of 54 patients at three months
anesthesia. In regard to inflammation, all of the 40 eyes at our institution, 9 (16.6%) had persistent mydriasis,
experienced mild anterior chamber inflammation and 1 (1.8%) had retrobulbar hemorrhage, 1 (1.8%) had
conjunctival hyperemia. Of those 40 eyes with mild hyphema, and 1 (1.8%) had PKP dehiscence.49 After
inflammation on exam, 36 (90%) resolved within one changing our technique to place the probe 2 mm
week on topical steroids. The other four resolved within posterior to the limbus instead of at the limbus, it was
four weeks. The authors reported zero cases of phthisis noted that no cases developed persistent mydriasis.
bulbi, endophthalmitis, or sympathetic ophthalmia. Again, for comparison purposes, one needs to look
This lack of post-procedural inflammation within the at the cohort from Gedde et al.61 to see the complica-
short-term follow-up period is striking in comparison tion rates from current standard of care. The rate of
to the inflammation seen with CWCPC. early complications was significantly higher in both of
The 2015 Aquino et al. study44 aimed to compare these groups relative to the noninvasive micropulse
CWCPC and MPCPC. There were significantly more technology. Within 1 month of each procedure, 21%
cases of inflammation reported in the CWCPC cohort. of tube patients and 37% of trabeculectomy patients
As seen in Table 9, 7/24 cases of the CWCPC cohort experienced complications of some sort. Choroidal
showed signs of prolonged anterior chamber inflam- effusions, flat anterior chambers, and wound leaks
mation, while only 1/24 cases in the MPCPC group were the three most common issues in the invasive
showed the same. Four cases of scleral thinning, two cohorts. In addition, late complications, designated as
cases of VA decline, and one case of phthisis bulbi were postoperative > 1 month, were experienced at 34% in
observed in the CWCPC group. These serious compli- the tube group and 36% in the trabeculectomy group,
cations occurred at a much lower rate in the MPCPC with persistent corneal edema making up the majority
cohort. A constant between the two groups seems to of cases. In all, 22% of the tube group and 18% of the
be the difficulty in treating NVG; each group had several trabeculectomy group were forced to reoperate at
NVG cases that remained uncontrolled after several some point during follow-up.
Table 9. Secondary outcome measures of success; a comprehen-
sive breakdown of MPCPC and CWPCP complication metrics 4.3. Improving outcomes
Despite many studies reporting a very good success and
MPCPC CWCPC safety profile of MPCPC, many clinicians anecdotally
N (%) N (%)
Total of 23 eyes Total of 23 eyes report highly variable results. One of the difficulties
of MPCPC is the variability of the treatment between
No complication 20 (88%) 9 (40%)
providers, which include probe position, laser settings,
Prolonged anterior 1 (4%) 7 (30%)
chamber inflammation
the speed of probe sweeping, topical anesthetic
Phthisis bulbi 0 (0%) 1 (4%)
use, and the setting of the procedure. The laser was
initially performed at the limbus. Moving the anterior
Scleral thinning 1 (4%) 4 (17%)
edge of the probe 1-2 mm posterior to the limbus
Visual acuity decline 1 (4%) 2 (9%)
improves outcomes from both an IOP and complication
a b c
Fig. 15. MP3 probe placement. (a) Proper probe placement. (b) Probe tilted and placed too anterior. (c) Probe tilted posteriorly and not
flush to the sclera.
standpoint. This position leads to less mydriasis and during a single treatment session.62 They noted that IOP
less damage to the limbal stem cells. In addition to the improvement correlated with total power; however,
area of treatment, the clinician also needs to be aware there were also more complications as total power
that the angle of treatment is extremely important. The increased. A good balance of IOP vs complications is
older G-Probe used for CWCPC was held perpendicular hypothesized to be between a total of 112 J and 140 J.62
to the cornea. If the MPCPC probe is held in a similar Sarrafpour et al. also found improved pressure-
fashion, the fiber optic probe will be lifted off the eye lowering at higher power settings (2000-2500 mW), but
and the laser energy with have a longer distance to they did not see any serious complications even at the
travel (Fig. 15). Noncontact with the globe has been highest power setting (2500 mW).48 Currently, Iridex still
shown to significantly reduce power output from the recommends using 2000 mW for treatment, but further
system, and likely impact the treatment (Table 5). clinical research is needed to look into optimal power
Even if the angle is correct (90° to the ocular surface), settings.
being flush against the eye is important for delivery
of the full desired power. Improper technique leads
to inadequate treatment and suboptimal outcomes. 5. Conclusion
In order to maximize outcome, the clinician must be
very detail-oriented in a procedure that superficially In summary, MPCPC is a safe and effective noninvasive
seems quite simple. The difficulties in positioning treatment for glaucoma that has significantly lower
present a possible target for improving the outcomes in complication rates compared to traditional methods.
the future. An MP3 probe designed in a similar fashion Given this and the decrease in inflammatory response,
to the G-Probe, which forces the clinician to hold the MPCPC can be used earlier in the treatment algorithm
probe properly, would drastically improve overall of glaucoma. Highly variable results are due to the
outcomes even for someone who is inexperienced with variability in power settings, probe position, dwell
the procedure. Another challenging aspect is variability time, contact substrate, etc. With its current iteration,
in laser settings. A review by Sanchez et al. shows that MPCPC with an MP3 probe is a highly successful and safe
settings set forth in previous publications on MPCPC procedure, but further studies need to be conducted in
have ranged from less than 100 J to more than 200 J order to optimize clinical outcomes.
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16. Excimer laser trabeculostomy (ELT): the laser-
based MIGS procedure for open-angle glaucoma
Michael S. Berlin1,2, Marc Töteberg-Harms3, Jonathan Shakibkhou1, Alyssa Francesca Ahorro1, Ryan Lamrani1,
Antonio Moreno Valladares4, Ulrich Giers5
1
Glaucoma Institute of Beverly Hills, Los Angeles, CA, USA; 2Jules Stein Eye Institute, UCLA, Los Angeles, CA, USA;
3
Department of Ophthalmology, University Hospital Zurich, Zurich, Switzerland; 4Glaucoma Unit, University Hospital
of Albacete, Albacete, Spain; 5Augen-Klinik, Detmold, Germany
This book chapter introduces and discusses excimer Elevated intraocular pressure (IOP) in most open-angle
laser trabeculostomy (ELT), the laser-based microinva- glaucoma is due to an obstruction of aqueous outflow
sive glaucoma surgery (MIGS) procedure for open-angle thought to be localized predominantly at the juxtacan-
glaucoma. Differing from other MIGS procedures, all of alicular trabecular meshwork (TM) and the inner wall of
which involve insertion of stents or other materials, ELT Schlemm’s canal (SC). There have been multiple surgical
utilizes an essentially nonthermal photoablative laser attempts to directly treat this pathology by creating
which removes tissue without scar or healing to enable channels to connect the anterior chamber to SC.
the creation of outflow obstruction bypass channels Various surgical iterations have included mechanical
between the anterior chamber and Schlemm’s canal. drilling techniques, thermal laser and alternative
The long-term patency of these channels enables thermal cautery techniques, and a variety of shunt
stent equivalent outflow without stents. ELT can be implants with the common goal of bypassing this site of
performed as a standalone procedure or simultane- increased outflow resistance. However, the majority of
ously with cataract surgery. Further, the ELT procedure these techniques concurrently or subsequently create
has the longest documented MIGS postoperative study sufficient adjacent tissue disruption to eventuate in
data, which verifies its safety and efficacy in long-term inflammatory healing responses adequate to overcome
lowering of both intraocular pressure and antiglaucoma the benefits of the procedures, resulting in short-term
medications. The next generation of ELT devices, called or long-term failures. To overcome these known causes
Guided ELT, are currently under development to enable of failure, technologies and techniques for the purpose
the first goniolens-free, angle-based MIGS procedure of creating such channels were sought which did not
by providing real-time virtual image guidance to the cause scar tissue formation and which minimize inflam-
surgeon. matory responses. The requirements include minimal
tissue disruption during the process of creating the
Keywords: excimer laser trabeculostomy (ELT), openings and channels which are of adequate size and
glaucoma surgery, goniolens-free MIGS, MIGS number to enable outflow, but not so large as to alter
the aqueous composition.
The excimer laser trabeculostomy (ELT, also
previously addressed as excimer laser trabeculotomy in
Correspondence: Michael S. Berlin, MD, MS, 8733 Beverly Blvd. Suite 301, Los Angeles, CA 90048, USA.

232 M.S. Berlin et al.
the literature) concept utilizes a 308 nm xenon chloride 1. ab interno microincision;

excimer laser to provide a precise and essentially 2. minimal trauma;
nonthermal approach to improve outflow in a manner 3. efficacy;
which does not provoke a healing response. ELT is 4. high safety profile; and
a procedure performed via a clear corneal incision, 5. rapid recovery.1
sparing conjunctiva, in which direct visualization of
the target tissue via a goniolens or an endoscope
provides immediate feedback to the surgeon. ELT, 3. Previous meshwork surgeries and
when compared to the more invasive glaucoma their disadvantages
surgical procedures such as trabeculectomy, is almost
as efficacious in both lowering IOP and decreasing Current MIGS procedures can successfully bypass the TM
pressure-lowering medication use, while being far in order to create direct flow from the anterior chamber
less traumatic. ELT is also far less traumatic in tissue into SC unlike earlier surgical attempts to address this
removal for creating precise channels when compared anatomic pathology, which often failed. Procedures
to bulk tissue removal with blades and with thermal utilizing mechanical devices and thermal lasers to
trabecular meshwork procedures. This microinvasive perforate the TM have been shown to adequately
glaucoma surgery (MIGS) procedure, another option in bypass the outflow obstruction for the short term, but
the armamentarium for the glaucoma surgeon, has a have been unsuccessful in the long term due to the
high safety profile, rapid stabilization, clinical verifica- amount of adjacent tissue damage related to the nature
tion of long-term efficacy with minimal negative impact of the technique or device. Adjacent tissue damage
on quality of life, and may also become a replacement evokes a healing response, which eventually closes
option for topical glaucoma medicinal therapies. Thus, the channels. As laser technology evolved, each “new”
it would be possible to eliminate associated cost, laser was applied for this purpose, but none enabled
compliance, and adherence problems, and to reduce the creation of long-lasting patent openings. Krasnov
side effects of the long-term use of topical medications. et al. showed moderate success using a ruby laser (943
In addition, the sparing of conjunctiva as with other nm) to perform “trabeculopuncture”.2 Other thermal
MIGS procedures is advantageous because success laser trabeculopuncture attempts including Hager’s3
rates of a subsequent trabeculectomy, if needed, would use of an argon laser (488 + 514 nm) and Fankhauser’s4
not be negatively compromised. use of a neodymium-doped yttrium aluminum garnet
(Nd:YAG) laser (1064 nm, continuous wave) have also
been unsuccessful due to scarring. These and other
2. What are MIGS procedures and where laser trabeculopuncture attempts limit prospective
do they fit in glaucoma treatment options for subsequent procedures5,6 should they
become necessary, as they induce destruction of
paradigms?
local tissue and scar formation of adjacent tissue,
The invasive procedure and lifestyle altering sequelae often involving large regional areas. In addition, with
of trabeculectomy limits the use of this procedure to large openings and markedly increased outflow, the
later stage and recalcitrant glaucoma patients. Issues subsequent inflammatory compositional alterations of
regarding medication costs, compliance, and toxicity the aqueous would supplement the tissue destructive
of preservatives suggest medicinal therapeutic options healing responses.
also have limitations. Thus, there remains an unmet Following these initial attempts using lasers to
patient need for treatments that could effectively treat perforate the TM or to create full thickness sclerosto-
mild to moderate glaucoma. In recent years, several mies, Wise et al. determined that a continuous wave,
MIGS procedures have been developed to address essentially long-pulsed argon laser (488 + 514 nm) could
these limitations of traditional treatment options. All successfully modify the TM to increase outflow without
have advantages and disadvantages and fulfill the MIGS perforation. Their argon laser trabeculoplasty (ALT)
defined requirements, which are: procedure effectively lowered IOP, but it functioned by
Excimer laser trabeculostomy: the laser-based MIGS procedure for open-angle glaucoma 233
creating thermal damage to the target tissue, causing peripheral anterior synechiae, and IOP spikes which
coagulative necrosis of the TM.7 In contrast to ALT, are sometimes observed in eyes that have undergone
laser trabeculoplasty (LTP) is now more commonly LTP.13
performed with solid-state (532 nm, frequency-doubled In contrast to the diffuse thermal effects of argon, of
Nd:YAG) and diode (810 nm) lasers. Studies comparing solid-state, and of diode lasers with relatively long pulse
efficacy of these thermal lasers demonstrate minimal durations in the range of 0.1 second, recent advances
differences in efficacy, longevity or repeatability. in LTP utilize lasers with short pulse durations of 3–10
The efficacy of LTP in lowering IOP has been well ns. Selective laser trabeculoplasty (SLT), based on
documented in the literature.8-10 However, long-term the principle of selective photothermolysis, relies on
studies have shown that the IOP lowering efficacy of selective absorption of short laser pulses to generate
LTP decreases over time, from a 77% success rate at 1 and spatially confine heat to pigmented targets within
year, to 49% at 5 years, and finally to 32% at 10 years TM cells.14,15 SLT uses a Q-switched, frequency-doubled
(Table 1).11 Additionally, because of the significant (fd) 532 nm Nd:YAG laser. Q-switching of the fd Nd:YAG
TM scarring caused by LTP, repeat treatments are laser allows for extremely brief and thus high-powered
not recommended and have not proven successful light pulses to be delivered to the target tissues. The
clinically.12 LTP causes thermal coagulative damage to short duration of each pulse is critical in preventing
the uveoscleral meshwork, disruption of the trabecular collateral damage to the surrounding tissues.16 The
beams, and heat damage to the surrounding collagen exact mechanisms of the pressure-lowering effects
fibers. This thermal damage is in part responsible for following ALT, LTP, and SLT that alter but do not
the inflammatory response, scarring of the TM tissue, perforate the TM remain unknown.
Table 1. Ten-year lifetable analysis of ALT. Reproduced from Shingleton et al.11
Time after Cumulative
No. No. No. of eyes Standard Probability of success given
treatment probability
of eyes of failures withdrawn error survival of 1 year
(years) of success
0-0.5 93 13 4 0.86 0.037
0.5-1.0 76 8 2 0.77 0.045
1.0-1.5 66 3 0 0.73 0.047
1.5-2.0 63 3 2 0.70 0.049 0.91
2.0-2.5 58 4 1 0.65 0.051
2.5-3.0 53 2 2 0.63 0.052 0.82
3.0-3.5 49 1 0 0.61 0.052
3.5-4.0 48 6 3 0.54 0.054 0.78
4.0-4.5 39 1 0 0.52 0.055
4.5-5.0 38 2 3 0.49 0.055 0.64
5.0-5.5 33 3 3 0.45 0.056
5.5.-6.0 27 0 1 0.45 0.056 0.58
6.0-6.5 26 0 0 0.45 0.056
6.5-7.0 26 2 0 0.41 0.057 0.54
7.0-7.5 24 1 1 0.40 0.058
7.5-8.0 22 2 1 0.36 0.057 0.47
8.0-8.5 19 2 1 0.32 0.058
8.5-9.0 16 0 0 0.32 0.058 0.42
9.0-9.5 16 0 1 0.32 0.058
9.5-10 15 0 3 0.32 0.058 0.42
Preserving the TM may become more important in stimulating a fibroblast response is paramount to the
the near future, as surgical techniques are developed successful maintenance of outflow. Another anatomic
to operate directly on SC or the juxtacanalicular TM, consideration is the space between the inner and outer
the region considered responsible for most of the walls of SC, which can be less than 20 microns. The
outflow obstruction that causes open-angle glaucoma. accuracy of the tool used to enter the inner wall such
Thermal LTP would preclude the use of the newer MIGS that it does not disturb the outer wall must be of this
procedures in these patients, as their TM and adjacent same scale. The ablation precision of 308 nm on this
tissues, including SC, would be likely to have been tissue, unlike that of lasers and devices utilized in earlier
damaged. Once methods of preoperative evaluations attempts to fistulize SC, facilitates the nonthermal and
of the patency of the required outflow pathways, such accurate tissue removal which thereby enables the ELT
as high-resolution anterior chamber optical coherence procedure’s efficacy.
tomography (OCT), are clinically useful, such patients Initial in vitro experiments led to animal trials.20 In
can be better evaluated as candidates for MIGS a study of the effects of 308 nm excimer laser energy
procedures. applied ab interno to the limbal sclera of rabbit eyes,
long-term decreases in IOP were achievable. The use of
this 308 nm wavelength, unlike that of earlier trials with
4. The concept of ELT thermal lasers, enables laser-tissue interactions with
significant advantages. This excimer laser is less likely
Ultraviolet excimer laser photoablation enables the to evoke a cicatricial response in the TM or sclera than
precise removal of targeted tissue with meticulous those seen in trials using visible or infrared lasers, which
local and adjacent temperature control to prevent cause thermal tissue damage and subsequent healing
thermal damage to surrounding tissues, exemplified responses. In addition, there is minimal exposure of
by the use of 193 nm excimer lasers for corneal surface adjacent tissue to radiation enabled by direct contact
ablation, which facilitates successful refractive surgery. of the laser energy to the target tissue via the fiber optic
However, the 193 nm wavelength, although precise delivery system. With evidence that TM and scleral
and non-tissue damaging, is not readily transmissi- tissue could be successfully removed without adjacent
ble via fiber optics and can therefore not be used for tissue damage, without subsequent scar formation or
intracameral procedures. In contrast, 308 nm excimer hole closure, and with ablation accuracy which would
laser generated light is amenable to fiber optic trans- enable precise targeting of the TM, juxtacanalicular TM,
mission, and after extensive preclinical experimenta- and inner wall of SC without perforating the outer wall of
tion, became the wavelength of choice for nonthermal, SC, these studies formed the basis for the development
precisely targeted ab interno fistulizing procedures. of the current ELT technology and techniques.21
The applications of this nonthermal, ab interno, fiber
optic-delivered energy evolved initially from full
thickness sclerostomy, creating a bleb via an ab interno 5. ELT technique
approach, subsequently to trabeculostomy, once the
parameters of the target tissue anatomy,17-19 localiza- ELT, first used clinically in 1997 by Vogel and Lauritzen,
tion of SC, and ablation rates for this wavelength in treats the pathology responsible for most open-angle
this tissue were determined and idealized to enable a glaucoma by decreasing outflow resistance at the jux-
successful procedure to bypass TM and juxtacanalicular tacanalicular TM and inner wall of SC.22 It is performed
TM obstructions allowing and improving physiological with a short-pulsed (80 ns) 308 nm xenon-chloride
outflow directly into SC. Target tissue anatomic consid- (XeCl) excimer laser that delivers photoablative energy
erations to minimize healing responses must specifical- to precisely remove the tissue which obstructs aqueous
ly address minimizing trauma to the outer wall of SC. outflow with minimal thermal damage to adjacent
The outer wall endothelium of SC contains fibroblasts, tissue.23 ELT surgery is performed as an outpatient
whereas the inner wall endothelium does not. Thus, procedure, under topical, peribulbar, or retrobulbar
avoiding trauma to the outer wall and thereby not local anesthesia. Following a paracentesis and sta-
a b c
d e f
Fig. 1. (a-f) Drawings and photos of the ELT procedure. a, c, d, and f: Images courtesy of R.G. Peschke; b and e: Images courtesy of M.S.
Berlin and U. Giers.
bilization of the anterior chamber with viscoelastic, structures without producing undesirable marginal
the surgeon introduces a fiber optic probe, which is necrosis.24 ELT excises the TM, juxtacanalicular TM, and
advanced across the anterior chamber to contact the inner wall of SC without damaging the outer wall of SC
TM (Fig. 1). Probe placement is controlled by direct or the collector channels.25 No filtering fistula or bleb is
observation using either a goniolens or an endoscope. created.21,26,27
Four to ten channels are created into SC. The probe is
then removed, the viscoelastic is replaced by balanced
salt solution (BSS), and the patient is monitored post- 6. Technical aspects of the ELT procedure
operatively. Most commonly, the probe insertion is
superotemporal and the laser channels inferonasal. The current ELT procedure is performed with a 308 nm
Surgical technique variations include: a) spacing the XeCl laser in the following manner:
channels over both inferior quadrants and b) creating 1. Topical, peribulbar, or retrobulbar local
temporary hypotony following removal of the probe to anesthesia is administered. Topical anesthesia
enable enumeration of the number of patent channels in combination with intracameral unpreserved
into SC by observing an induced blood reflux followed anesthesia is another alternative. In ELT Alone,
by repressurization, among others. Minor blood reflux topical pilocarpine 2% is often used preopera-
is a common but inconsequential occurrence. To date, tively to constrict the pupil. In phakic patients,
no studies have shown benefit from treatment in more this may also assist in protecting the lens. Alter-
than one quadrant. As no single protocol has been natively, intracameral Miochol (acetylcholine
established, each surgeon tends to create their own 10mg/ml) (Bausch & Lomb, Bridgewater, NJ,
technique. In spite of these numerous variations, the USA) may be used.
outcomes are remarkably similar. 2. The laser is automated to internally calibrate and
By means of the essentially nonthermal photoab- control the output fluence in accordance with the
lation using the specified laser parameters, ELT manufacturer’s specifications. Unlike solid-state
“evaporates” human tissue, denaturing the organic lasers, this XeCl gas laser requires a short “warm
Fig. 2. Paracentesis in the superotemporal perilimbal cornea. Fig. 3. Viscoelastic agent is introduced. Image courtesy of M.S.
Image courtesy of M.S. Berlin and U. Giers. Berlin and U. Giers.
up” time of less than a minute during which the SC is targeted whenever visible or surgeons
output energy is stabilized before use. are advised to alternate placement of the fiber
3. The sterile fiber optic delivery system is coupled to anterior, mid, and posterior TM regions to
to the laser. The output beam is then adjusted ensure some of the channels will, in fact, enter
at the fiber tip to ensure suprathreshold fluence into SC. The number of pulses, which controls
for tissue ablation at the fiber tip. The console the penetration depth, is fixed, similar to the
includes a power meter to enable this calibration, penetration depth control in LASIK. Perforation
which is performed prior to each procedure, of the inner wall of SC into SC depends, therefore,
similar to the tuning of a phacoemulsification on its distance from the fiber tip, which can be
handpiece before use. variable depending on the angle of placement
4. A 1 mm paracentesis is created in the superotem- and the amount of pressure on the fiber. The
poral perilimbal cornea 2 o’clock for left eyes and calculation of this distance was determined in
10 o’clock for right eyes; in combined cataract numerous preclinical experiments.28,29 Thus, the
and ELT procedures, the previously created pha- current protocol consists of ten probe placement
co-tunnel may be used in a similar fashion (Fig. 2). sites on the TM, a percentage of which is likely to
5. A cohesive viscoelastic agent fills the anterior enter SC.
chamber through the paracentesis. Depending 8. The laser is activated, delivering laser pulses at
on the surgeons’ preference, the IOP may be 20 Hz per treatment site. Each pulse converts
unchanged or increased by this injection, thereby the tissue at the fiber tip into gas. This gas may
enabling or precluding visualization of SC by be seen exiting around the fiber tip during each
blood reflux into the canal (Fig. 3). ablation (Fig. 8).
6. The laser probe is inserted into the anterior 9. The probe tip is then repositioned such that ten
chamber through the paracentesis (Fig. 4) and channels are created.
is advanced to the opposite chamber angle 10. The probe is removed and viscoelastic is
via gonioscopic (using the surgeon’s preferred exchanged for BSS with irrigation/aspiration,
goniolens) (Fig. 5) or endoscopic visualization coaxial or bimanual (Fig. 9).
(Fig. 6). The ELT fiber may be attached coaxial The anterior chamber can be monitored for the number
with an endoscope or a second paracentesis and location of patent trabeculostomy sites by blood
endoscopic view may be utilized. reflux from SC (Fig. 7b and 7c) during a period of
7. The fiber tip is centered on the pigmented TM and iatrogenic temporary hyopotony during the viscoelas-
advanced to be in contact with the TM (Fig. 7a). tic/fluid exchange.
Fig. 4. Laser probe is inserted through the paracentesis to cross the Fig. 5. Gonioscopic view. IOP high = SC not visible. Image courtesy
anterior chamber. Image courtesy of M.S. Berlin and U. Giers. of M.S. Berlin and U. Giers.
Fig 6. Endoscopic view. IOP low = SC visible, blood filled. Image

courtesy of J. Funk and M. Töteberg-Harms.
a b c
Fig. 7. (a) ELT probe in contact with the TM, gonioscopic view. (b) Blood in SC verifies appropriate targeting and depth, gonioscopic view.
(c) Induced blood reflux verifies success and enables documentation of number of successful channels into SC. Images courtesy of M.S.
Fig. 8. Laser pulse. Image courtesy of M.S. Berlin and U. Giers. Fig. 9. Viscoelastic is exchanged for BSS. Image courtesy of M.S.
Fig. 10. Patent trabeculostomy channels into SC (arrow) noted 2.5 Fig. 11. Blood reflux from SC induced by “pumping” the goniolens
years after ELT. Image courtesy of M.S. Berlin and U. Giers. three years after ELT. Image courtesy of M.S. Berlin and U. Giers.
a b c
Fig. 12. Photos of the ELT procedure demonstrating pneumatic canaloplasty. (a) Coaxial endoscopic view. (b) As the second channel is
created into SC, (c) bubble expansion is observed at the first ELT site, confirming channel patency into SC at both sites. Image courtesy of
M.S. Berlin and J. Funk.
Postoperative topical ophthalmic medication gonioscopic views of ELT have revealed gas bubble
regimens are individualized by the surgeon. Most formation in the tissue and the anterior chamber as
include: a result of photoablation of the TM tissue. When the
1. A fixed combination of steroid and antibiotic eye ablation penetrates the outflow obstruction, gas is able
drops or ointment administered immediately at to enter SC through the newly formed channels through
the end of the procedure. the inner wall of SC. The pressure of this gas has been
2. The operated eye is shielded or patched, and the proposed to dilate SC and collector channels to improve
patient is released once stable, similar to after aqueous outflow, thereby contributing to lowering IOP.
phacoemulsification. Observing gas bubbles exiting the adjacent channel
3. The operated eye is usually treated with a topical openings confirms continuity of flow from SC.
fixed combination of steroid (dexamethasone This hypothesis has yet to be confirmed via real-time
0.1%) and antibiotic eye drops qid for one week imaging or histologic studies. Real-time imaging
and then tapered over 3 weeks. and post mortem histologic studies — in addition to
4. In the rare case of an anterior chamber inflam- histologic studies after ELT to evaluate the long-term
matory reaction, mydriatic eye drops may be changes which occur subsequent to this procedure
added and the topical steroid can be increased — will enable better understanding of the effects and
per surgeon’s preference. effectiveness of the current procedure and enable
5. In floppy iris syndrome patients as well as suggestions for modifications to potentially further
patients who experience greater intraoperative improve the outcomes (Fig. 12).
anterior chamber bleeding, pilocarpine 1% may
be useful during the first five days to prevent iris
synechiae. 9. ELT as a MIGS procedure
Most surgeons discontinue all antiglaucoma
medications after the procedure. However, preopera- Pache et al. published the largest sample size study
tive antiglaucoma medication may be continued and of ELT patients to date, which included 135 eyes with
later reduced dependent on postoperative IOP. When open-angle glaucoma or ocular hypertension after
medications are reduced, IOP should be monitored ELT Alone or ELT combined with phacoemulsifica-
carefully on a regular basis. tion (Phaco + ELT).41 Follow-up was one year. Two
subgroups (subgroup 1 [SG1] with IOP > 22 mmHg at
baseline and subgroup 2 [SG2] with IOP ≤ 21 mmHg
7. After ELT at baseline) were analyzed separately. Success (IOP ≤
21mmHg, 20% reduction from baseline, antiglauco-
Ideally, the patients are monitored postoperatively ma medications (AGM) ≤ baseline, and no subsequent
with gonioscopy in addition to IOP and the findings IOP-lowering surgery) for ELT Alone was 57% in SG1
documented as to number and location of patent (baseline IOP: 27.9 ± 3.9 mmHg; IOP at 1 year follow-up:
channel sites noted. In the cases that have been 19.3 ± 5.5 mmHg) and 41% in SG2 (baseline IOP: 20.2 ±
followed in this manner, channels are documented to 1.1 mmHg; IOP at 1 year follow-up: 17.6 ± 3.3 mmHg);
remain patent years after the ELT procedure. In some for combined Phaco + ELT, it was 91% in SG1 (baseline
patients, goniolens “pumping” can induce blood to IOP: 26.4 ± 2.8 mmHg; IOP at 1 year follow-up: 16.7 ±
appear at the channels, further confirming the patency 2.8 mmHg) and 52% in SG2 (baseline IOP: 19.6 ± 1.1
of these channels into SC (Figs. 10 and 11). mmHg; IOP at 1 year follow-up: 16.3 ± 2.2 mmHg).
Hence, IOP reduction by ELT appears to be effective
in both groups, but much more effective in eyes with
8. ELT enables pneumatic canaloplasty higher baseline IOP.
Wilmsmeyer et al. investigated outcomes after ELT
Another potential benefit of ELT is that it enables Alone (70 eyes) vs Phaco + ELT (60 eyes) after a follow-up
pneumatic canaloplasty. Both endoscopic and of 2 years in patients with open-angle glaucoma or
ocular hypertension.42 They found a higher reduction difference is thought to be due to the nonthermal
of IOP after Phaco + ELT (IOP reduced from 24.1 ± 0.7 approach of ELT compared to the remarkably thermal
mmHg to 16.8 ± 1.0 mmHg at 2 years after ELT Alone approach of Trabectome.
vs reduced from 22.4 ± 0.6 mmHg to 12.6 ± 1.5 mmHg In a retrospective longitudinal study, Berlin et al.
at 2 years after Phaco + ELT. AGM use did not change monitored 164 eyes that were stratified into two
significantly. groups, ELT Alone (N = 90) and Phaco + ELT (N = 74)
Babighian et al. found comparable results in an followed through 6 years postoperative.38 In the ELT
ELT study with a 2-year follow-up of 21 eyes with Alone group, IOP was lowered from a mean of 22.17 ±
open-angle glaucoma.43 Success (IOP decrease 20% 7.00 mmHg at baseline (N = 90 patients) to 16.84 ± 5.2
with no additional medication or IOP-lowering surgery) mmHg at 1 year (N = 69 patients); to 16.17 ± 4.83 mmHg
rates were 54% and IOP was reduced from 24.8 ± 2.0 at 2 years (N = 54 patients); to 15.73 ± 5.77 mmHg at 4
mmHg at baseline by 7.9 ± 0.1 mmHg at 2 years. years (N = 26 patients); and to 15.2 ± 2.95 mmHg at 6
Töteberg-Harms et al. demonstrated simultaneous years (N = 20). AGM were reduced from 1.85 ± 0.81 at
IOP reduction and AGM reduction after Phaco + ELT baseline to 1.19 ± 1.10 at 1 year, 1.08 ± 1.09 at 2 years,
(IOP decreased from 25.33 ± 2.85 mmHg at baseline and 0.76 ± 1.06 at 4 years. In the combined Phaco + ELT
to 16.54 ± 4.95 mmHg at 1 year, while medication group, IOP was lowered from a mean of 21.9 ± 6.44
decreased from 2.25 ± 1.26 at baseline to 1.46 ± 1.38 mmHg at baseline (N = 74) to 14.04 ± 4.1 mmHg at 1
at 1 year).44 Complete success (IOP < 21 mmHg, IOP year (N = 63 patients); to 14.4 ± 4.48 mmHg at 2 years
reduction ≥ 20%, without AGM, and no subsequent (N = 58 patients); to 14.6 ± 4.26 mmHg at 4 years (N
IOP-lowering surgery) in their study population was = 42 patients); and to 14.22 ± 2.51 mmHg at 6 years (N
21.4%; qualified success (same as complete success = 18 patients). AGM were reduced from 1.58 ± 0.81 at
but additional AGM were not excluded) was 64.3% at baseline to 0.97 ± 0.95 at 1 year, 1.08 ± 0.93 at 2 years,
1 year. and to 1.16 ± 0.9 at 4 years. The single, non-repeated
Töteberg-Harms et al. also demonstrated the rela- ELT procedure effectively lowered IOP in both groups
tionship of the IOP-lowering efficacy of ELT to baseline over the entire follow-up through 6 years. Patients
IOP with greater IOP reduction in patients with higher have been monitored over 12 years, with the longest
baseline IOP.45,46 In addition, this study also validated postoperative patient data at 17 years. However, the
the efficacy of ELT in patients with baseline IOP below sample size of these earlier treated patients is too
21 mmHg, which thereby could support the use of ELT small to be representative for inclusion in this study.
in normal-tension glaucoma (NTG) patients as well In a recent retrospective study, Moreno Valladares
as in patients with ocular hypertension treated with et al. analyzed the ELT learning curve of surgeons
topical medications for the purpose of reducing their previously naïve to gonioscopic MIGS surgery. In a
medication requirements. sample size of 29 patients aged 72 ± 8.4 years with
The longest peer-reviewed ELT publication to date moderate glaucoma (Humphrey MD: 7.2 ± 5.85 dB),
is the paper by Töteberg-Harms et al. on Phaco + ELT 25 eyes underwent Phaco + ELT surgery and 6 eyes
with 4-year post-ELT follow-up data. They showed no underwent ELT Alone. The baseline IOP was 25 ± 2.4
difference in efficacy between years 1 and 4 after this mmHg without treatment and medicated preoperative
combined procedure (N = 51 eyes). IOP was 21 ± 2.46 mmHg with 1.69 ± 0.6 medications.
In a pending publication currently under review, The learning curve for these surgeons appeared to be
Jozic et al. compared Phaco + ELT (N = 105) to combined nine surgical cases. At 8 weeks, the IOP decrease was at
Phaco + Trabectome (N = 102) to Phaco Alone (N = 38).47 its maximum (-21.8%) and medications decreased by
These three surgical techniques yielded a statisti- 70% (P = 0.000). IOP at 12 months was 16 ± 2.6 mmHg,
cally significant (P < 0.01) decrease in IOP of 1.5 ± 4.0 with a reduction of 1.2 AGM. Medicated IOP decreased
mmHg in Phaco Alone; 4.3 ± 5.6 mmHg in Phaco + ELT; 32% in patients who underwent Phaco + ELT, and 28%
and 5.3 ± 4.5 mmHg in Phaco + Trabectome. However, for patients who underwent ELT Alone. At one year,
survival time after Phaco + ELT was significantly longer 70% of all patients did not require medications. Rare
than survival time after Phaco + Trabectome. This time and inconsequential surgical complications included
microhypema (9%) and short-term IOP spikes (6%), all 11. Limitations and next generation
of which resolved within one week, and one case of
peripheral anterior synechiae (3%).48 Feedback from leading surgeons who have performed
Summarizing, current published data demonstrates over 5,000 ELT procedures have identified several
that ELT has a short learning curve, low complication potential enhancements to current ELT techniques
rate, and can reduce IOP and lower AGM simultaneous- which, at present, are procedurally comparable to goni-
ly for up to 12 years. The combined procedure, Phaco olens-based stent MIGS surgical techniques, if not, in
+ ELT, appears to be more effective than ELT Alone and fact, actually easier to perform. The next generation
the amount of IOP lowering seems to be dependent on of ELT devices, called Guided ELT, is currently under
baseline IOP and is more effective in eyes with higher development to enable the first goniolens-free,
baseline IOP. angle-based MIGS procedure by providing real-time
virtual images combined with real image guidance to
the surgeon. New technologies are being utilized and
10. ELT compared to other MIGS sensors are being designed to better enable the surgeon
procedures and to other outflow to precisely identify and locate SC and the TM as well
as to automate laser control without goniolenses. In
procedures
contrast, tactile contact currently provides feedback as
As an invasive surgical procedure, ELT has also to the amount of pressure applied by the fiber tip to the
shown favorable outcomes when compared to other meshwork. Furthermore, new system controls guide the
MIGS procedures. Patients undergoing clear cornea surgeon as to the depth of tissue removal and automate
phacoemulsification followed by ab interno gonio- the number of laser pulses required to penetrate the
scopically guided implantation of one iStent achieved inner wall of SC with these automated detectors and
an IOP decrease of 40.3% and a mean medication imaging, especially real-time imaging. In addition, the
change of -1.23 ± 0.10 at 1 year postoperative.49 ongoing development of spectral domain OCT shows
Patients undergoing phacoemulsification cataract promising abilities to enable preoperative and intra-
extraction combined with Trabectome achieved IOP operative localization of collector channel networks to
decreases of up to 18% and medication decreases of enable optimization of TM channel locations.
17% at 1 year postoperative. 50
Of most relevance is the finding that ELT has shown
comparable long-term IOP-lowering results (decrease 12. Conclusion
of 38.6% after 5 years and 36.9% after 8 years) to tra-
beculectomy and tube-shunt procedures that are sig- ELT is a safe and effective implant-free MIGS procedure
nificantly more invasive and risk-inherent traditional to reduce both IOP and medication use with minimal
operating room surgeries. Although trabeculecto- complications in most patients with open-angle
my has demonstrated IOP decreases of 57.1% and glaucoma. lt is less invasive relative to the methodol-
medication decreases of up to 90%, when comparing ogies currently being practiced and thus reduces many
the data obtained in the Collaborative Initial Glaucoma postoperative issues, including patient discomfort,
Treatment Study (CIGTS) on trabeculectomy patients, number of postoperative visits required to assure
the 5-year postoperative ELT IOP measurements at adequacy and stability, and especially the long-term
all time points averaged 1 mm higher than those in risks of filtering procedures. By essentially eliminating
the 300 patients who underwent trabeculectomy the healing response-inducing and damaging thermal
documented in CIGTS. In addition, trabeculectomy effects as well as the tissue trauma seen with other
had an intraoperative complication rate of 12% and alternative Iasers, device-based, and implant-based
a 1-month postoperative complication rate of 50% vs procedures, ELT enables implant-free IOP lowering on a
ELT intraoperative and postoperative complication long-term basis. Furthermore, due to the minimal tissue
rates of 0%. 51,52 trauma associated with UV tissue photoablation, only
a few, small channels into SC have proven adequate to
Fig. 13. Comparison of various outflow procedures based on the published results of exemplary studies.30-41
control IOP. Unlike trabeculectomy, ELT preserves the procedures have been successful in lowering and
integrity of the meshwork and SC, which restores the maintaining lower IOP for years (Fig. 13). ELT patient data
natural outflow without the creation of blebs or invasive is the longest longitudinal MIGS data to date confirming
foreign body implants. ELT is an important adjunct to the safety and efficacy of MIGS as an important con-
cataract surgery, allowing physicians to address two sideration for the management of most open-angle
pathologies in one surgical intervention without cutting glaucoma patients. Currently, clinical studies are
the conjunctiva. pending in both the United States and Canada. We look
ELT has been approved for use in the European forward to a better future for our glaucoma patients
Union and Switzerland since 1998. Thousands of ELT and especially for their children.
References
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24. Neuhann T, Scharrer A, Haefliger E. Excimer laser trabecular American Society of Cataract and Refractive Surgery, American
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43. Babighian S, Rapizzi E, Galan A. Efficacy and safety of ab interno submitted for: the 14th Congress of the Spanish Glaucoma As-
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44. Töteberg-Harms M, Wachtl J, Schweier C, Funk J, Kniestedt C. microstent combined with phacoemulsification in routine
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45. Töteberg-Harms M, Ciechanowski PP, Hirn C, Funk J. [One-year ened Exact Matching of Phaco-Trabectome to Trabectome in
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46. Töteberg-Harms M, Hanson JV, Funk J. Cataract surgery Excimer laser trabeculostomy: 5-year follow-up. Abstract sub-
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BMC Ophthalmol. 2013;13:24. doi:10.1186/1471-2415-13-24. 52. Jampel HD, Musch DC, Gillespie BW, et al. The CIGTS Study
47. Jozic L, Magner J, Funk J, Töteberg-Harms M. Success of Group. Perioperative complications of trabeculectomy in the
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my exceeds that of combined ab interno Trabeculectomy with Ophthalmol. 2005;140:16-22.
the Trabectome or Cataract Extraction alone. Int Ophthalmol.
[under review].
17. Mixing and combining MIGS procedures
Steven R. Sarkisian, Jr.
Oklahoma Eye Surgeons, Oklahoma City, OK, USA
Abstract
Purpose: To elucidate the many ways surgeons are and difficult learning curve to adopt canaloplasty,
combining minimally invasive glaucoma surgery (MIGS) with results improving after 50 or more procedures.
procedures. Thankfully, the newer procedures have a much easier
Methods: The data and current experience were learning curve; however, upon review of the data, they
researched and analyzed. clearly are less effective than older, riskier procedures.
Results: Surgeons have been individualizing the surgical Most of the newer procedures, like the iStent (Glaukos,
care of glaucoma patients using the canal, supracili- San Clemente, CA, USA) and the Hydrus (Ivantis, Irvine,
ary space, subconjunctival space, and ciliary ablation CA, USA) have been FDA approved for mild to moderate
techniques in combination to lower intraocular pressure glaucoma, but they are effective in lowering intraocular
(IOP) in patients with glaucoma. pressure (IOP) and can get patients with controlled IOP
Conclusion: There are a variety of modalities currently off one or two glaucoma medicines, or with moderately
used to mix and combine MIGS to treat each patient elevated IOP with a better IOP on the same medicines.
based on severity of glaucoma, number of preoperative Moreover, many creative surgeons determined to help
medications, level of IOP, and individual patient needs their patients with safer options to lower IOP and save
and demands. vision have been combining MIGS procedures in one
sitting to expand the IOP-lowering effects of these
Keywords: eye surgery, glaucoma, glaucoma surgery, procedures. The following will review the different ways
MIGS surgeons have been mixing MIGS procedures.
1. Introduction 2. Mixing and combining MIGS
The options for the surgical treatment for glaucoma There are only so many ways to modulate aqueous
have exploded over the last few years. We used to have humor. The two broad categories involve the two sides
only trabeculectomy, with or without EX-PRESS (Alcon of the facility equation: viz., inflow and outflow. For
Laboratories, Inc., Fort Worth, TX, USA), tube shunts, years, we have been suppressing aqueous production
and cyclophotocoagulation. In the 2000s, surgeons with medications. There are two relatively safe ways
started doing viscocanalostomy, followed by ab externo to decrease aqueous production surgically: endocy-
canaloplasty. Sadly, these canal procedures, much like clophotocoagulation (ECP, Beaver-Vistec International,
the minimally invasive procedures that have followed, Waltham, MA, USA) and micropulse cyclophotocoagu-
were met with much skepticism by the glaucoma lation (MPCPC) (Iridex, Mountain View, CA, USA) (both
community. This was partly due to the high skill level procedures also discussed in Chapter 15). On the other
Correspondence: Steven R. Sarkisian, Jr., MD, Oklahoma Eye Surgeons, 5600 N Portland Avenue, Oklahoma City, OK, USA.

246 S.R. Sarkisian, Jr.
side of the equation, we have several ways of increasing glaucoma severity, and other personal factors. Often,
outflow. These include bypassing the canal with stents the choices are not based on what might be best for
such as the iStent, iStent inject (also discussed in the patient in the mind of the surgeon (or the patient),
Chapter 9), and the Hydrus (also discussed in Chapter 8), but rather on what can get reimbursed by a third-party
and viscodilating the canal in an ab interno fashion with payor. For example, if the patient has a cataract, then a
ab interno canaloplasty with either the iTrack Microca- stent of some kind can often be combined with another
theter (Ellex Medical, Adelaide, Australia) or the OMNI MIGS. If the patient does not have a cataract, then most
Device (Sight Sciences, Inc., Menlo Park, CA, USA). The stents may not be reimbursed in the USA if done in a
OMNI Device is also FDA indicated and approved to standalone fashion. However, patients willing to forgo
perform 360° goniotomy, and the iTrack Microcathe- insurance coverage can sign an advance beneficiary
ter can also serve this purpose in a procedure known notice (ABN) and have an “off-label” stent or even a
as gonioscopy-assisted transluminal trabeculotomy or combination of stents. For the sake of this discussion,
GATT (also discussed in Chapter 7). Finally, other devices we will not outline what can and cannot be done based
can perform a goniotomy/trabeculotomy; namely, on a reimbursement or regulatory basis, but on what is
the Kahook Dual Blade (KDB) (New World Medical, possible based on common sense, surgeon experience,
Rancho Cucamonga, CA, USA), and the Trabectome and and data, where available.
Goniotome devices (Neomedix, Tustin, CA, USA). As with the medical management of glaucoma — or
Another way to increase outflow is to access the systemic hypertension for that matter —doctors often
suprachoroidal or supraciliary space. The CyPass combine medications that have different mechanisms
(Alcon) is an FDA-approved stent that was voluntarily of action. For example, patients are often using a pros-
pulled from the market due to an increased risk of taglandin analog that increases uveoscleral outflow and
corneal endothelial cell loss seen at four years post- also simultaneously an aqueous suppressant. This is a
operative in patients from the pivotal FDA clinical trial. routine and effective treatment combination for many
This was particularly seen in patients in which the stent patients. In the same fashion, combining a surgery that
had migrated anteriorly or in which they were underim- improves outflow facility through the natural drainage
planted. The iStent Supra by Glaukos has not yet been system via the trabecular meshwork and Schlemm’s
FDA approved, but is the next supraciliary implant. canal, with a surgery that increases outflow through
Finally, aqueous humor can be shunted to the sub- a novel path such as the supraciliary space can have
conjunctival space. This is not an area typically done in and additive effect on IOP lowering. This approach may
combination with anything except cataract surgery and draw criticism, because when starting a fixed-combi-
will not be part of this discussion. nation drug, determining which of the two (or three in
Given these many options to lower IOP, we can some cases) medications is having the greater effect is
now cater the surgical treatment of glaucoma to each not possible. Similarly, when combining surgeries, it
individual patient. When considering which surgery may be also unclear which procedure is contributing
is best, there are several factors that influence the the most efficacy; however, given the risk and expense
decision. The key to serving each patient lies in under- of multiple surgeries on the patient and the “system”,
standing the patient’s visual needs, occupation, lens performing them at the same time is often most
status, number of glaucoma medications, preopera- appropriate.
tive IOP, and glaucoma severity. If IOP is well controlled There are several possibilities to combine MIGS
on one to two medications and the patient has a procedures. First, given that it is the only MIGS treatment
cataract, then picking one procedure is usually the best that works on the production side of the equation, ECP
practice. Much time can be spent elucidating which one can be combined with any of the other MIGS surgeries.
procedure may be appropriate; however, the focus of Although I have minimal experience mixing MPCPC
this discussion is on combining MIGS procedures. If a with other MIGS, I do have considerable experience
patient has an elevated IOP with or without a cataract, with MPCPC as a standalone procedure, which I find is
and is on medications, then the choices are going to be fit for purpose, but may still be too inflammatory to be
influenced by the number of medications, IOP level, truly considered MIGS. In contrast, my experience with
Mixing and combining MIGS procedures 247
ECP demonstrates that it does not create excessive

inflammation if the surgeon modulates the energy to
the level of pigment (less energy in more pigmented
eyes) and does not cause any of the ciliary processes to
“pop” during the treatment. Moreover, avoiding hitting
the iris completely helps prevent inflammation. I have
extensive experience combining ECP and the first-gen-
eration iStent, a combination termed ICE (iStent +
cataract + ECP), which was popularized by Nathan
Radcliffe.1
Although this combination surgery had been
performed for several years by many surgeons, Dr.
John Berdahl was the first to publish his results, which Fig. 1. iStent and CyPass implant in the same eye. Image courtesy
demonstrated significantly more improvement in IOP of Steven R. Sarkisian, Jr., MD.
lowering with the combination than with the iStent
alone. The study group combined cataract surgery with MIGS are using viscodilation combined with the iStent,
a single iStent and ECP, while the control group had iStent inject, or Hydrus implants. The logic behind the
cataract surgery with a single iStent alone. The mean combined procedure is to open the canal and collector
preoperative IOP was 21.49 mmHg ± 9.56 (SD) in the system, enhancing the efficacy of the trabecular bypass
study group (51 eyes) and 20.66 ± 3.23 mmHg in the stent. One could also combine viscodilation with
control group (50 eyes). Twelve months postoperatively, any goniotomy/trabeculotomy procedure, including
mean IOP reduction was 7.14 mmHg in the study group GATT, KDB, Trabectome, or Goniotome. This can also
and 4.48 mmHg in the control group, and medication be combined with ECP. Finally, the most frequent
reduction was 38% (0.68) and 63% (1.06), respectively.2 combination that is actually FDA indicated is the OMNI
Although there is limited data on combining ECP procedure, where the canal and collector system is
with other MIGS, there have been several presentations opened with 360° viscodilation and the entire 360°
at national and international meetings. Ponte et al. of trabecular meshwork is stripped off with the same
presented their data combining ECP with the KDB at the catheter. As this device came out in 2018, publication
European Glaucoma Society in 2018. Although the study regarding its efficacy is pending. Preliminary data
had no control group, it was prospective and involved was presented at the World Glaucoma Congress in
27 eyes in 21 patients. At 6 months follow-up, average Melbourne, Australia in 2019. Grabska-Liberek and
IOP decreased from 17 mmHg to 11.9 mmHg, 70% of colleagues reported a 38% drop in IOP at 1-year
patients were on no medications, and all patients had follow-up (baseline of 23.42 mmHg down to a mean of
a 30% reduction in IOP.3 14.6 mmHg) and average reduction in medications at
At the UK and Eire Glaucoma Society, Barata et al. 1-year follow-up of 43% (baseline of 3.17 and mean of
presented a prospective study combining the iStent 1.8 medications) in patients undergoing the OMNI as a
inject with ECP in 55 eyes of 48 subjects. At 6 months standalone procedure.5
follow-up, IOP was reduced from 19.4 to 13.4 mmHg and The future looks bright for our patients with
medication use dropped from 2.2 to 1.3 medications.4 glaucoma. Many patients who have MIGS procedures
Little has been published about combining other still need to be on at least one medication. With the
MIGS. However, several surgeons have combined the impending approval of sustained-release medication
iStent and the CyPass in the same eye in an “off-label” modalities such as the iDose (Glaukos) and Bimatoprost
fashion (Fig. 1). I have combined many cases of the OMNI SR (Allergan, Dublin, Ireland), I envision these
procedure (360° viscodilation and 360° goniotomy) modalities being done in combination with standalone
with the CyPass before the CyPass was removed from or mixed MIGS procedures, freeing the majority of
the market; however, the number of patients was too patients from eye drops. Much work needs to be done
small to publish. Currently, several surgeons combining in this area and the data will be exclusively investiga-
248 S.R. Sarkisian, Jr.
tor-initiated rather than industry-sponsored. The next surgeons, in partnership with industry, are driving the
few years will be especially informative, as surgeons car of innovation, patients are screaming from the back
push the MIGS frontier in an ever-evolving landscape seat demanding safer, less invasive options to treat
where there may not be consensus for years to come. their glaucoma. If we are to fulfill our calling, we must
In the end, our patients will benefit. Charlie Kelman, keep fighting for our patients by continually changing
the father of modern cataract surgery, has been quoted our treatment algorithms and tailoring them to individ-
as saying “Doctors debate, patients decide”. Although ualize care for each patient.
References
1. Personal communication with Nathan Radcliffe, MD. 4. Barata A, Georgeopulos M, Ratnarajan G. Short and medi-
2. Ferguson TJ, Swan R, Sudhagoni R, Berdahl JP. Microbypass an-term outcomes of phacoemulsification combined with two
stent implantation with cataract extraction and endocyclo- iStent inject trabecular microbypass stents and endocyclopho-
photocoagulation versus microbypass stent with cataract ex- tocoagulation. Poster Presentation at the UK and Eire Glaucoma
traction for glaucoma. J Cataract Refract Surg. 2017;43(3):377- Society Annual Meeting. London, England. December 13, 2018
382. doi: 10.1016/j.jcrs.2016.12.020. 5. Grabska-Liberek I, Majszyk-Ionescu J, Duda P, Rogowska M,
3. Ponte MC, Izquierdo, JC, Quezada F, Ramirez I, Rubio B, Cano- Skowyra A, Kane I. OMNI In Open Angle Glaucoma Treatment,
la-Ramirez LA. Phacoemulsification plus ABI Trabeculecto- A 1 Year Follow-Up. Poster Presentation at the World Glaucoma
my-Kahook Dual Blade and Endocyclophotocoagulation in Congress. Melbourne, Australia, March 28, 2019.
Patients with Primary Open Angle Glaucoma and Cataract.
Poster Presentation at the European Glaucoma Society,
Florence, Italy. May 20, 2018
18. Trabeculectomy with suprachoroidal derivation
Rodolfo A. Pérez-Grossmann1, Daniel Grigera2, Alan Wenger3, Rodolfo A. Perez-Simons4
Cataract and Glaucoma Institute, Lima, Perú, 2Santa Lucía Eye Hospital, Buenos Aires, Argentina, 3Glaucoma Service,
1
Hospital San Juan de Dios, Santiago, Chile, 4Scientific University of the South, Lima, Perú.
Although trabeculectomy has evolved over time, The objective of a glaucoma surgical technique is to obtain
fibrosis remains the main enemy of success, and the a long-lasting, consistently low intraocular pressure (IOP)
shape and vulnerability of the blebs, an obstacle to with a minimal complication rate and acceptable comfort.
comfort and long-term safety. For this reason, we The technique of trabeculectomy was described for the
modified the conventional trabeculectomy by directing first time in 1968 by Cairns1 and has evolved in recent
the aqueous humor flow to the suprachoroidal space by years2,3 in the continuous effort to attain those goals. Even
means of a specially created canal, without the use of so, fibrosis remains the main enemy of effectiveness,4-6 and
any artificial space-maintaining device and preserved the shape and vulnerability of the blebs7-9 are obstacles
by the patient’s own scleral tissue. The aqueous humor to comfort10,11 and long-term safety.12,13 This is why we
drains from the trabeculectomy into the tunnel and, decided to create a variant of conventional trabeculecto-
eventually, part of the aqueous can also drain to an my with suprachoroidal derivation (trabeculectomy SCD),
external bleb. External blebs, if present, should not be directing the aqueous humor flow to the suprachoroi-
prominent. dal space by means of a specially created canal without
We carried out a retrospective, ultrasound biomi- the use of any artificial, space-maintaining device. Here,
croscopy (UBM) study of 18 eyes of 14 patients whose the risk of fibrosis is negligible and even the need for an
surgery with the modified technique was successful external bleb of considerable dimensions is superfluous.
in the long term (a minimum of two years follow-up).
Average follow-up time was 42.94 months, median: 47
months. The most frequent UBM finding was an evident 2. The surgical procedure
suprachoroidal anechoic space in 88% of the eyes. In
63.5% of these, the space was classified as extensive. The surgery14 (Video 1) is performed under topical and
One-third of the eyes (six) had no ultrasonographic subconjunctival anesthesia (proparacaine hydrochlo-
evidence of an external bleb. Blebs tended to be shallow ride 0.5%, and 0.5 cc lidocaine 2%, respectively). If the
and diffuse. The average final intraocular pressure was patient has undergone previous surgeries, the upper
strikingly low (12.66 ± 2.49 mmHg, median: 13 mmHg), quadrant with the least amount of fibrosis is chosen as
as was the complication rate, with no devastating com- the surgical site.
plications.
Keywords: suprachoroidal, suprachoroidal derivation, 3. Bleb appearance

trabeculectomy, ultrasound biomicroscopy (UBM)
Correspondence: Rodolfo A. Pérez-Grossman, MD, Avenida Reducto 1330, Miraflores, Lima, Perú.

250 R. A. Pérez-Grossmann et al.
Fig. 1. Step-by-step guide for the surgical

procedure. The first step is to perform 1 2
a fornix-based, conjunctival incision
of approximately 6 mm with relaxing
incisions at the edges. A complete,
blunt Tenon’s dissection with slight cau-
terization of episcleral vessels allows
optimal exposure and visualization of the
operative area.
After measuring and marking the Mitomycin C (0.4 mg/ml for 3 minutes)
operative area, a 5 x 5 x 5 mm lim- is applied with microsponges to the
bus-based, half-thickness scleral flap is operative area under the conjunctiva
performed using a crescent knife until the and Tenon´s capsule, and then washed
clear cornea is reached. abundantly with balanced saline solution.
3 4 5
A second, deeper, limbus-based scleral The second flap is divided radially into The central part is removed, leaving two
flap of 4 x 3 x 4 mm and 30% of the three limbus-based parts 1 mm wide lateral portions.
scleral thickness is performed inside the each.
previous one, leaving 1 mm free space on
each side of the previous flap.
6 7 8
Approximately 3 mm from the limbus, in A bite with the 0.9 mm Kelly punch is The paracentesis is performed.
the remaining 20% of the sclera, a 3 mm taken at the center of the posterior lip of
transversal incision is made using a 2 the scleral incision.
mm crescent knife to reach the choroid,
carefully dissecting a suprachoroidal
channel with a blunt spatula.
Trabeculectomy with suprachoroidal derivation 251
9 10
The lateral flaps are then inserted into each side of the suprachoroidal space, forming a View of the lateral flaps into the supracho-
channel that will lead the aqueous humor from the anterior chamber into the suprachoroidal space.
roidal space.
11 12 13
Next, the trabeculectomy is performed: a A bite is taken with the 0.9 mm Kelly A basal iridectomy is performed with
1 mm penetrating incision is made in the punch. Vannas scissors, allowing the anterior
clear cornea — close to the limbus — with chamber to communicate with the scleral
a side-port knife. channel.
14 15 16
The scleral channel is covered with the The first scleral flap is tightly sutured with Finally, the fornix-based conjunctiva is
first flap. nylon 10/0 (two stitches in each of the closed with nylon 10/0 sutures.
three sides of the flap and one stitch in
each corner), in order to get a watertight
seal. This flap forms the roof of the tunnel.
252 R. A. Pérez-Grossmann et al.
There is not always an obvious bleb in the postoper- 4. Ultrasound biomicroscopy

ative biomicroscopic examination. When there is, it is
usually diffuse, of small height, and extended towards In a retrospective study of 18 eyes of 14 patients, whose
the posterior zone (Fig. 18). Occasionally, the bleb may surgery was successful in the long term15 (average
be limited by fibrosis (Fig. 19); when this happens, IOP follow-up time: 42.94 months, median: 47.00 months),
is not significantly affected since the suprachoroidal the most frequent ultrabiomicroscopic finding was the
bypass can act as a second filtration mechanism. presence of an evident suprachoroidal, anechoic space
in 88.0% of the eyes (Fig. 20). In 63.5% of these, the space
was classified as extensive. One-third (six) of the eyes
Fig. 18. Image of a diffuse bleb of small height and extended Fig. 20. The most frequent ultrabiomicroscopic finding was the
posteriorly. presence of an evident suprachoroidal, anechoic space in the sub-
conjunctival space.
Fig. 19. Occasionally, fibrosis may be present, which does not affect Fig. 21. Some cases had no ultrasonographic evidence of a subcon-
IOP significantly. junctival bleb.
Trabeculectomy with suprachoroidal derivation 253
had no ultrasonographic evidence of an external bleb16

(Fig. 21) and the lateral flap is visible in some UBM scans
(Fig. 22). The average final IOP was strikingly low — 12.66
± 2.49 mmHg; median 13.00 mmHg — as was the compli-
cation rate, with no devastating complications.
Fig. 22. The lateral flap is visible in the suprachoroidal space in

some cases.
References
1. Cairns JE. Trabeculectomy. Preliminary report of a new 10. Budenz DL, Hoffman K, Zacchei A. Glaucoma filtering bleb
method. Am J Ophthalmol. 1968;66(4):673-679. dysesthesia. Am J Ophthalmol. 2001;131(5):626-630.
2. Jones E, Clark J, Khaw PT. Recent advances in trabeculectomy 11. Barton K. Bleb dysesthesia. J Glaucoma. 2003;12(3):281-284.
technique. Curr Opin Ophthalmol. 2005;16(2):107-113. 12. Luebke J, Neuburger M, Jordan JF, et al. Bleb-related infections
3. Khaw PT, Chiang M, Shah P, et al. Enhanced trabeculectomy: the and long-term follow-up after trabeculectomy. Int Ophthalmol.
Moorfields safer surgery system. Dev Ophthalmol. 2017;59:15-35. 2019;39(3):571-577.
4. Seet LF, Finger SN, Chu SW, et al. Novel insight into the in- 13. Razeghinejad MR, Havens SJ, Katz LJ. Trabeculectomy bleb-
flammatory and cellular responses following experimental associated infections. Surv Ophthalmol. 2017;62(5):591-610.
glaucoma surgery: a road map for inhibiting fibrosis. Curr Mol 14. Perez-Grossmann R, Grigera DE, Wenger A. Trabeculectomy
Med. 2013;13(6):911-928. with suprachoroidal derivation in eyes with uncontrolled
5. Rao A, Chatterjee S. Epiconjunctival mitomicin-C application for glaucoma: a case series with a 24-month follow-up. Ophthal-
early failing filtering blebs. Semin Ophthalmol. 2014;29(1):48-51. mol Ther. 2019;8(2):323-331.
6. Schlunck G, Meyer-Ter-Vehn T, Klink T, et al. Conjunctival 15. Perez Grossmann R, Grigera DE, Wenger A. UBM imaging
fibrosis following filtering glaucoma surgery. Exp Eye Res. patterns in successful trabeculectomy with suprachoroidal
2016;142:76-82. derivation: a long term analysis. Poster session presented at:
7. Pederson JE, Smith SG. Surgical management of encapsulated 8th World Glaucoma Congress; 2019 Mar 27-30; Melbourne, Aus-
filtering blebs. Ophthalmology. 1985;92(7):955-958. tralia.
8. Ophir A. Encapsulated filtering bleb. A selective review –new 16. Ito K, Matsunaga K, Esaki K, et al. Supraciliochoroidal fluid in
deductions. Eye (Lond). 1992;6:348-352. the eyes indicates good intraocular pressure control despite
9. Francis BA, Du LT, Najafi K, et al. Histopathologic features absence of obvious filtering bleb after trabeculectomy. J
of conjunctival filtering blebs. Arch Ophthalmol. 2015;123(2): Glaucoma. 2002;11(6):540-542.
166-170.
19. Modern retinal laser for neuroprotection in
open-angle glaucoma
Jeffrey K. Luttrull1, David Kent2,3
1
Private Practice, Ventura, CA, USA; 2The Vision Clinic, Kilkenny, Ireland; 3University of Liverpool School of Medicine,
Institute of Aging and Chronic Disease, Liverpool, England
Abstract
Purpose: To examine the rationale for modern laser Conclusion: Progression of OAG despite intraocular
treatment of the retina to provide neuroprotection in pressure (IOP) control indicates significant other
open-angle glaucoma (OAG). drivers of glaucomatous optic neuropathy. The
Method: The effects of therapeutic thermal laser mechanism of SDM as modern retinal laser therapy
stimulation of the retinal pigment epithelium (RPE) and clinical effects in OAG suggest that OAG includes
are reviewed in relation to RPE function in glaucoma or arises from a retinopathy evidenced only by a
and the pathogenesis of OAG. failure of normal RPE-derived neurotrophism that
Results: Modern retinal laser therapy is epitomized can be restored by laser treatment. Clinical trials are
by low-intensity/high-density subthreshold diode recommended to determine if modern retinal laser-in-
micropulse laser (SDM), which is both clinically duced neuroprotection can improve outcomes in OAG
effective and reliably sublethal to the RPE. The safety by preventing or slowing progression of glaucomatous
of SDM, and the mechanism of action as a biologic optic neuropathy.
“reset” phenomenon, has expanded application of
modern retinal laser for both treatment and prevention Keywords: laser, neurodegeneration, neuroprotec-
of diseases prohibited to older forms of retinal laser tion, neurotrophy, open-angle glaucoma (OAG), retinal
inherently destructive to the retina, such as photoco- pigment epithelium
agulation. SDM is especially effective in the treatment
of chronic progressive retinopathies (CPRs), which, as
neurodegenerations, share many key commonalities. 1. Introduction
By addressing these commonalities, SDM reverses the
disease process and reduces the risks of visual loss. Modern retinal laser therapy represents a sea change
OAG, like age-related macular degeneration (AMD), in the conception and clinical application of retinal
diabetic retinopathy (DR), and other CPRs, is also a laser treatment for all but retinal cautery.1,2 Con-
neurodegeneration. The RPE is fundamentally neuro- ventional photocoagulation, universally thought for
trophic to the neurosensory retina, and thus the optic decades to be the necessary and sufficient cause of
nerve. Therefore, SDM-induced improvement and nor- all therapeutic retinal laser effects, is now known to
malization of RPE and retinal function in the face of be entirely unnecessary, making no unique contribu-
neurodegeneration is, by definition, neuroprotective. tion to the therapeutic result.2 Instead, as the single
Clinical evidence of neuroprotection from SDM in OAG source of all risks, adverse effects, limitations, and
is reviewed. complications of retinal laser treatment, photocoagu-
Correspondence: Dr. Jeffrey K. Luttrull, MD, Private practice, 3160 Telegraph Rd, Suite 230, Ventura, California, 93003, USA.

256 J. K. Luttrull and D. Kent
lation, and indeed any degree of laser-induced retinal treatment (sublethal to the RPE) are therapeutic. No
damage (LIRD), is now known to be nothing more than adverse effects or products have ever been identified
a complication of treatment, rather than a necessary clinically, or in the laboratory. 5-28 Thus, the clinical
therapeutic measure.3 In this upending of the conven- safety of modern retinal laser therapy is unparal-
tional wisdom lays the promise of modern retinal laser leled. The principal mediator of retinal laser effects
therapy to become one of most useful and important is activation of RPE heat-shock proteins (HSPs). 5-22 As
tools in the future management of ocular disease, HSPs are enzymes triggered by meeting an activation
and uniquely with regard to prevention. For such a threshold, exceeding this threshold produces no
statement to be true it would necessarily extend to additional benefits — only risks. 5-30 Thus, in contrast
open-angle glaucoma (OAG), one of the most important to conventional thinking and practice, clinical
causes of progressive irreversible visual loss.4 experience and clinically-informed biophysical
analyses with modern retinal laser therapy have
identified retinal laser parameters that can be used in
2. What is “modern retinal laser all patients without adjustment, and without regard to
therapy”? the traditional considerations of pigmentation, media
opacity, retinal thickening, or macular pathology,
It is now known without question that the therapeutic which are both safe and effective in all eyes (“fixed”
effects of all retinal laser treatment arise entirely from laser parameters).11,23-31 Treatment is thus simplified
sublethal thermal stimulation of the retinal pigment and adverse effects are precluded. As a general
epithelium (RPE).1-22 There is much in this sentence. principle, all treatments that are therapeutic are also
Recognition of photocoagulation and all other forms preventive, given early.32 Unfortunately, preventive
and degrees of LIRD as complications of treatment treatment is generally precluded by the risks and
has allowed, for the first time, a cogent and useful adverse effects of treatment. This is not a limitation of
understanding of the therapeutic mechanisms of modern retinal laser therapy. Thus, the unique safety
retinal laser treatment. This understanding accounts of modern retinal laser treatment opens the door,
for the effects of all modes of retinal laser treatment, for the fist time, for effective preventive treatment of
including photocoagulation, for all traditional retinal the most important causes of irreversible visual loss:
laser applications such as diabetic macular edema chronic progressive retinopathies. These appear to
(DME), proliferative diabetic retinopathy (PDR), retinal include OAG.23-31,33,34
vein occlusion, and central serous chorioretinopathy.
In a critical test of any theory, it has also accurately
predicted novel retinal laser indications unimag- 3. What modern retina laser therapy is
inable in the photocoagulation age. These include not
reversal of tolerance to vascular endothelial growth
factor (VEFG) inhibitors; improved retinal and visual All light is not equal. It is a common mistake to consider
function in age-related macular degeneration (AMD) all forms of light-based therapy as simply variations
and inherited retinal degenerations (IRDs), including on a theme, and essentially the same. Fortunately,
retinitis pigmentosa (RP); improved retinal ganglion this is not the case. Important differences in various
cell layer (RGC), optic nerve function, and visual light-based treatment modalities exist that increase
function in OAG; and reduced risks of long-term visual treatment options and indications, and create oppor-
loss in AMD.23-27 tunities for complementarity and synergy. Most often,
Arising entirely from selective sublethal laser this confusion conflates laser therapy with biomod-
thermal stimulation of the target RPE, the biologic ulation. While the effects of each may have areas of
effects of modern retinal laser therapy have been overlap, the processes and mechanisms of action
confirmed and characterized with increasing depth are fundamentally different, and thus the potential
and breadth in vivo and in vitro.1-22 Of particular note therapeutic applications.35 The basic differences are
is that all known effects of modern retinal laser illustrated in Table 1.
Modern retinal laser for neuroprotection in open-angle glaucoma 257
Table 1. Comparison of modern retinal laser therapy to biomodulation
Attribute Modern retinal LASER Biomodulation
Thermal Yes No
Ionizing No 1
No
Visible wavelength (WL) No 2
Always
Light source Laser Any
Sublethal to retina Yes Yes
RPE selective Yes No
WL specific effects No Yes
Effects specific to WL order of NA Yes
presentation
Duration of effect Long Short
Duration of treatment Short Long
Mechanism of action RPE HSP activation Respiratory chain metal ion electron photonic excitation
1
Wavelengths below 550 nm at sufficient energy may cause ionizing photochemical effects that are cytotoxic and should thus be avoided.
The intensity of visible light used in biomodulation is physiologic and thus non-ionizing.
2
Visible wavelengths as well as invisible wavelengths in the near infrared spectrum can be used, such as 810 nm.
HSP: heat shock protein; RPE: retinal pigment epithelium.
4. Ageing 5. How does modern retinal laser

therapy address chronic disease?
The expectation of reaching old age is a new
phenomenon. For all but the most recent moments of Acquired abnormalities of protein secondary and
human history, human life span was generally limited tertiary structure are the currency of cellular, and thus
to only a few decades by disease, trauma, starvation bodily, dysfunction.5,8,9,12-15 Correcting these abnor-
and/or exposure. Longevity exceeding the biological malities by repairing or degrading misfolded proteins
imperative of reproduction and child rearing (less and toxic protein aggregates is a fundamental role of
than 20 years), thereby allowing a leisurely retirement, the HSP system.5,8,9,12-15 As protein misfolding occurs
is not a biologic concern.36 Thus, while the body has continually, HSPs have an important role in the
powerful processes for repair and healing, these maintenance of baseline cell function and homeostasis.
processes are specifically designed to address the Pathologic states, such as hyperglycemia, age, or
acute existential threats of youth. Ageing, and the genetic defects, increase protein damage and may
chronic progressive diseases that accompany and lead to cellular dysfunction if left to accumulate.37-41
indeed define ageing, including chronic progressive The “menu” of these secondary protein abnormal-
retinopathies, are different. Chronic disease begins ities is unique to, and reflective of, the underlying
and proceeds slowly and insidiously. Hence, under disease process, defining the clinical syndromes and
normal circumstances, chronic progressive diseases phenotypes we give names to. 5,8,12-15,37-41
do not activate the body’s inherent and otherwise Beyond homeostatic surveillance, HSPs are also
effective capacities for repair and restoration. This critical to protecting cells from damage and death
allows age-related degenerations to develop and from acute threats and injuries. This salvific and
progress unimpeded. 5,6,8,12-15 restorative function of HSPs is poorly engaged by
chronic disease.5,8,12-15 Unengaged, chronic disease may
lead to failure of the HSP system itself.37-41 Designed
to respond to acute existential threats to the cell, HSP
activation is highly sensitive to the severity and acuity
of the threat or injury.5,8,12-15 As cellular repair is relevant accomplished by confluent treatment of large areas of
only to cells that survive an insult, the most effective diseased retina (“high-density” treatment) to achieve
triggers of the salvific HSP response are those that are a mass effect of laser-normalized RPE optimizing the
severe but sublethal and sudden. Laser irradiation is therapeutic effects.30 Established and epitomized by
an effective method of delivering such a stimulus to SDM, these are the key principles — low-intensity and
the retina. high-density treatment — that define modern retinal
Low-intensity/high-density subthreshold diode laser therapy.1-3
micropulse laser (SDM) defines modern retinal laser Activation of HSPs to meet an existential threat to
therapy.2,31 The first retinal laser approach designed the cell results in repair of not only proteins damaged
to be reliably sublethal to the RPE and thus clinically acutely by the threat stimulus, but also proceeds to
harmless, SDM delivers a series of laser pulses repair of pre-existing misfolded and dysfunctional
(“micropulses”) to the cell that damage intracellular functions that have escaped homeostatic surveil-
proteins sufficiently to trigger the salvific HSP response, lance.5-15 Cell function is thus not just maintained,
but still far below the lethal threshold.11,42 In practical but normalized. This in turn leads to a myriad of
terms, SDM tricks the cell into thinking it is going to consequent reparative and restorative processes that
die (the acute existential threat). In response, the cell improve retinal function and autoregulation, and thus
tries to save itself (via HSP-mediated protein repair, visual function.5 This process is largely independent
the “salvific” HSP response) leading to normalization of the underlying cause(s) of the protein misfoldings
of cell and tissue function.5,8 The therapeutic effects and character of the subsequent cellular dysfunction.
of retinal laser stimulus are entirely thermal.2 Lasers Thus, sublethal thermal HSP stimulation can be
of wavelengths less than 550 nm have ionizing, pho- thought of as a “reset to default” phenomenon.11,23
tochemical effects. These are generally cytotoxic and The reset hypothesis accounts for all retinal laser
cytocidal, and damage the neurosensory retina as well effects (even due to photocoagulation) observed
at the RPE. Such damage is adverse and detrimental clinically, in vivo and in vitro.2,23,24 These include
to the desired effects of treatment, worsens clinical activation and induction of HSPs including 70, 90,
outcomes, and should thus be avoided. Therefore, and alpha-A crystallins; decreased VEGF, transform-
modern retinal laser therapy abandons the conven- ing growth factor beta, and basic fibroblast growth
tional photocoagulation era preference for short factor; increased pigment epithelial derived factor
wavelengths in the blue and blue-green spectra.2 (PEDF); modulation of tissue matrix metalloproteinas-
To raise the temperature within a cell by a therapeutic es; immunomodulation including local and systemic
but sublethal 6-8° centigrade, the rate of temperature recruitment and activation of bone marrow-derived
change from a conventional continuous wave (CW) stem cells (BMSC), monocyte and hematopoiet-
laser is approximately 1000 C/second. For micropulsed ic progenitor cells; improved macro- and microglial
laser such as SDM, the rate of change is 100,0000 C/ function; reduced free radical species and increased
second.11 These repetitive pulses of SDM also produce superoxide dismutase activity; increased mRNA
thousands of sudden but still sublethal temperature expression of cytokine and interleukin markers of
spikes superimposed over the average intracellu- reparative acute inflammation and decreased markers
lar temperature rise.11,42 Thus, SDM is an especially of chronic inflammation; improved mitochondrial and
effective activator of the salvific HSP response.2 This, thus metabolic function; increased retinal nitrous
and the fact that enzymatic activation thresholds may oxide; activation of heat-sensitive trans-membrane
be lowered by reaction acceleration (the temperature calcium channels and HSP response modulation; and
rate of change of SDM compared to CW laser), widen inhibition of apoptosis.5-22 Given that SDM has no effect
the therapeutic target range of pulsed lasers such as on already normal cells and improves dysfunctional
SDM, and thus safety and effectiveness compared to cells according to their disease-specific dysfunction,
continuous wave lasers.3, 11,29-31,42,43 These “low-intensi- modern retinal laser treatment is “pathoselective”.23,24
ty” (sublethal to the target RPE) therapeutic effects are This property of pathoselectivity eliminates the need
then amplified and maximized by recruitment. This is for focal or local treatment targeting of modern retinal
laser therapy; allowing treatment of large geographic death) to participate in repair along with other resident
areas of retina to capture and recruit all dysfunctional and systemic immune cells.20 These BMSCs appear to
retina to maximize treatment benefits, much like drug support repair through paracrine factors (restoration),
therapy.30 rather than trans-differentiating into new RGCs (regen-
Chronic inflammation is the driver of all age-related eration).72 Via this supportive function, these sys-
disease, including OAG.44 The self-perpetuating, pro- temically recruited BMSCs orchestrate the rescue of
gressively degenerative state that ultimately develops distressed and dying RGCs, restoring function and
as the result has been described as “inflammaging”.44,45 inhibiting apoptosis.73 Additional BMSC-derived neu-
Inflammaging occurs when the everyday inflammato- roprotective mechanisms may include secretion of
ry-based repair mechanisms, present in all cells and neurotrophins, survival-promoting growth factors and
required to maintain homeostasis and normal tissue cytokines; restoration of synaptic transmitter release;
function, are gradually overwhelmed by the increasing stem cell engraftment into existing neural and synaptic
burden of repair. This leads to gradual compromise of networks; and the re-establishment or mending of
cellular function that can progress to eventual loss of functional afferent and efferent connections.73,74 The
function due to cell death and tissue atrophy. This classic events triggered by homeotrophic laser treatment
picture of progression also takes place in OAG, where of the RPE counter and reverse the chronic disease
dysfunction and damage takes place in the RGC layer, processes, improving tissue function and stopping,
triggering molecular cascades consistent with inflam- slowing, or reversing disease progression. In disease,
maging.46-49 This age-related RGC injury may generate these retinal laser effects may be considered neuropro-
damage-associated molecular pathogens (DAMPs) tective.26,71,76,80
that are deposited into the extracellular matrix (ECM),
where they trigger activation of resident immune cells,
both astrocytes and microglia.50-56 DAMPs associated 6. OAG: a retinopathy?
with glaucoma include HSPs and double-stranded DNA
from RGC axons, as well as Tenacin C, a matricellular Progression of OAG despite IOP lowering indicates that
protein, secreted by microglia and astrocytes.46-49,57,58 OAG is multifactorial and that the development and
A multitude of genes associated with inflammation in progression of glaucomatous optic neuropathy is, to
the retina and optic nerve head may be upregulated some degree, independent of IOP. These other contrib-
in glaucoma, with the immune response mediated utors to OAG may be amenable to treatment to improve
by toll-like receptor (TLR) activation on the surface of prognosis.4
astrocytes and microglia.46,48,53,54,59-63 Binding of DAMPs Identification of early abnormalities in Alzheimer’s
to TLRs leads to activation of nuclear factor kappa- disease and frontotemporal dementia with retinal
light-chain-enhancer of activated B cells (NFkB) and optical coherence tomography (OCT) illustrates that
secretion of cytokines such as interleukin (IL)-1 beta, the retina is part of the central nervous system.75 All
IL-6, and tumor necrosis factor (TNF) alpha, amplifying chronic progressive retinopathies, including AMD,
the immune response through the recruitment of diabetic retinopathy, and RP, are therefore neurode-
systemic immune cells and activating the complement generations.76-78 As neurodegenerations, all chronic
cascade.46,59-71 All such changes may contribute to the progressive retinopathies, regardless of cause, share
development and progression of chronic inflammation much in common.75-78 This includes OAG.26
and degeneration recognized clinically as OAG. SDM was developed in 2000 as the first retinal laser
SDM as modern retinal laser therapy reverses these treatment for the complications of diabetic retinopathy
abnormalities by eliciting a reparative acute inflam- designed to be clinically effective while entirely
matory response, uniquely in the absence of tissue eliminating LIRD.3 SDM was found to be effective in the
damage.5-22 This mechanism has been demonstrated in absence of photocoagulation or any other LIRD in the
a murine model of retinal laser injury.20 Current under- management of both DME and PDR.3,31,34,79 While details
standing indicates that BMSCs home to sites of injury of the mechanism of action were not understood at
(in the case of SDM, again absent tissue damage or that time, this much was clear: by selectively treating
the RPE without LIRD, the effect of SDM was normaliza- Prior to SDM treatment, topical medications ranged 0-3
tion of RPE, and thence retinal, physiologic function.3 (avg. 1.6), and nearly all had undergone prior laser tra-
By exclusion, the most likely mediator of this effect beculoplasty. Thirty-three eyes had undergone filtering
was sublethal thermal activation of RPE HSPs.3 This surgery. All had optic nerve cupping, visual field loss,
connection has now been firmly established and and abnormal MVFT. Following SDM there were no
expanded upon.10,11,16-22 As HSP-mediated repair is changes in IOP. However, visual acuity (P = 0.005), PERG
largely independent of the cause of the inciting damage (P = 0.05), VEP (P = 0.0005), and MVFT (P < 0.0001) were
and resultant cellular dysfunction (the “reset to default” improved following panmacular SDM treatment.26
phenomenon), SDM as modern retinal laser therapy Most eyes in this study had a concurrent retinopathy,
acts as a “non-specific trigger of disease-specific such as AMD or RP. However, 12 eyes had no concurrent
repair”.23,24 This homeotrophic, or restorative, function conventional retinopathy. Thus, it is interesting to
of SDM in retinal neurodegenerations is by definition note that the results of SDM in the OAG eyes with and
neurotrophic; and as neurotrophic, neuroprotective in without a concurrent retinopathy were the same.26
the presence of progressive disease.26,80 As noted above, SDM treatment of dry AMD and IRDs,
The reset function of SDM suggested that it should including RP, had previously been shown to signifi-
improve retinal and visual function not only in the cantly improve retinal function by PERG and various
traditional indications for retinal laser treatment, visual function tests.24 The improvements in patients
such as diabetic retinopathy, but in any chronic with OAG were different, however.26 In AMD and IRDs
progressive retinopathy of any cause.23,24 Subsequently, without glaucoma, SDM treatment was followed by
panmacular SDM was found to improve retinal function robust improvements in measures of PERG signal
by pattern electroretinography (PERG) and visual latency. In OAG, latencies were improved, but not sig-
function by contrast visual acuity and microperimetry nificantly. Instead, signal amplitudes were significant-
in dry AMD and various IRDs.24 Abnormalities of PERG ly improved.26 VEP responses were not tested in the
were well known in OAG, and may anticipate disease non-glaucomatous AMD/IRD eyes.24 However, the VEPs
progression by nearly a decade.81 Thus, the question improved significantly following SDM in OAG, and sur-
arose: if worsening of retinal function measured by prisingly to a greater extent than the improvements in
PERG predicts disease progression in OAG, what might the PERG, which includes a significant RCG contribu-
it mean to improve the PERG? Could selective SDM tion.80-83 Similar to the PERG in OAG, although all VEP
treatment of the RPE produce electrophysiologic and measures improved following SDM, it was the signal
visual improvements indicative of neurotrophy in OAG, amplitudes rather than latencies that improved most.
in the absence of a retinopathy evidenced by nothing Thus, the SDM-elicited improvements in these eyes
other than glaucomatous optic neuropathy?82 If so, this with advanced OAG appear to be due to improvements
would indicate a retinopathy in OAG characterized by a in optic nerve rather than retinal function, even in
modifiable failure of RPE-derived neurotrophy.26,80,81 eyes with concurrent retinopathies.24,26 Of note is that
while the PERG has been noted to improve following
IOP lowering in OAG, this is the first report of treat-
7. SDM as modern retinal laser therapy in ment-associated improvement in the PERG absent
OAG IOP lowering and the first VEP improvement in OAG
or any other clinical setting.26,84 Impressively, visual
While proof is yet lacking, there is compelling evidence function, especially MVFT, demonstrated the most
that this is indeed the case. A recent study identified robust improvements following panmacular SDM in
88 consecutive eyes of 48 patients with OAG and glau- OAG.26 These results suggest that SDM treatment of
comatous optic neuropathy and controlled IOPs who the retina improves apparently pathologically insuffi-
had undergone panmacular SDM and were evaluated cient RPE-derived neurotrophy in OAG. If maintained
before and after treatment by PERG, visually evoked by periodic retreatment, might SDM-elicited neuropro-
potential (VEP), and mesopic visual function testing tection contribute to slowing or stopping progressive
(MVFT).26 The patients were aged 57-94 years (avg. 74).26 glaucomatous optic neuropathy and visual loss in OAG?
8. A focus on mesopic visual function of mesopic BC logMAR VA, creating a visual acuity or
“resolution” visual field. A number of digital readouts or
Standard chart visual acuity measures are typically reports can be obtained. Our custom is to use the BA6
performed under photopic, high-luminance, conditions (BC mesopic logMAR VA within 6° of fixation); the GMA
and represent predominantly macular cone function. (global macular acuity, an average of the BC logMAR VAs
Rod function can be isolated under conditions of low in the central 20° inversely weighted by distance from
luminance (scotopic conditions), as the light intensity fixation); and the Visual Area (the area within the central
is insufficient to engage the macula cones. At the 20° with a BC logMAR VA of 20/160 or better). All testing
mid- (mesopic) range of luminance, both rod and cone was done at 99% contrast, although various levels of
function contribute, and thus macular function is contrast can be employed as desired.
engaged, but challenged.85 As noted above, eyes with glaucomatous optic
Like a whisper is more likely to uncover a hearing neuropathy demonstrated marked improvement in all
deficit than a shout, MVFT is more sensitive to macular ORP measures of MVF after panmacular SDM compared
dysfunction than standard chart visual acuities.86-90 It to pretreatment levels (P < 0.0001).26 In the following
is abnormal in typical macular disease and in OAG.89-92 analysis we compare the MVFT responses of these same
In AMD, abnormality of MVFT in normal-appearing eyes eyes with OAG and glaucomatous optic neuropathy
has been shown to anticipate development of AMD by to normal controls, and to eyes treated with SDM for
three years.93 Over a number of years of using retinal other conventional chronic progressive retinopathies,
and visual function testing to identify and monitor including dry AMD and RP. If OAG is, at least in part, a
the effects of SDM in various clinical settings, we have retinopathy, the expectation is that it should respond
found MVFT to be the simplest, most informative, to SDM treatment of the macular RPE similarly to other
most intuitive, and highly sensitive visual and retinal chronic progressive retinopathies. MVFT is one such
function testing method for doctor and patient alike. point of comparison.
Unlike electrophysiology, MVFT testing takes no special
Table 2. Eye-level characteristics of the control eyes
training or expertise to perform and interpret. By the
method we employ, MVFT results are easily appreciated N (%) or mean (SD)
and demonstrated to patients. In practice, therefore, Total number of eyes 229

MVFT has largely replaced more complex and abstract Eye, (Nmiss = 4)
methods of retinal and visual function testing, such as OD 114 (50.7)
electrophysiology.24-26 OS 111 (49.3)
To perform MVFT we have employed the Omnifield Visual area
Resolution Perimeter (ORP) (Sinclair Technologies, Inc, First measurement (Nmiss = 1) 358.1 (96.2)
Media, PA, USA). ORP is FDA-approved for measurement Second measurement (Nmiss = 111) 337.6 (116.8)
of mesopic visual acuity. ORP measures the best-cor- GMA, LogMAR
rected (BC) logMAR visual acuity (VA) at various First measurement (Nmiss = 0) 0.4 (0.4)
intercepts (generally 17-24, depending on the testing Second measurement (Nmiss = 111) 0.5 (0.5)
protocol) throughout the central 20° of the retina, under BA6, LogMAR
mesopic illumination. To perform ORP, the patient is First measurement (Nmiss = 0) 0.0 (0.2)
corrected for the testing distance of 30 cm. Each eye
Second measurement (Nmiss = 111) 0.1 (0.4)
is tested separately. Landolt “C”s representing various
levels of logMAR VA are presented on a monitor at the BA6: best corrected logMAR VA within 6° of fixation under mesopic
illumination at 99% contrast; GMA: average macular acuity
various intercepts for 250 ms. The logMAR VA at each (best corrected logMAR VA within 10° of fixation under mesopic
intercept is determined by asking the patient to indicate illumination at 99% contrast inversely weighted by distance from
the open position of the C by deflecting a hand-held fixation); miss: number missing; N: number; OD: right eye; OS: left
eye; SD: standard deviation; visual area: area within the central 20°
joystick in the direction of the C opening to determine of visual field with a best corrected logMAR VA of 20/160 or better
the resolution threshold. This VA data is then processed under mesopic illumination at 99% contrast.
by a computer algorithm to construct a false-color map
Therefore, the MVFT results of 229 normal eyes second ORP 1-3 months after initial testing (Table 2).
undergoing ORP for evaluation of visual complaints or In addition to the eyes described above with OAG, 462
in conjunction with diagnostic evaluation of unilateral eyes with dry AMD tested by ORP were also identified.
pathology in the fellow eye were identified for use as In addition to baseline testing, 359 of these eyes
controls. One hundred eighteen of these eyes had a underwent ORP testing 1 month following panmacular
Table 3. Eye-level characteristics of all treated eyes including AMD, Table 4. Baseline pre-SDM treatment mesoptic visual function
RP, and OAG measures by ORP by diagnosis subsets
N (%) or mean (SD) Variable Subset Treated Control P-value

eyes eyes
Total number of eyes 569
GMA
Eye (Nmiss = 2)
All AMD 0.9 (0.5) 0.4 (0.4) < 0.0001
OD 295 (52.0)
AREDS category 1, 2 0.7 (0.5) < 0.0001
OS 272 (48.0)
AREDS category 3 0.9 (0.5) < 0.0001
Visual area
AREDS category 4 1.3 (0.6) < 0.0001
Pre-treatment (Nmiss = 103) 233.5 (150.6)
RP 1.4 (0.8) < 0.0001
Post-treatment (Nmiss = 166) 262.6 (144.5)
Glaucoma 1.0 (0.5) < 0.0001
GMA, LogMAR
BA6
All AMD 0.3 (0.3) 0.0 (0.2) < 0.0001
AREDS category 1, 2 0.2 (0.3) < 0.0001
BA6, LogMAR
AREDS category 3 0.3 (0.3) < 0.0001
AREDS category 4 0.6 (0.4) < 0.0001
RP 0.5 (0.4) < 0.0001
BA6: best corrected logMAR VA within 6° of fixation under mesopic
Glaucoma 0.4 (0.3) < 0.0001
illumination at 99% contrast; GMA: average macular acuity (best
corrected logMAR VA within 10° of fixation under mesopic illumina- AREDS: Age-Related Eye Disease Study; BA6: best corrected
tion at 99% contrast inversely weighted by distance from fixation); logMAR VA within 6° of fixation under mesopic illumination at 99%
miss: number missing; N: number; OD: right eye; OS: left eye; SD: contrast; GMA: average macular acuity (best corrected logMAR VA
standard deviation; visual area: area within the central 20° of visual within 10° of fixation under mesopic illumination at 99% contrast
field with a best corrected logMAR VA of 20/160 or better under inversely; weighted by distance from fixation).
mesopic illumination at 99% contrast.
Table 5. Difference in measures from pre- to post-treatment

Treated Control Comparison
Variable
N Mean (SD) P a
N Mean (SD) P a
Pb
Visual area 402 29.9 (109.7) < 0.0001 117 1.6 (54.0) 0.66 0.003
GMA 402 20.1 (0.3) < 0.0001 118 0.0 (0.2) 0.27 0.0004
BA6 402 20.1 (0.3) < 0.0001 118 0.0 (0.3) 0.02 < 0.0001
In order to test whether the mean difference is different from zero, linear mixed models predicting the measure were performed using
an indicator for time as a covariate, also adjusting for left or right eye, and including a random patient intercept. The P-values are those
associated with the time (pre- vs post-) regression coefficient. A significant P-value indicates that the mean difference is significantly
different from zero. In order to test whether the mean difference of treated eyes is significantly difference from the mean difference of
control eyes, linear mixed models predicting the measure, using indicators for time, eye, and treatment were performed. Also included
is an interaction between time and treatment. The P-values are those associated with the interaction regression coefficient. A signifi-
cant P-value indicates that the mean differences are significantly different across treatment groups. This method accounts for inter-eye
correlation.
BA6: best corrected logMAR VA within 6° of fixation under mesopic illumination at 99% contrast; GMA: average macular acuity (best
corrected logMAR VA within 10° of fixation under mesopic illumination at 99% contrast inversely weighted by distance from fixation); N:
number; SD: standard deviation; visual area: area within the central 20° of visual field with a best corrected logMAR VA of 20/160 or better
under mesopic illumination at 99% contrast.
Table 7. Eye-level characteristics of the treated RP eyes before and

SDM treatment; and 224 eyes were tested again 1 after the first SDM treatment session
month after a second SDM treatment 6–9 months
N (%) or mean (SD)
(avg. 8) after initial treatment. Finally, 22 eyes of
11 patients previously reported with RP also tested at
Eye
baseline, and 1 month after SDM, were also included for
OD 11 (50.0)
comparison.25, 26 (Tables 3-11)
OS 11 (50.0)
Compared to normal controls, baseline MVFT by
ORP for the combined group of AMD, OAG, and RP were Visual area
all significantly abnormal. (Table 4). Following SDM, Pre-treatment 140.5 (162.8)
MVFT by ORP for the group was significantly improved. Post-treatment 185.8 (156.4)
(Table 6). GMA, LogMAR
Pre-treatment 1.4 (0.8)
Post-treatment 1.3 (0.7)
BA6, LogMAR
Table 6. Eye-level characteristics of the treated AMD eyes before BA6: best corrected logMAR VA within 6° of fixation under mesopic
and after the first two SDM treatment sessions illumination at 99% contrast; GMA: average macular acuity (best
corrected logMAR VA within 10° of fixation under mesopic illumina-
N (%) or mean (SD) tion at 99% contrast inversely weighted by distance from fixation);
Total number of eyes 462 N: number; OD: right eye; OS: left eye; SD: standard deviation;
visual area: area within the central 20° of visual field with a best
Eye, (Nmiss = 2) corrected logMAR VA of 20/160 or better under mesopic illumina-
OD 240 (52.2) tion at 99% contrast.
OS 220 (47.8)
GMA 99%, LogMAR Table 8. Eye-level characteristics of the OAG eyes before and after
the first SDM treatment session
Pre-SDM #1 (Nmiss = 103) 0.9 (0.5)
N (%) or mean (SD)
Post-SDM #1 (Nmiss = 166) 0.8 (0.5)
Pre-SDM #2 (Nmiss = 239) 0.9 (0.5)
Eye
Post-SDM #2 (Nmiss = 282) 0.9 (0.5)
OD 44 (51.8)
BA6 99%, LogMAR
OS 41 (48.2)
Pre-SDM #1 (Nmiss = 103) 0.3 (0.3)
Visual Area
Post-SDM #1 (Nmiss = 166) 0.3 (0.3)
Pre-SDM #2 (Nmiss = 238) 0.3 (0.4)
Post-SDM #2 (Nmiss = 282) 0.3 (0.3)
GMA, LogMAR
Area ≥ 20/160 at 99%
Pre-SDM #1 (Nmiss = 103) 237.0 (150.1)
Post-SDM #1 (Nmiss = 166) 258.6 (146.8)
BA6, LogMAR
Pre-SDM #2 (Nmiss = 238) 238.0 (153.6)
Post-SDM #2 (Nmiss = 282) 239.8 (153.7)
BA6: best corrected logMAR VA within 6° of fixation under meso-
pic illumination at 99% contrast; GMA: average macular acuity BA6: best corrected logMAR VA within 6° of fixation under mesopic
(best corrected logMAR VA within 10° of fixation under mesopic illumination at 99% contrast; GMA: average macular acuity (best
illumination at 99% contrast inversely weighted by distance from corrected logMAR VA within 10° of fixation under mesopic illumina-
fixation); miss: number missing; N: number; OD: right eye; OS: left tion at 99% contrast inversely weighted by distance from fixation);
eye; SD: standard deviation; SDM: subthreshold diode micropulse N: number; OD: right eye; OS: left eye; SD: standard deviation;
laser; visual area: area within the central 20° of visual field with visual area: area within the central 20° of visual field with a best
a best corrected logMAR VA of 20/160 or better under mesopic corrected logMAR VA of 20/160 or better under mesopic illumina-
illumination at 99% contrast. tion at 99% contrast.
Table 9. Difference in measures from pre- to post-treatment for AMD treated eyes vs normal controls
Variable Time Point
N Mean (SD) P a
N Mean (SD) P a
Pb
GMA, 99% Post-SDM #1 – Pre-SDM #1 295 -0.1 (0.4) < 0.0001 118 0.0 (0.2) 0.27 0.001
Post-SDM #2 – Pre-SDM #2 172 0.0 (0.4) 0.006 0.005
BA6, 99% Post-SDM #1 – Pre-SDM #1 295 0.0 (0.3) 0.01 118 0.0 (0.3) 0.02 0.001
Post-SDM #2 – Pre-SDM #2 173 0.0 (0.3) 0.006 0.0003
Area ≥ 20/160, 99% Post-SDM #1 – Pre-SDM #1 295 21.9 (114.6) 0.002 117 1.6 (54.0) 0.66 0.02
Post-SDM #2 – Pre-SDM #2 173 0.0 (110.7) 0.10 0.12
an indicator for time as a covariate, also adjusting for left or right eye, and including a random patient intercept was performed. The
P-values are those associated with the time (pre- vs post-) regression coefficient. A significant P-value indicates that the mean difference
is significantly different from zero. In order to test whether the mean difference of treated eyes is significantly different from the mean
difference of control eyes, linear mixed models predicting the measure, using indicators for time, eye, and treatment and an interaction
between time and treatment were performed. The P-values are those associated with the interaction regression coefficient. A significant
P-value indicates that the mean differences are significantly different across treatment groups. This method accounts for inter-eye
correlation. To account for the 15 tests conducted in this table, the Bonferroni-corrected critical P-value is 0.003. This means that for a
P-value to be considered significant, it needs to be less than 0.003 in this table.
number; SD: standard deviation; SDM: subthreshold diode micropulse laser; visual area: area within the central 20° of visual field with a
best corrected logMAR VA of 20/160 or better under mesopic illumination at 99% contrast.
Table 10. Difference in measures from pre- to post-treatment for RP treated eyes vs normal controls
Variable
N Mean (SD) P a
N Mean (SD) P a
Pb
Visual area 22 45.3 (79.2) 0.006 117 1.6 (54.0) 0.66 0.01
GMA 22 -0.2 (0.2) 0.002 118 0.0 (0.2) 0.27 0.008
BA6 22 -0.2 (0.4) 0.02 118 0.0 (0.3) 0.02 0.0001
an indicator for time as a covariate, also adjusting for left or right eye, and including a random patient intercept was performed. The
p-values are those associated with the time (pre- vs post-) regression coefficient. A significant p-value indicates that the mean difference
is significantly different from zero. In order to test whether the mean difference of treated eyes is significantly different from the mean
difference of control eyes, linear mixed models predicting the measure, using indicators for time, eye, and treatment and an interaction
between time and treatment were performed. The p-values are those associated with the interaction regression coefficient. A significant
p-value indicates that the mean differences are significantly different across treatment groups. This method accounts for inter-eye
correlation.
Tables 6-8 show eye level characteristics for AMD, retinopathies and optic neuropathies. Most examples
RP, and OAG separately. Tables 9-11 show the changes are chronic progressive diseases; a few are non-progres-
in MVFT by ORP following panmacular SDM treatment sive optic atrophies. Note the similarities in abnormal
for each diagnosis individually. For AMD, two SDM baseline function, and improvements following SDM
treatment sessions are documented (Table 9). Note that treatment in each case despite the widely different
for each diagnosis, MVFT was significantly improved etiologies and disease processes. These responses
following SDM. reflect the neurotrophic, and thus neuroprotective,
Figure 1 shows examples of MVFT by ORP at baseline effects of SDM in each different disease state. In each
and one month following SDM in a number of different case, these treatment responses illustrate and are
Table 11. Difference in measures from pre- to post-treatment for OAG treated eyes vs normal controls
Variable
N Mean (SD) P a
N Mean (SD) P a
Pb
Visual Area 85 53.7 (95.0) 0.0006 117 1.6 (54.0) 0.66 0.0006
GMA 85 -0.1 (0.3) 0.003 118 0.0 (0.2) 0.27 0.005
BA6 85 -0.2 (0.3) < 0.0001 118 0.0 (0.3) 0.02 < 0.0001
In order to test whether the mean difference is different from zero, linear mixed models predicting the measure were performed using an
indicator for time as a covariate, also adjusting for left or right eye, and including a random patient intercept was performed. The P-values are
those associated with the time (pre- vs post-) regression coefficient. A significant P-value indicates that the mean difference is significantly dif-
ferent from zero. In order to test whether the mean difference of treated eyes is significantly different from the mean difference of control eyes,
linear mixed models predicting the measure, using indicators for time, eye, and treatment and an interaction between time and treatment
were performed. The P-values are those associated with the interaction regression coefficient. A significant P-value indicates that the mean
differences are significantly different across treatment groups. This method accounts for inter-eye correlation.
a
predicted by the reset theory of retinal laser action.23-26
They exemplify the clinical utility of SDM. In particular,
note that the treatment response in OAG is similar
to each of the other conditions.23-26 If worsening of
MVFT predicts disease progression and visual loss, the
changes shown here should represent disease reversal
and reduced risks of visual loss.88 Where MVFT was
poor prior to treatment, SDM improves function. This
improvement illustrates the homeotrophic, function-
ally normalizing “reset” effects of treatment. In some
eyes, SDM restores visual function to areas where none
was previously detected. Such functional restoration
may represent rescue of viable but profoundly dysfunc-
tional and possibly preapoptotic cells. Fig. 1. (a) Normal mesopic visual function depicted by ORP.
Fig. 1. (b) Mesopic visual function depicted by ORP pre- (left) and post- (right) SDM treatment.
Fig. 1. Mesopic visual function depicted by ORP pre- (left) and post- (right) SDM treatment in (c) RP; (d) Stargardt’s
disease; and (e) type 2 idiopathic macular telangiectasis.
Fig. 1. Mesopic visual function depicted by ORP pre- (left) and post- (right) SDM treatment in (f) high/degenerative
myopia; (g) pattern dystrophy of the RPE; and (h) chronic vitamin A deficiency retinopathy.
Fig. 1. Mesopic visual function depicted by ORP pre- (left) and post- (right) SDM treatment in (i) sectoral optic atrophy
post non-arteritic anterior optic neuropathy; (j) post-hypertensive optic atrophy; and (k) optic nerve drusen.
l
Fig. 1. Mesopic visual function depicted by ORP pre- (left) and post- (right) SDM treatment in (l) idiopathic autoimmune
retinopathy; (m) diabetic retinopathy; and (n) OAG with advanced optic neuropathy and visual field loss.
9. Synthesis and summary integral part of OAG.26 This loss of retinal neurotropism
may account for the high percentage of OAG eyes that
The currency of ageing is chronic disease, charac- progress despite low, normal, and controlled IOPs.4
terized by the accumulation of misfolded intracellu- Retinal and visual function testing can demonstrate
lar proteins that lead to cellular dysfunction, death, both the loss, and post-SDM restoration, of retinal
chronic inflammation, tissue degeneration, and neurotrophy in OAG.26 Because abnormality of such
finally, functional organ failure. Although the body tests predicts disease progression and future visual
has significant capacity to repair and prevent such loss, the robust improvements documented following
dysfunction, these restorative processes are not SDM as modern retinal laser therapy represent reversal
engaged by the slowly developing, insidious changes of disease progression and reduced risks of visual loss.
that typify ageing and chronic disease. There are as yet no controlled prospective studies of
Modern retinal laser therapy, epitomized by SDM, modern retinal laser therapy for neuroprotection for
breaks this cycle of relentless progression by awakening OAG. We hope they will come soon. However, there
restorative repair, leading to improved retinal and is evidence in other chronic retinopathies that SDM
visual function. These improvements represent in OAG may be of long-term benefit. First, SDM has
reversals of disease progression. Such reversals, been found to reduce progression of severe non-pro-
maintained over time by periodic retreatment, have liferative to proliferative diabetic retinopathy from
the potential to prevent disease progression and visual the expected 50% per year, to just 8.6% per year (P =
loss. The effects of SDM can be detected and measured 0.0002).31 Second, long-term follow-up of a large
in a number of ways. Because homeotrophic (func- cohort of patients with high-risk dry AMD (avg. age
tionally normalizing) modern retinal laser therapy 84 years) found a marked decrease in progression to
such as SDM has no effect on cells already functioning advanced AMD, and thus risks of visual loss, following
normally, the improvements in retinal, optic nerve, SDM. These included a reduction in the expected rate
and visual function following SDM are clear evidence of conversion from dry to wet AMD of 93-98% per
of pre-existing RPE dysfunction central to the disease year, compared to the 4% per year reduction in the
process. This includes diabetic retinopathy, AMD, Age-Related Eye Disease Study (AREDS); and slowing
IRDs, and OAG. While the primary defect in each of the rate of geographic atrophy progression by
chronic retinopathy is different (such as age, abnormal 55% per year following SDM compared to untreated
metabolic state, or genetic defect) and thus the palette controls.27,28 Thus, there is reason for hope that, via
of secondary defects and subsequent characteristic neuroprotection, modern retinal laser therapy may
disease phenotype, the nature of those secondary also aid management and improve outcomes in OAG.
defects is the same in all cases — protein misfolding
—which is mutable by laser-stimulated HSP activation.
This restorative process is effected in and mediated by Acknowledgements
living RPE cells. Therefore photocoagulation, or any
other form of LIRD, is contraindicated as contributing Dr. Jeffrey K. Luttrull wishes to disclose the following
only to loss of structural integrity, chronic inflamma- financial interests: management, equity, and patent in
tion, scarification, loss of function, and diminution of Ojai Retinal Technologies, LLC (CA, USA); management
the desired therapeutic effects. and equity in Retinal Protective Sciences, LLC (CA,
All chronic progressive diseases of the retina are USA); and equity and patent in Replenish, Inc. (CA,
neurodegenerations. Thus, any process that improves USA). Dr. Kent has no financial interests to disclose.
retinal function is necessarily neurotrophic. In the
presence of neurodegenerative disease, improved
neurotrophy is neuroprotective, as it impedes disease
progression. The fact that such effects can be elicited
in eyes with no abnormality other than OAG, suggests
an acquired loss RPE-derived neurotrophy may be an
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1413-y.
20. What is the ideal conjunctival bleb and how
to achieve it? Learning from the Microfistula-XEN
procedure
Dao-Yi Yu, Stephen John Cringle, William H. Morgan, Er-Ning Su
Lions Eye Institute, Centre for Ophthalmology and Visual Science, The University of Western Australia,
Nedlands, Australia
Abstract
Purpose: We ask the following questions: What is the of drainage longevity. We have identified that in
ideal conjunctival bleb following glaucoma filtration long-term aqueous drainage (more than 6 years for
surgery (GFS) and how to achieve it? We reviewed our monkeys and 2.4 years for rabbits,) the initial lymphatic
data on cross-linked gelatin microfistula implantations vessels are very close to the aqueous exit point in the
in preclinical and clinical studies of a new type of GFS bleb. The placement of the Microfistula-XEN implant
we developed. This procedure is a minimally invasive in the right position is essential for achieving the best
glaucoma surgery (MIGS), a modified form of which — surgical outcomes. The right position for this ab interno
the XEN Gel Stent — is now in widespread clinical use. approach using a needle-based implanter is that the
Methods: The preclinical studies involved the implanta- implant should be placed through the trabecular
tion of gelatin microfistula tubes into 168 rabbits and 34 meshwork, scleral channel, and the distal end of the
monkeys. The follow-up periods extended out to more implant should be located in the superficial region of
than two years in rabbits and six years in monkeys. Tenon’s capsule. The ideal length of the implant tube in
Drainage from the blebs was monitored following the anterior chamber is ~1.5 mm, ~3 mm in the sclera,
anterior chamber injection of fluorescein. Clinical data leaving ~1.5 mm in the conjunctival tissue for a 6 mm
from the subsequent clinical trial was also reviewed. implant tube. Good fixation of the eyeball avoiding
Our new form of MIGS, which avoids damage to the deformation and a good gonioscopic view are required.
conjunctiva, provides a great opportunity to study the The clinical studies suggest that a diffuse, flat bleb
mechanisms by which aqueous humor drains from the produced the optimum outcome. The mechanisms to
bleb after GFS. re-establish balance of interstitial fluid in the conjuncti-
Results: Long-term drainage was monitored experimen- val tissue by which aqueous humor drains from the bleb
tally in both rabbits and monkeys. Essentially, aqueous after GFS have not been fully elucidated.
humor enters the subconjunctival tissue, joins the inter- Conclusions: It is proposed that efficient conjuncti-
stitial fluid, and forms a conjunctival bleb. In the bleb, val lymphatic drainage of aqueous from the bleb is a
there are close communications between aqueous key parameter for longevity of bleb drainage. Minimal
humor and the structural molecules of the interstitial disruption of the conjunctiva and the formation of a flat
or the extracellular matrix, the blood and lymphatic diffuse bleb appear to be optimal. Noninvasive methods
vessels, and parenchymal cells. The presence of con- of examining the conjunctival lymphatics are proposed.
junctival lymphatic drainage was a key determinant
Correspondence: Dao-Yi Yu, MD, PhD, Lions Eye Institute, Centre for Ophthalmology and Visual Science,
The University of Western Australia, 2 Verdun Street, Nedlands, Perth, Australia.

276 Dao-Yi Yu et al.
Keywords: bleb, conjunctival lymphatics, glaucoma Allergan plc (Dublin, Ireland) as the XEN Gel Stent (also
filtration surgery, microfistula, XEN discussed in Chapter 12), which has modifications to
the inner and outer diameters of the original Microfis-
tula.9
1. Minimally invasive glaucoma surgery In addition to technical improvements, very inter-
estingly, we found that the conjunctival bleb was sig-
Glaucoma affects around 70 million people worldwide. nificantly different after the Microfistula procedure
It is the second most common cause of blindness when compared with that after trabeculectomy in
and the leading cause of irreversible blindness.1,2 The both animal and human studies. We have also learnt
importance of lowering intraocular pressure (IOP) in from the Microfistula procedure to understand what
delaying glaucomatous progression has been well properties of the conjunctival bleb result in long-term
documented.3 drainage from the conjunctival bleb.
Trabeculectomy has been a gold standard for almost
50 years.4-6 Trabeculectomy and glaucoma drainage
devices are currently the most commonly used surgical 2. Conjunctival bleb appearance after
procedures, but in both cases, the inadequacy of safe the Microfistula procedure in glaucoma
surgical treatments for uncontrolled IOP has led to
patients
the development of new technologies. The purpose of
glaucoma filtration surgery (GFS) is to lower IOP and We found that the conjunctival bleb after the Microfis-
avoid further glaucomatous damage. The procedure tula procedure is relatively flat and diffusely covered
hopes to achieve a permanent reduction in the outflow a large area. The Microfistula creates a direct shunt
resistance and restore normal IOP without complica- between the anterior chamber and the conjunctival
tions. The foremost goal is preservation of sight and tissue. The distal end of the Microfistula tube can be
stabilization of the visual field defect.7 seen in the conjunctival tissue (Fig. 1). The conjunctival
Many of the emerging technologies can offer tissue surrounding the distal end is slightly thicker than
significant improvements in surgical outcomes. normal tissue, indicating some swelling. Importantly,
One of these new technologies is the Microfistu- we note such a conjunctival bleb is very stable and the
la-XEN procedure. We developed a bioengineered conjunctiva is almost normal in appearance, including
cross-linked gelatin tube called Microfistula. The color with normal blood vessels, except that the
purpose in using a biological material was to reduce conjunctiva is slightly elevated.
possible implant-induced inflammatory reaction in The Microfistula procedure avoids damage to the
the immunoactive conjunctival tissue. Our invention conjunctiva. The avoidance of surgical trauma to the
also included an ab interno surgical procedure and conjunctiva allowed us to explore for the first time
needle-type implanter to perform minimally invasive the critical role of conjunctival lymphatics on the
surgery and avoid damage to the conjunctival tissue outcomes of GFS. We demonstrated that the longevity
(PCT/AU97/00811, US patent #6544249). We performed of a functional bleb was increased 8.8 times in rabbits
extensive experimental studies to test and refine the and 14.3 times in monkeys in a group with effective
technique in rabbits and monkeys.8 We implanted lymphatic drainage when compared with a group
these gelatin microfistulae in 168 rabbits and 34 without lymphatic drainage after Microfistula implan-
monkeys, with a follow-up of > 2 years in rabbits and 6 tation.8 Our definition of a functional bleb is not the
years in monkeys. The insertion technique and device same as for a conventional bleb after trabeculectomy.
were later commercialized by AqueSys Inc., (CA, USA), After our surgical procedure, IOP was lowered to
which modified the procedure and conducted human 8 mmHg and was well maintained during follow-up
trials. Here, we present some more detailed findings (2.5 years) without any complications or a need for
from our animal studies and discuss examples from postoperative management. The most notable finding
those long-term patient results. The technique has is a functional, slightly elevated and diffuse bleb with
now received full FDA approval and is marketed by normal appearance of the conjunctiva (Fig. 1D). We
What is the ideal conjunctival bleb and how to achieve it? Learning from the Microfistula-XEN procedure 277
Fig. 1. A representative case after Microfistula-XEN implantation. (A) Schematic drawing of implanted Microfistula-XEN. (B-D) Images from
one of the patients in the pilot critical trial in Perth, Australia. The implanted Microfistula-XEN can be seen (red arrows). This patient had
a failed trabeculectomy previously (yellow arrowhead indicating the location of previous trabeculectomy), increasing the probability of a
poor outcome for subsequent filtration surgery.
analyzed data from more than 130 patients and found of fluorescein into the anterior chamber, showing
that most of the patients with such functional blebs lymphatic drainage and a slightly elevated diffuse bleb
had the best surgical outcomes. and veins.
Achieving an ideal functional bleb requires not only
avoiding injury from surgical wounds in the conjunctiva,
3. Conjunctival bleb appearance after but also avoiding unfiltered aqueous humor accumu-
the Microfistula procedure in animal lating in the immunoactive conjunctival tissue.8,12,13
Localized aqueous humor accumulation is associated
experiments
with inflammation and scar tissue formation. Aqueous
We have also found that such functional blebs occur humor needs to be removed, which can occur by several
experimentally in monkeys and rabbits in which dye mechanisms, including diffusion and drainage by both
injection into the anterior chamber can be used to blood vessels and lymphatics. Lymphatic vessels are
monitor the flow through lymphatic drainage vessels, the most critical in the removal of large molecules, such
which were clearly found at the exit point of the Microfis- as proteins and cells, as well as water. A major limitation
tula implant.8,10,11 Figure 2 is an example of a Microfistu- of previous clinical studies of the lymphatic drainage
la implanted in a rabbit. The Microfistula-XEN is clearly mechanism for aqueous humor was the reliance on
visible in both the conjunctival tissue and the anterior dye labelling to identify the lymphatics, which is not
chamber. A functional bleb can be seen after injection suitable for routine clinical use.10
Fig. 2. A Microfistula implanted in a rabbit (black arrows). A functional bleb (B) can be seen after injection of fluorescein into the anterior
chamber with lymphatic drainage (orange bent arrows), a slightly elevated diffuse bleb (yellow arrowhead), and veins (blue arrows).8
4. How is a conjunctival bleb formed the ocular immune privilege system, phagocytic
after the Microfistula procedure and function of the trabecular meshwork, and a fully endo-
thelium-lined drainage pathway. Aqueous humor does
what are its functional components?
not normally contact conjunctival tissue. GFS allows
This is an exciting and important question to address. altered and unfiltered aqueous humor to come into
We do not know exactly how a conjunctival bleb is intimate contact with conjunctival tissue. Assuming
formed after the Microfistula procedure or which total aqueous production is ~2 µL per minute, the
structural elements lead to long-term drainage. The volume of aqueous to be drained via the conjunctival
answers to these questions will be of benefit for all tissue could be almost 3 mL per day. It is clear that there
types of GFS, including trabeculectomy, various types must be adequate pathways and mechanisms to allow
of drainage implants, and the Microfistula procedure. aqueous humor to be removed from the bleb following
All GFS attempt to lower IOP by the surgical formation GFS. The role of the conjunctiva in the outcomes of GFS
of an artificial drainage pathway from the anterior has not received enough attention and many critical
chamber to the conjunctival tissue where the tissue questions remain unanswered.
pressure is low (almost equal to atmospheric pressure). A filtering bleb has been considered a cornerstone
Filtering procedures, such as trabeculectomy or of IOP control after GFS.14-16 The bleb, formed by the
drainage implant surgery, have been used extensively pooling of aqueous humor in the conjunctival tissue,
in the treatment of glaucoma may be considered to be the cornerstone of IOP control
Great effort has been expended to improve surgical in GFS, but it is also an unstable and problematic
techniques over the more than 180 years since the first tissue.17 Bleb-related complications can be serious and
attempts, but relatively little attention has been paid the surgeon has little control over the final appearance
to the question of the consequences of the presence of the filtering bleb after surgery.18 Such complications
of aqueous humor in the conjunctival tissue. Arguably, require very careful management to avoid loss of vision.
the answer to such a question could be critical for In this chapter, we would like to describe in detail
improving the clinical outcomes of GFS. This question how aqueous humor enters the conjunctival tissue
is not easy to answer. The challenges arise mostly from and joins the interstitial fluid to form the conjunctival
the multiple mechanisms involved in the formation and bleb, as well as the mechanisms by which aqueous
longitudinal changes of the bleb we described in our humor drains from the bleb after GFS, which have not
previous publications.8,10,11 Briefly, the normal aqueous been fully elucidated.19-22 Fortunately, the Microfistula
outflow pathways can be maintained throughout our procedure provides a good opportunity to study the
lifetime due to many protective mechanisms, including nature of the conjunctival bleb. Unlike trabeculecto-
my, in which unavoidable wound healing process and Figure 3 shows selected frames taken from a
inflammatory changes in the surgical site occur, the sequence of video clips after injection of fluorescein
absence of conjunctival damage with the Microfistu- into the anterior chamber of a rabbit 2.4 years after
la procedure makes it possible to find the external Microfistula implantation. As far as we know, this is
exit end in the conjunctival tissue after implantation. longest maintenance of the drainage pathway after any
Cells and tissue around the newly formed pathways rabbit filtration surgery in the literature. The advantage
are continuously bathed in aqueous humor. Altered of recording a video clip after fluorescein injection into
aqueous humor composition could play a critical role in the anterior chamber is that it allows us to dynamically
the outcome of filtration surgery. The failure of trabe- follow the pathway of aqueous humor after Microfistu-
culectomy is most commonly associated with a fibrotic la–XEN implantation.
response at the wound site in the conjunctival tissue.23 It is critical to elucidate the relationship between
The role of aqueous humor in the success of filtration the aqueous from the exit point of the Microfistula
surgery remains controversial. and the lymphatic drainage in the conjunctival tissue.
Fig. 3. (A–I) A sequence of video frames after injection of fluorescein into the anterior chamber of a rabbit 2.4 years after Microfistula implan-
tation. (A) Frame recorded immediately after fluorescein injection, showing filling in the anterior chamber (AC). The first appearance of
extraocular fluorescein (B, yellow arrow) is a small patch near the distal end of the scleral channel. The extent of fluorescein increases (C)
and draining lymphatics become apparent (D–F, wavy arrows). An aqueous vein can be seen located at the distal edge of the bleb (G–I).
However, it was difficult to determine whether this vein was a normal aqueous vein superimposed on the bleb, or whether it played a role
in draining the bleb. (J) Magnified image of the late phase (I). The conjunctival bleb was small in size and surrounded by a narrow diffusion
zone along with a number of drainage vessels. At least two large lymphatic vessels were seen with uneven caliber located each side of the
conjunctival bleb and running parallel to the limbus (brownish bent arrow). A conjunctival vein was also visible.8
Fig. 4. Two key frames have been selected from Figure 3C and 3I and schematic drawings have been added to illustrate the key features.
(A) Small lymphatic capillary. The exit point of aqueous humor is located at the external end of the Microfistula tube, evidenced
by fluorescein dye. Some small fluorescein dot stains are visible just adjacent to the exit point of the Microfistula (A, B). When more
dye-stained aqueous humor enters into the conjunctival tissue and bleb, these small dots extend and connect to the lymphatic precollec-
tors (C, D). The bleb has a high concentration of fluorescein dye in the center, with a diffusion zone around the edge. It is predictable that
this diffusion zone will extend further with longer timeframes. A vein (BV) can also be seen.
Fortunately, the relative lack of conjunctival lymphatics trabecular meshwork.28,31 GFS are designed to bypass
in rabbits provides an opportunity to investigate such the trabecular meshwork. The lymphatic capillaries
relationships (Fig. 4). act as a cleaner to remove large molecules, such as
This information provides us some important proteins and cells, from the unfiltered aqueous humor
knowledge regarding the functioning of the bleb. After in the conjunctival tissue. It is critical to have lymphatic
GFS, unfiltered aqueous humor enters immunoactive capillaries adjacent to the exit point of aqueous humor
conjunctival tissue. Trabecular meshwork cells have from the Microfistula. In this case, the proteins and
a highly phagocytic function, continuously removing cells can be effectively removed as soon as aqueous
particles, cellular debris, or protein molecules from the humor enters into the conjunctival tissue. Thus, the
circulating aqueous humour.24-26 The meshwork cells inflammation induced by proteins and cells can be
are capable of incorporating not only particles, but largely avoided. This may explain why the drainage
also red blood cells and pigment granules, as well as pathway can last for a long period and maintain
bacteria.27-30 Phagocytosed materials are enclosed in normal conjunctival function without inflammatory
membrane-limited vacuoles that fuse with lysosomes reaction and scarring. Blood capillaries may also play
forming phagolysosomes, which are stored within the a role in draining the water component, as evidenced
cells. Normally, macrophages are also found within the by fluorescein in the vein. In addition, water could
also diffuse into conjunctival tissue, evidenced by the experimental study of the Microfistula-XEN procedure,
diffusion zone around the bleb. In successful implanta- fluorescein dye injection into the anterior chamber
tions in rabbits, we found that 37% of blebs had only was used for imaging the passage of aqueous humor
diffusion without lymphatics, lasting a mean time of 1.1 from the anterior chamber to the conjunctival tissue
months, whereas 63% of blebs which had lymphatics as well as the drainage by the conjunctival lymphatics.
lasted a mean time of 9.7 months, significantly longer However, such a technique is invasive, so we sought
than diffusion-only blebs. In successful implantations to develop a noninvasive and label-free technique. We
in monkeys, 19% of blebs had only diffusion without collaborated with engineering teams to develop an
lymphatics and lasted a mean time of 2.6 months, optical coherence tomography (OCT)-based imaging
which is longer than in the rabbits without drainage system named OCT lymphangiography (OCTL). Such
vessels. The 81% of blebs with lymphatics lasted a a system not only helps us study the normal distri-
mean time of 37.3 months, significantly longer than dif- bution of human conjunctival lymphatics, but allows
fusion-only blebs and much longer than similar blebs examination before and after the GFS procedure. It will
in rabbits. These data demonstrate how critical the help us translate the knowledge gained on improving
formation of lymphatic drainage channels is for the filtering bleb longevity from experimental study to
survival of the bleb following GFS. It also illustrates the clinical practice. It is expected that OCTL will help
greater success in monkeys when compared to rabbits, improve the surgical outcomes of the Microfistula-XEN
presumably reflecting the greater density of normal and other GFS procedures, including trabeculectomy.
lymphatics in the monkey conjunctiva. The failure of MIGS such as the Microfistula show some significant
long-term bleb survival in 19% of the monkeys may be advantages when compared with traditional
improved if we are able to determine the major factors procedures, such as trabeculectomy, in terms of being
influencing the development and maintenance of con- less invasive and safer, although long-term outcomes
junctival lymphatic drainage from the bleb. need further follow-up. However, any GFS has to face
the fundamental question of how to remove aqueous
humor from the conjunctival tissue and maintain
5. It would be valuable to examine normal conjunctival tissue. From our clinical and
and monitor conjunctival lymphatics experimental studies, we find the exit point of the
aqueous humor from the Microfistula to be the critical
clinically
location where inflammation and scarring could cause
Examining the conjunctival lymphatic distribution, problems. We have often used needling procedures
including the lymphatic capillaries, initial lymphatics, and mitomycin to reopen the drainage pathway.
and precollectors, before GFS would be ideal. The con- Therefore, we need to urgently develop a noninvasive
junctival lymphatics, and particularly the lymphatic and label-free imaging technique to examine and
capillaries, are unevenly distributed in the con- monitor conjunctival lymphatics for clinical use.
junctival tissue.8,32 It would be optimum to select
a surgical location which has sufficient lymphatic
capillaries. Monitoring the changes of lymphatic 6. How can the surgical outcome of
capillaries and initial lymphatics after GFS would also the Microfistula-XEN procedure be
be desirable.8,10,11 Up to now, we do not know how and
improved and what is the optimum
when lymphatic capillaries approach the exit site of
aqueous humor from the Microfistula. Although other
surgical procedure?
clinicians and our team33-36 attempted to determine Creating the ideal filtrating bleb is believed to be a
the role of lymphatics in the bleb using trypan blue milestone for successful outcome of all GFS, including
or fluorescein dyes clinically, such techniques using the Microfistula-XEN procedure. There is no doubt that
invasive dye injection are not suitable for routine surgery influences the achievement of an optimum
clinical application. bleb. The three main characteristic features of the
To visualize the conjunctival lymphatics in our Microfistula-XEN procedure are:
1. ab interno procedure; (0.41 mm diameter) so without viscoelastic, significant

2. bioengineered microfistula tube; and aqueous leakage occurs, leading to hypotony and a
3. ergonomically designed needle-based implanter deformed globe during surgery. Although viscoelas-
for minimally invasive implantation. tic agents may help deepen the anterior chamber and
open the angle, IOP and eyeball shape may not be stable
These design features are critical for the Microfis- during surgery, and there is loss of primary aqueous.
tula-XEN procedure. Importantly, surgeons should Ocular immune privilege is a product of multiple
understand these features before performing this anatomical, physiological, and immunoregulatory
procedure. processes that help keep the stability of the intraocular
environment, including aqueous flow. Soluble immu-
6.1. Ab interno procedure nomodulatory factors in primary aqueous humor are
GFS drains the aqueous humor from the anterior one of five important features in the eye that maintain
chamber into the conjunctival tissue via the created ocular immune privilege (Fig. 5A). A wide variety of
drainage pathway. Therefore, the conjunctival tissue anti-inflammatory and immunosuppressive molecules
is downstream of aqueous humor drainage after GFS. have been found to be expressed in ocular tissues and
The ab interno surgical approach used by the Microfis- fluids, including CD95L (FasL), transforming growth
tula-XEN procedure avoids conjunctival damage, factor-b, macrophage migration inhibitory factor, a-
minimizing any surgical wound or surgical disturbance melanocyte-stimulating hormone, calcitonin gene-
in the conjunctiva. This avoids surgically induced related peptide, somatostatin, and complement
inflammation and scarring. This requires consideration regulatory proteins.8,15,37,38 Primary aqueous humor
of the ab interno approach used intraoperatively. is believed to contain numerous anti-inflammatory
and immunosuppressive molecules. In fact, all GFS,
6.1.1. The corneal entry including the Microfistula-XEN procedure, drain the
The position of the corneal entry point is critical aqueous humor from an immune-privileged anterior
because it influences the position of the Microfistula - chamber into an immune-active conjunctival tissue
XEN tube. The position of the corneal entry we choose (Fig. 5B). It is beneficial to keep primary aqueous humor
is about 2 mm away from the limbus and opposite the during the tube implantation. Possibly, a small needle
desired location of the scleral channel. The advantages implanter (25-g or smaller) obliquely penetrating the
of this position are that it allows creation of a scleral cornea without loss of aqueous humor could maintain
channel ~3 mm in length and keeps the Microfistu- IOP and eyeball shape, obviating some of these
la-XEN tube in the anterior chamber, away from the iris problems in select patients. However, one challenge is
and the corneal endothelium. The length of the scleral that the surgeon has to ensure very little loss of aqueous
track tends to help lock the Microfistula-XEN tube into humor, particularly critical in phakic eyes.
position and minimize axial slippage. The ideal length
of the tube in the anterior chamber is ~1.0-1.5 mm. 6.1.3. The Microfistula-XEN tube position
Any blockage of the open end of the tube could cause It is important to implant the tube in the correct
failure of the drainage. Additionally, if the tube touches location.
the corneal endothelium or the iris, unwanted damage
to the endothelium and inflammation may occur. 6.1.3.1. The entry point in the anterior chamber angle
The most suitable entry point in the anterior chamber
6.1.2. Aqueous humor angle is the anterior trabecular meshwork in order to
An arguable question is whether viscoelastic agents avoid damage to the corneal endothelium and ciliary
should be used to replace the primary aqueous humor. body. From our experience in experimental studies and
Viscoelastic agents have been widely used for anterior clinical application, we prefer the entry point to be close
segment surgeries, such as cataract. The current to Schwalbe’s line. This avoids Schlemm’s canal and
shoulder design of the implanter requires a larger minimizes the risk of back-flow bleeding and hyphema.
incision (1.2–1.5 mm) than the terminal 27-G needle The meridional width of the trabecular meshwork and
Fig. 5. (A) Normal aqueous outflow pathways. A histological section of anterior chamber angle from a normal monkey is used for illustra-
tion of aqueous outflow pathways schematically. Aqueous humor is secreted by the ciliary body into the posterior chamber and circulated
through the pupil towards the anterior chamber angle, where it drains via trabecular meshwork and Schlemm’s canal into the aqueous
vein and episcleral veins. (B) Additional aqueous drainage pathway after GFS. Aqueous humor bypasses the trabecular meshwork into the
conjunctival tissue.8
Fig. 6. (A) Gonioscopic view of the trabecular meshwork (TM). (B) Schematic drawing of the anterior chamber angle and the trabecular
meshwork (TM, outlined by dashed red lines) and Schlemm’s canal (SC).39
Fig. 7. (A) The Microfistula creates a direct shunt between the anterior chamber and the conjunctival tissue. The portion of the Microfis-
tula can clearly be seen within the anterior chamber and the other portion can also be found in the conjunctival tissue (arrows). The
position of the Microfistula within the scleral channel is difficult to visualize. (B) Histological section of the scleral channel one month
after implantation. Scleral channel is well patent and endothelium-like cells lined on the wall. There is no evidence of inflammation
along the scleral channel.
Schlemm’s canal is only ~350-500 μm (Fig. 6B).39 A good conjunctiva to move fluid to the designated site of
gonioscopic view is required to identify the correct the exit point of the implant tube is useful. If primary
entry point in the anterior chamber angle (Fig. 6A). aqueous humor has not been replaced by viscoelas-
tic agent, aqueous humor could enter the conjuncti-
6.1.3.2. Scleral channel val tissue when the needle fully penetrates the sclera,
A clearly patent scleral channel with minimal fibrosis driven by the pressure difference between the IOP and
and inflammatory signs is formed after Microfistula-XEN tissue pressure in the conjunctival tissue. The needle
insertion, as demonstrated by our rabbit experiments position could be slightly adjusted to ensure the exit
(Fig. 7). Several hundred microfistulae were implanted end of the implant tube is located in the superficial
in these experiments, followed up by extensive histo- region of Tenon’s capsule. This technique was used
logical examination. Endothelium-like cells could be in all our implantation procedures in experimental
found along the wall of the scleral channel without any animals.
histological evidence of inflammation.
The length of the scleral channel is critical. Currently, 6.2. Bioengineered Microfistula tube
the tube length supplied by Allergan is 6 mm, which is The bioengineered Microfistula-XEN tube is the central
the same as we used in monkeys, whilst we were using component of this procedure. The tube is made of
8 mm for rabbits. We recommend keeping ~3 mm in gelatin, a natural polymer prepared from biological
length for the scleral channel for the 6 mm implant raw materials, that has better biocompatibility when
tube and leaving ~1.5 mm in the conjunctival tissue. compared with most artificial materials. Given it is a
The exit point of the implant tube from the scleral biological implant, raw materials cannot be used, and
channel should be ~3 mm from the limbus, where the should be modulated to satisfy our special require-
conjunctiva is thicker and more clearly separated from ments by a chemical and physical cross-linking
the underlying sclera, rather than closer to the limbus. process. Knowledge of gelatin and its cross-linking as
The normal thickness of the human conjunctiva is about well as the special design requirements of the Microfis-
250 mm. Placing the exit end of the implant into the tula-XEN tube allows one to perform a more ideal
location of the initial lymphatics (lymphatic capillaries), surgical procedure.
which are normally located in the superficial region of Some special requirements include:
Tenon’s capsule, can prove challenging. However, it is 1. good biocompatibility;
important to allow the lymphatic capillaries to remove 2. suitable to make required sizes and lengths;
large molecules, such as proteins and cells, from the 3. a certain rigidity to allow implantation using a nee-
aqueous humor as soon as it becomes interstitial fluid dle-based implanter;
in the conjunctival tissue. This is potentially achievable 4. a certain degree of swelling after contacting the
because we know that the initial lymphatics and pre- aqueous humor; and
collectors are normally located in different layers. 5. ability to soften after a certain contact time with
Therefore, the most suitable location to place the exit the aqueous humor.
end of the implant tube is in the superficial region of For long-term biomedical applications, the mechanical
Tenon’s capsule.. Our approach is to create conjuncti- stability of gelatin can be improved by cross-linking.
val edema before finalizing the position of the exit end We have optimized the cross-linking protocols,
of the implant tube. Without viscoelastic, this can be having made thousands of tubes and performing
achieved by slow advancement of the needle, allowing several hundred implantations in animals. Fortunately,
aqueous to flow into the conjunctival tissue. If a vis- we have achieved all the required specifications
coelastic agent has been used, it could be difficult to and in addition performed extensive and long-term
enter the conjunctival tissue during the implantation experimental studies to confirm biocompatibility and
procedure through the tiny lumen. In this case, injecting long-term drainage before translating our technique to
a small amount of fluid, such as local anesthetic, the clinic.
into the conjunctival tissue at a location away from Cross-linked gelatin needs to be characterized using
the exit point of the implant tube and massaging the chemical and physical testing, but a most useful test
for the Microfistula-XEN procedure is the degree and tube, which may be suitable for subsets of patients
timing of gelatin tube swelling. The degree of swelling where hypotony is of less concern, such as pseudopha-
is critical for the performance of the Microfistula. First, kic patients who are not highly myopic.
the implant tube should stay in the scleral channel
without moving axially postoperatively. Hence, the 6.3. One needle-based implanter
outer diameter needs to increase after implantation At least eight different types of needle-based
in the scleral channel. The outer diameter of the tube implanters were developed for this technique.
increases gradually by ~30-40%. The timing from These included fully robot- and motor-controlled to
a dry tube to a fully swollen tube is approximate- hand-held motorized versions, and subsequently,
ly 100 seconds. Ideally, the implantation procedure manually operated disposable products. Principally,
should match the timing of the gelatin tube swelling. the Microfistula-XEN procedure can be carried out
The dry tube is relatively hard and can be implanted with only one needle entry, which makes it a minimally
more easily, particularly from within a narrower invasive procedure. Ideally, the implanter should be
needle inserter. However, a wet and more swollen easy to handle and manipulate, allowing the surgeon
tube becomes softer to match the curved eyeball. The to place the implant tube in the correct location. It
latter is a likely problem with the more rigid glaucoma should also be simple and reliable. There is still scope
drainage device tubes and may explain the higher rates to improve the implantation device to achieve the
of corneal damage postoperatively. The inner diameter best outcomes. A custom-built special needle could
of the implant tube is only slightly increased during be considered to create an optimal match between
swelling. The swelling properties are important for the implant tube diameter, swelling rate, and size of
implanter design, particularly for considering optimum the scleral channel created. Creating a scleral channel
needle size and wall thickness. could be easier with a specially designed needle tip and
There is no doubt that the inner diameter of the size with improved eye fixation to reduce eye distortion
implant tube is important in determining the outflow during scleral penetration. We believe that the shift
resistance of the tube, which can be calculated using from traditional drainage surgery such as trabeculec-
Poiseuille’s law, the diameter and length parameters, tomy to the Microfistula-XEN is similar to that which
and the estimated pressure at either end of the occurred when moving from extracapsular cataract
tube.40 However, the role of the conjunctiva and the surgery to phacoemulsification. The contribution of
drainage mechanism of the aqueous humor from the many surgeons over time contributed to the current
conjunctival tissue also have to be considered, as this safe and efficient cataract surgery. Similarly, we believe
adds downstream resistance to the outflow pathway. that surgeons would like to contribute their experience
Currently, the inner diameter of the Microfistula-XEN and knowledge to further improve the XEN implanter,
tube is 45 µm. A 63 µm tube was used in the initial surgical procedure, and implant tube to extend the
clinical trial; larger tubes were tested in the rabbits longevity of the filtering bleb, thus achieving a safer
and monkeys and initial clinical trials. Although the and more effective operation.
smaller size of the inner diameter tube could effectively
avoid hypotony, particularly in the first few days after
surgery, there may be more chance of scar tissue 7. Summary and future perspectives
formation due to a reduction of aqueous flow into the
conjunctival tissue. This is supported by our evidence Clinically identifying the conjunctival lymphatics
of the role of conjunctival lymphatics in the outcome that removes aqueous humor is difficult because the
of filtration surgery8 and recent and advanced studies lymphatics have a very thin wall and lymph fluid is
in the field of lymphatic function and lymphangio- transparent. Furthermore, current drainage surgeries,
genesis.41,42 However a larger lumen size may induce such as trabeculectomy, produce significant conjunc-
a low resistance pathway, resulting in hypotony. An tival damage with unavoidable inflammation and
optimized inner diameter of the tube lumen needs to scarring, making it even more difficult to study the
be determined with any new type of Microfistula-XEN mechanisms of aqueous humor drainage from the
bleb. Isolated reports in which fluorescein was used 1622,46 many different types of glaucoma surgeries
as a tracer injected into the anterior chamber to study have been developed. More than 200 years later, the
aqueous humor dynamics after drainage surgery in first fistulizing procedure was reported.18 Subsequent-
patients have suggested a role for lymphatic drainage ly, filtration surgery has been refined and success
in successful filtration surgery.43,44 It will be interesting rates have increased.47 There have been significant
to further investigate the relationship between the contributions made by numerous surgeons in this
lymphatic vessels and aqueous humor drainage from field. Trabeculectomy, developed 50 years ago,4-6 was
conjunctival tissue in all types of GFS. a remarkable achievement. Currently, a number of
In addition to recent advances in scientific research groups are working to develop MIGS. It is important to
on interstitial fluid and interstitium, noninvasive emphasize that developing an ideal glaucoma surgery
imaging techniques to study initial lymphatics in the is a real challenge. We not only need to improve
bleb need to be developed. Such noninvasive and surgical instruments and procedures, but we should
label-free techniques have already been developed for also address many unknown questions behind the
skin lymphatics.45 Hopefully, noninvasive and label-free surgical interventions. Any surgical intervention may
techniques will soon be available for clinical use to be beneficial for a certain disease, but may also cause
monitor the progress of the bleb and its relationship harm. Therefore, it is important to further optimize
with capillary, initial, and collecting lymphatics. The the Microfistula-XEN procedure and improve its safety
combination of scientific research and new diagnostics and effectiveness. Hopefully, the Microfistula-XEN
for the conjunctival interstitium and lymphatics have procedure will be further improved by the accumulated
the scope to improve GFS outcomes in the very near knowledge from the many surgeons who are now using
future. the technique, building upon this experience to create
Since the association between glaucoma and a safer and more effective surgical procedure.
elevated IOP was first suggested by Bannister in
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21. Special considerations for pediatric glaucoma
Peter A. Netland1, John R. Samples2,3
Department of Ophthalmology, University of Virginia, Charlottesville, VA, USA; 2Floyd Ellison School of Medicine,
1
Washington State University, Spokane, WA, USA; 3Western Glaucoma Foundation, Olympia, WA, USA
Purpose: Our purpose was to review current medical The goal in the management of pediatric glaucoma is
and surgical management of pediatric glaucoma, and early detection and successful control of intraocular
to describe potential glaucoma therapies for use in pressure (IOP) through surgery and adjunctive medical
pediatric patients. therapy. Current treatment options can prevent loss
Methods: We reviewed the literature using available of visual acuity, preserve visual field, and allow the
databases. Personal communications were included development of binocular stereoscopic vision.1-3
for therapies currently being developed and evaluated. Surgical and medical therapies in development offer
Results: Surgery provides effective treatment for the potential for effective and safe treatment of
most developmental glaucomas. Adjunctive medical pediatric glaucomas.
therapy is useful in patients with developmental Surgical intervention provides the most effective
glaucomas, and primary medical therapy may be and definitive treatment for most developmental
effective in some patients with secondary causes of glaucomas. Medical therapy serves a supportive role in
pediatric glaucoma. Less invasive approaches and temporarily reducing IOP and clearing the cornea until
technological innovations have introduced modifi- surgery can be performed. A minority of patients with
cations of goniotomy, trabeculotomy, trans-scleral congenital glaucoma may respond to medical therapy
filtration, and cyclophotocoagulation. In addition, alone. Some secondary glaucomas may respond
recent developments in medical therapy may have a to medical therapy, such as glaucoma associated
role in the management of pediatric patients. with aphakia or pseudophakia. Common glaucoma
Conclusions: Treatment of pediatric glaucoma patients medications in these pediatric patients include topical
is evolving, with innovations in medical and surgical beta-blockers, carbonic anhydrase inhibitors, and
treatment of glaucoma influencing the management of prostaglandin analogues. Alpha-2-agonists are avoided
children with glaucoma. in young children due to problems with sedation and
other untoward side effects.
Keywords: congenital glaucoma surgery, MIGS in
congenital glaucoma, MIGS in pediatrics, pediatric
glaucoma surgery, post-goniotomy 2. Current surgical therapy
Surgical intervention provides the most effective
and definitive treatment for most developmen-
tal glaucomas. Patients with only mild or moderate
corneal edema at the time of referral for treatment
Correspondence: Peter A. Netland, MD, PhD, Vernah Scott Moyston Professor and Chair, Department of Ophthalmology, University of
Virginia School of Medicine, P.O. Box 800715, Charlottesville, VA 22908-0715, USA.

290 P.A. Netland and J.R. Samples
may be candidates for goniotomy, which has a high (Kamji KF, Arora S, Maeda M, Francis B, Maeda M, Sit
success rate in Western populations. In other areas A, Mosaed S, presented at the American Glaucoma
of the world, such as India and the Middle East, Society Annual Meeting, 2013). Direct comparisons of
nearly all patients with infantile glaucoma present use of goniotomy to Trabectome or Dual Blade have
with significant corneal clouding making goniotomy not been performed in pediatric patients.
technically impossible. For these patients, trabeculot-
omy or trabeculotomy combined with trabeculectomy 3.2. Trabeculotomy modification
are preferred. Patients who present late or who have Trabeculotomy is an alternative surgical treatment
refractory cases can also be treated with combined to goniotomy in cases of congenital and childhood
trabeculotomy-trabeculectomy.4 Patients who do glaucoma, which is especially useful when corneal
not respond to one or more angle procedures may be edema obscures the gonioscopic view of the anterior
candidates for other modalities such as trabeculecto- chamber angle. Trabeculotomy in patients with
my with antimetabolites, glaucoma drainage implant primary developmental glaucoma shows similar
surgery, or combined trabeculotomy-trabeculecto- results compared with goniotomy. The procedure
my.4,5 involves cannulation of Schlemm’s canal through a
scleral incision with a trabeculotome, which is then
rotated to rupture trabecular meshwork. Numerous
3. Proposed surgical therapy modifications to trabeculotomy have been described,
3.1. Trabectome and Kahook Dual Blade including ‘nylon filament trabeculotomy’ described
The surgical objective of goniotomy is to remove by Redmond Smith in 1960, and 360° trabeculotomy
obstructing tissue that causes resistance to aqueous using a blunted 6-0 polypropylene suture described
outflow and to reestablish access of aqueous to by Beck and Lynch.10,11 However, misdirection of the
Schlemm’s canal. Rather than making an incision into suture may occur into the suprachoroidal space.12,13
Schlemm’s canal, the Trabectome (NeoMedix Corp., More recently, ophthalmic microcatheters have been
Tustin, CA, USA) ablates trabecular meshwork tissue, used in trabeculotomy to provide visual cues during
opening a pathway for aqueous flow into Schlemm’s cannulation and allow viscodilation of Schlemm’s
canal. Similarly, the Kahook Dual Blade (New World canal. An illuminated tip on a 250 um microcatheter
Medical, Rancho Cucamonga, CA, USA) unroofs the can be visualized in Schlemm’s canal, avoiding the
trabecular meshwork using two parallel incisions, problem of misdirection of the catheter. An illuminated
creating an ab interno trabeculectomy.6 microcatheter has been used to perform trabeculoto-
Goniotomy for developmental glaucoma has a high my in 16 eyes, with 12 (75%) achieiving complete 360°
success rate of approximately 80%, ranging from 70% trabeculotomy and significantly lower postoperative
to 93% in most large series.7,8 It appears that goniotomy IOP at 6 months follow-up.14 In another retrospec-
is most successful in patients whose glaucoma is tive review, 11 eyes were treated with circumferential
recognized early and treated between one month trabeculotomy using an illuminated microcatheter,
and one year of age, although good success rates are with a 91.6% qualified success and 83.3% unqualified
achieved in patients up to two years of age. Minckler success rate at 8 to 12 months follow-up.15 Transient
and colleagues described the use of Trabectome in 18 hyphema was common in both series, but no major
children between ages 3 days to 18 years old, although complications were reported.
no outcomes were reported.9 The Trabectome may be The illuminated microcatheter may be used to
useful in milder forms of congenital glaucoma, without perform canaloplasty by passing the microcatheter
corneal edema obscuring the view, or in older children around Schlemm’s canal, tying a prolene suture to the
with uveitis treated with goniotomy. In 73 eyes of 63 microcatheter, removing the microcatheter leaving
patients with juvenile-onset open-angle glaucoma, the suture in the canal, and tying the suture before
the Trabectome was safe and effective, with significant closing the surgical incisions. Canaloplasty has been
(P < 0.01) lowering of IOP from 26.8 ± 7.6 mmHg at tried with individual successes in older children who
baseline to 19.1 ± 15.7 mmHg at 6 months after surgery have been treated with other glaucoma procedures
Special considerations for pediatric glaucoma 291
(Susan Senft, MD, personal communication). However, difficulty of the procedure, which has limited the
there are no reports of comparisons of results of popularity of this approach. The technical challenges
canaloplasty to other procedures used in pediatric of the procedure are compounded in children, who
glaucomas. have a thinner and more elastic sclera (leaving less
room for the superficial and deep flaps), and the
3.3. Trabecular stents variability of anatomical features making identifica-
According to the manufacturer (Glaukos, Laguna tion of Schlemm’s canal more difficult.
Hills, CA, USA), the safety and effectiveness of iStent
has not been established in children. As experience 3.5. Suprachoroidal shunts
with the device increases, it is likely that usage will Suprachoroidal shunts lower the IOP by shunting
include pediatric patients, especially older children aqueous within the eye from the anterior chamber
where trabecular meshwork can be readily identified to the suprachoroidal space. While the device is no
for gonioscopic surgery. Perhaps better imaging of longer commercially available, the SOLX gold shunt
Schlemm’s canal would allow accurate placement of has been implanted with encouraging results in
the device in younger children. Further information is pediatric patients (Gabriel Simone, personal com-
needed regarding the results of trabecular meshwork munication). The CyPass shunt is also no longer com-
bypass shunts (iStent and Hydrus, also discussed mercially available. Other suprachoroidal shunts in
in Chapters 9 and 8, respectively) in children. From development may be useful in pediatric patients,
a strictly theoretical viewpoint, they may have especially in the treatment of refractory pediatric
significant advantages in the presence of a non-func- glaucomas after failure of primary surgical treatment.
tioning infantile meshwork, but conceptually they
require a normal canal. 3.6. EX-PRESS Glaucoma Filtration Device
Mean intraocular pressures, medication use, and
3.4. Deep sclerectomy surgical success were similar after treatment of adults
Use of deep sclerectomy as a primary procedure in with trabeculectomy and the EX-PRESS Glaucoma
pediatric patients has been reported.16-18 One study of Filtration Device (Alcon, Inc., Fort Worth, TX, USA).20
35 eyes of patients with various pediatric glaucomas Vision recovery was more rapid for the EX-PRESS
showed complete and qualified success rates after 9 group, IOP variation was lower during the early post-
years of 52.3% and 70.6%, respectively.16 In another operative period, and postoperative complications
study of 74 eyes with primary congenital glaucoma were less frequent after EX-PRESS implantation
and at least 3 years follow-up, the overall success compared with trabeculectomy.21 This device may be
rate was 82.4% without any catastrophic complica- useful clinically in older children who are candidates
tions.18 The authors did not recommend deroofing for trabeculectomy. Although trans-scleral filtration
of Schlemm’s canal, because this tissue is difficult is usually not recommended in patients with elevated
to identify and remove in children, with attempts at episcleral venous pressure, an 11-year-old boy
deroofing frequently associated with perforation. with Sturge-Weber syndrome was treated with the
The use of deep sclerectomy for congenital glaucoma EX-PRESS Glaucoma Filtration Device, without post-
refractory to treatment has been evaluated in one operative complications.22 A retrospective analysis
study, showing poor results (100% failure) in eight of 7 eyes from 5 pediatric patients with aphakic
patients who had failed other surgeries, and serious or juvenile glaucoma treated with the EX-PRESS
complications such as vitreous hemorrhage and retinal Glaucoma Filtration Device showed reduction of
detachment.19 Thus, results in the literature suggest average IOP from 41.6 mmHg baseline to 15.3 mmHg
possible use of the procedure in primary surgical at 6 months after surgery, with no vision threatening
treatment, but it is less attractive in treatment of complications.23 While short-term biocompatibility of
refractory pediatric glaucomas. Potential advantages the EX-PRESS device has been excellent, the long-term
of the procedure include safety of the procedure and potential for device-related adverse effects in patients
moderate efficacy. Disadvantages include technical treated as children is not known.
3.7. Transscleral shunt Although smaller-sized drainage implants have been

The Xen implant (Allergan, Dublin, Ireland) (also marketed for use in pediatric patients, most surgeons
discussed in Chapters 12 and 20) is approved for use use standard-sized implants in children, in order to
in adults. To date, this device has not been tested in achieve the desired long-term IOP reduction. In small
pediatric patients, but may offer a safe alternative for eyes (nanophthalmos) or those with immature orbits,
trans-scleral filtration in children, possibly combined small-sized implants may be helpful. In the future,
with antifibrosis drugs during the perioperative alternative plate designs and materials may be helpful
period. in pediatric patients.
At the time of this writing, a second trans-scleral
device (the Santen glaucoma shunt from InnFocus, 3.9. Endoscopic cyclophotocoagulation
currently known as PRESERFLO MicroShunt) (also Cyclodestructive procedures damage the ciliary epi-
discussed in Chapter 13) was pending. thelium, reducing aqueous production, and thereby
lowering the IOP. Studies in children indicate that
3.8. Glaucoma drainage implants success rates with a single treatment are low, and
Glaucoma drainage implants offer a valuable surgical re-treatment is often required to achieve an average
option for pediatric patients who have failed conven- success of approximately 50%.30-33 Complications
tional filtration surgery, or when significant conjuncti- can be vision-threatening and include postoperative
val scarring precludes filtration surgery. They may be inflammation, hypotony, retinal detachment, and
utilized as a primary procedure when the prognosis phthisis. Micropulse cyclophotocoagulation (MPCPC,
for success with primary angle surgery is poor, as in Iridex, Mountain View, CA) may have advantages over
aniridia, anterior segment dysgenesis, Sturge-Weber other trans-scleral techniques; however, comparative
syndrome, and aphakic or pseudophakic glaucoma. studies of MPCPC to other procedures in pediatric
Success rates in refractory pediatric glaucomas patients are not yet available.
are generally high, although results vary between Endoscopic cyclophotocoagulation (ECP) has been
studies due to differences in the type of implant valve, performed in children with refractory glaucoma
follow-up period, and outcome criteria.24 with mixed results. Neely and Plager34 reported an
Two-stage implantation of a glaucoma drainage overall success rate of 43% of 36 eyes receiving one
device may be considered for eyes at high risk for or more treatments. They noted two cases of retinal
hypotony.25,26 In the first stage, the plate is implanted detachment, one case of hypotony and one case of
and the tube is left under the conjunctiva near the progressive vision loss. All complications occurred in
limbus. A period of four to six weeks prior to the second aphakic glaucoma patients. Carter and Plager35 later
stage allows a capsule to form, which provides some studied ECP in a group of 34 eyes with aphakic and
resistance to aqueous flow in the immediate postoper- pseudophakic glaucoma and found a final success rate
ative period after tube insertion. In the second stage, of 53% after one or more treatments. In that study, two
the tube is inserted into the anterior chamber. Tradi- patients developed retinal detachments within the
tionally, this approach has been utilized most often in first postoperative month. In general, treatment with
open tube implants, but it may also be used for flow-re- cyclodestructive procedures, including ECP, is reserved
strictive implants, especially in pediatric patients at for use after other primary and secondary treatments
high risk for complications. Two-stage implantation of for pediatric glaucomas.
glaucoma drainage implants (valved and non-valved)
has been helpful in patients with Sturge-Weber
syndrome requiring additional surgical treatment.27,28 4. Current medical therapy
In high risk eyes, we currently use a 7-0 polyglactin In pediatric patients with primary developmen-
suture ligature around the tube, covered with a clear tal glaucoma, currently available medical therapy
cornea patch graft (VisionGraft, CorneaGen, Seattle, primarily serves a supportive role.36,37 The goal is
WA, USA), 29 which allows visualization for laser suture to temporarily reduce IOP and allow clearing of
lysis during the postoperative period. the cornea so that definitive surgical treatment
can be achieved. Refractory cases in which the IOP devices (pSivida and SKS Ocular), polymer-based
remains elevated following surgery may necessitate intraocular delivery devices (GrayBug), drops that
adjunctive use of IOP-lowering medications. Finally, improve the effect of medications (Kala Pharmaceu-
medical therapy may be first-line treatment for some ticals), punctal plugs that release medication (Ocular
secondary causes of pediatric glaucoma, and some Therapeutix), and a slow-release delivery system for
children with congenital glaucoma and elevated IOP bimatoprost (Lumigan SR, an ozurdex-like injection;
will respond to medical therapy alone.36,37 Clinicians Allergan). Some of these approaches to prolonging
should exercise caution in the use of IOP-lowering drug release and reducing dosing will likely be helpful
medications in children due to the increased risk for in managing pediatric glaucoma.
systemic side effects. The minimum dosage required
to achieve a therapeutic benefit should be used, and
careful monitoring should be performed.37 6. Conceptual approaches to treatment
of pediatric glaucoma
5. Proposed medical therapy Some potential therapies have no evidence in human
Rho kinase inhibitors appear to be effective and studies, but sufficient experimental evidence allows
well-tolerated, and may have a role in the treatment of speculation regarding possible use in pediatric patients.
pediatric glaucomas.38 Drugs that inhibit rho-associat- Ultrasound may cause infant trabecular meshwork
ed protein kinase (ROCK) alter the cell shape and extra- to elaborate matrix metalloproteinases, increasing
cellular matrix of the trabecular meshwork, thereby outflow facility (Donald Schwartz, MD, personal com-
increasing aqueous outflow and lowering IOP. The munication). Nanoparticles and matrix metallopro-
drug ripasudil hydrochloride hydrate 0.4% solution has teinases may be used to reset the infantile extracel-
been approved in Japan for twice-daily treatment of lular matrix in the trabecular meshwork (Beatrice
glaucoma. Rho kinase inhibitor significantly lowered Yue, MD, personal communication). Mani pulating
IOP with mild hyperemia noted as the most common homeobox genes may accelerate the development
side effect.39 Ripasudil was additive to timolol and of the immature meshwork in vivo with gene therapy.
latanoprost in randomized clinical trials.40 Immature trabecular meshwork may be treatable
New fixed combinations in development may impact with iRNA therapy. Stem cells may seed and stimulate
management of pediatric glaucoma patients. A fixed extracellular matrix formation of the infantile or
combination of nitric oxide and latanoprost (Vesneo, immature trabecular meshwork. Medications that read
Bausch & Lomb, and Nicox) will be submitted to the through nonsense mutations will prevent glaucoma
FDA as a new drug application for once-daily adminis- development in mutations associated with glaucoma
tration. Another new drug in development combines a (Kevin Gregory- Evans, MD and Peter Netland, MD,
rho kinase inhibitor and a latanoprost (Roclatan, Aerie personal communication).
Pharmaceuticals). These drugs may provide benefits
for some patients with pediatric glaucoma.
Administration of glaucoma drops can be 7. Long-term management for children
problematic in some children, potentially influencing with glaucoma
compliance. New drug delivery systems may reduce
the need for frequent administration of drops, and may Early diagnosis and advanced microsurgical techniques
be helpful in treatment of children who require medical have enabled children with glaucoma to develop
therapy for management of IOP. Various approaches to longstanding useful vision. After treatment, visual
prolonged release of drug under development include: rehabilitation requires regular continuing evaluation
a contact lens with slow release polymer (Amorphex and correction of refractive errors, treatment of
Therapeutics), microneedles for site-specific treatment corneal and lens opacities, and orthoptic treatment
(ClearSide Biomedical), slow-release micro/nano-parti- to stimulate development of binocular, stereoscop-
cle implants (Envisia Therapeutics), long-term delivery ic vision. Strabismus, amblyopia, and anisometropia
should be treated aggressively during the years of special teachers, orientation and mobility instructors,
visual development to give the best chance for good low vision specialists and parents. Better ways to
vision in both eyes. Protective eyewear should be monitor IOP (including external and intraocular
recommended for many children with glaucoma, par- devices), improved ability to restore vision, and any
ticularly those who are monocular. Low vision reha- improvements in visual maintenance and rehabilita-
bilitation for children with developmental glaucoma tion will be welcome additions in the management of
should be a multidisciplinary effort that involves children with glaucoma.
References
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Strabismus, 3rd ed, pp. 801-826. New York, NY: Oxford Univer- congenital glaucoma: preliminary results. J Fr Ophtalmol
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6. Seibold LK, Soohoo JR, Ammar DA, Kahook MY. Preclinical 21. Netland PA, Sarkisian SR Jr, Moster MR, et al. Randomized, pro-
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al-blade device. Am J Ophthalmol 2013;155:524-529. Device versus trabeculectomy (XVT Study). Am J Ophthalmol
7. Barkan O. Surgery of congenital glaucoma. Review of 196 eyes 2014;157:433-440.
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8. Shaffer RN. Prognosis of goniotomy in primary infantile glaucoma implant in a child with Sturge-Weber syndrome. J
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1982;80:321-325. 23. Crouch E, Crouch E. Experience with Ex-PRESS shunt in pediat-
9. Minckler D, Mosaed S, Dustin L, Francis B. Trabectome (trab- ric glaucoma. JAAPOS 2010;14:e14
eculectomy ‒ internal approach): additional experience and 24. Ishida K, Mandal AK, Netland PA. Glaucoma drainage implants
extended follow-up. Trans Am Ophthalmol Soc 2008;106:149- in pediatric patients. Ophthalmol Clin North Am 2005;18:431-
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10. Smith R. A new technique for opening the canal of Schlemm. Br 25. Molteno AC, Ancker E, Van Biljon G. Surgical technique for
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11. Beck AD, Lynch MG. 360° trabeculotomy for primary congenital 26. Billson F, Thomas R, Aylward W. The use of two-stage Molteno
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12. Neely DE. False passage: a complication of 360o suture trabec- Strab 1989;26:3-8.
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30. Phelan MJ, Higginbotham EJ. Contact transscleral Nd:YAG laser 36. Kanner EM, Netland PA. Pregnancy and pediatric patients. In:
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Ophthalmologica 2003;217:393-400. M. Phase 2 randomized clinical study of a rho kinase inhibitor,
34. Plager DA, Neely DE. Intermediate-term results of endoscopic K-115, in primary open-angle glaucoma and ocular hyperten-
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AAPOS 1999;3:131-137. 40. Tanihara H, Inoue T, Yamamoto T, et al. Additive intraocular
35. Carter BC, Plager DA, Neely DE, Sprunger DT, Sondhi N, Roberts pressure-lowering effects of the rho kinase inhibitor ripasudil
GJ. Endoscopic diode laser cyclophotocoagulation in the man- (K-115) combined with timolol or latanoprost: a report of 2 ran-
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Video index
Videos
Videos can be accessed directly through: newconceptsinglaucoma.com/surgery1/videos/chapter-number
e.g. for chapter 10 go to to newconceptsinglaucoma.com/surgery1/videos/10)
10. The iStent devices: iStent, iStent

Inject, and iStent Supra
Video 1. Suboptimal visualization of the TM: the pressure Video 9. (a, b) The iStent Inject inserter is introduced
on the goniolens determines the occurrence of wrinkles into the anterior chamber. The insertion sleeve is
on the cornea and the presence of bubbles under retracted when close to the TM, revealing the trocar.
the goniolens, which hamper correct visualization of The trocar is placed perpendicular to the TM before
the angle structures. Furthermore, the relative angle firing the iStent.
between the goniolens and the cornea is incorrect. Video 10. (a) Correct firing of two iStent Injects. Please
Video 2. Correct visualization of the angle through the note that the stents are placed more than two hours
goniolens: some blood is visible in SC of the first patient, away from each other. (b) The stents are in the correct
whereas some areas of pigmentation are evident in position but the spacing between the two stents
the second patient. By applying gentle pressure, it is close to two clock hours. Please note that in both
is possible to move the lens on the cornea to explore cases a slightly higher indentation is applied on the
different areas. TM for the placement of the second stent; this is due
Video 3. Differences between two goniolenses. The first to the fact that the firing mechanism is more effective
goniolens (Glaukos) allows a wider view but has a lower on its first shot.
magnification than the Ocular Instrument (Bellevue, Video 11. After having implanted the second stent,
WA, USA) lens. the operator revises the relative position of the two
Video 4. (a, b) Implantation of the iStent using different stents. On the first implanted stent the outflow of
approaches. blood exactly from the bore of the stent is evident.
Video 5. Checking the position of the iStent using vis- This is a favorable sign of correct stent placement and
coelastic material to displace the blood: the correct of patency of the outflow pathway.
position is controlled by tapping on the device with the Video 12. (a-d) After implantation, balanced saline
inserter. solution is used to clear the blood from the angle.
Video 6. (a) Checking the correct positioning of the Then, by pressing on the incision, the pressure in the
iStent. (b) The stent, sitting in SC, is seen through the anterior chamber is reduced to visualize the reflux of
TM. blood from the bore of the stent. At the slit lamp, the
Video 7. (a) The iStent is superficially placed but can reflux of blood is visualized through the bore of the
be inserted into the right position by pushing on it. stent because of the pressure changes induced during
(b) The same maneuver is used in this case, but the gonioscopy at the one-week follow-up examination.
stent is too superficial. It is regrasped and pushed into Video 13. The iStent Inject is too superficial; the
position. insertion sleeve is used to insert it deeper into the TM.
Video 8. (a, b) The inserter is used to grab the iStent,
which was obliquely implanted. Viscoelastic is used
to clear the blood and the iStent is then successfully
implanted in a different area.
12. XEN: the evolution of the stent and Video 2. The illuminate version of the G-Probe is used
in a very similar fashion to the standard G-Probe. The
technique
fiber optic light is constantly illuminated during the
Vanessa Vera, Daniel Lee, Natasha N. Kolomeyer, M. Reza application of laser so as to guide the treatment to
Razeghinejad, Jonathan S. Myers be over the ciliary body. The surgeon starts at the
standard position with the leading edge of the probe at
Video 1. Transconjunctival XEN implantation. The the limbus, but looks for transillumination of the ciliary
conjunctiva is marked at 3 mm from the limbus. The body. If transillumination is seen, the laser pulses are
needle of the injector should enter the conjunctiva placed as usual. If it is not, the surgeon moves the probe
at least 7 mm posterior to the limbus. The needle is posteriorly until transillumination occurs and then
advanced anteriorly under the conjunctiva and around laser pulses are placed as usual. This new version of the
the 3 mm marks it engages the sclera, tunneling G-Probe allows for confirmation of proper placement.
through against countertraction. At the surgical limbus, Video 3. Once the endoscope is placed through the main
the needle approach is steepened to enter the anterior wound, the ciliary body is visualized on the monitor.
chamber parallel to the iris plane. A gonioscopy lens When the aiming beam is properly positioned over
can be used at this point to confirm needle entry in the the ciliary body, the laser is discharged in continuous
anterior chamber, away from the iris and cornea. Once fashion. The surgeon confirms adequate treatment
position is appropriate, the blue slider of the injector is when the ciliary contracts and becomes discolored.
pushed forward until the needle is retracted and the Video courtesy of Lucy Shen MD.
implant is released. No forward bias is needed during this Video 4. The micropulse trans-scleral cyclodiode is
step. After deployment, final positioning is confirmed, applied to the eye once adequate anesthesia is achieved
ideally following the “1-2-3” rule, as recommended by and the eye is opened using a speculum. The laser is
the manufacturer. Adjustment with toothless forceps delivered in a continuous fashion one hemisphere or
can be done to the implant, as needed. A subconjuncti- quadrant at a time. The probe is held perpendicular
val injection of MMC after stent placement is performed, to the scleral surface with the leading edge 1-2 mm
which allows targeting fluid placement at the distal end posterior to the limbus. Delivery of the laser is done in
of the implant. Video courtesy of Jonathan Myers. a sweeping fashion, moving across each hemisphere in
10 seconds or each quadrant in 5 seconds. The surgeon
sweeps back and forth until the desired treatment time
15. Cyclophotocoagulation is achieved. As with the G-Probe, most clinicians avoid
Michael Giovingo, Shyam Patel, Shweta Chaudhary, Amar the 3 o’clock and 9 o’clock positions to avoid damage to
Mannina, Thomas Patrianakos the long ciliary nerves.
Video 1. With the patient under adequate sedation and

a lid speculum in place, the G-Probe is positioned with 18. Trabeculectomy with suprachoroidal
its anterior edge at the limbus. Laser pulses are placed derivation
using the foot pedal, which is depressed for the entire
desired time. The surgeon moves on to the next desired Rodolfo A. Pérez-Grossmann, Daniel Grigera, Alan
laser spot adjacent to the previous and fires the laser Wenger, Rodolfo A. Perez-Simons
again. The procedure is continued on the superior and
inferior halves of the eye with equidistant laser pulses. Video 1. Demonstration of the trabeculectomy with
The 3 o’clock and 9 o’clock positions are avoided so that suprachoroidal derivation surgical technique.
the long ciliary nerves are not damaged.
Also available: Glaucoma Research and Clinical
Advances - 2016 to 2018
Edited by: P.A. Knepper & J.R. Samples
Volume 1 of the New Concepts in Glaucoma Series
This first volume of the New Concepts in Glaucoma series was conceived
as a platform to express new ideas and approaches to understanding
and solving primary open-angle glaucoma. The authors have attempted
to expand levels of knowledge, present new ideas and challenge existing
theories. Although the authors have painted a broad picture, the central
theme of the book is to ask the right questions and seek the answers for
patients with primary open-angle glaucoma.
ISBN: 978-90-6299-247-8
8-90-6299-247-8
Publication details: 2016. x and 326 pages. Hardbound. Letter format, with
062 992478
many full color figures
Table of Contents
Preface 14. Glaucoma and stem cells - Mary J. Kelley, Ted S. Acott, Diala W.
1. Trabecular meshwork cell death in primary open-angle Abu-Hassan, Xinbo Li, Kevin Phan, John R. Samples
glaucoma -Kelsey A. Green, Beatrice Y.J.T. Yue, John R. Samples, 15. The microenvironment of subconjunctival tissue after glaucoma
Paul A. Knepper filtration surgery - Dao-Yi Yu, Stephen J. Cringle, Er-Ning Su
2. The histopathological changes in the trabecular outflow pathway 16. Cerebrospinal fluid dynamics and primary open-angle
and their possible effects on aqueous outflow in eyes with primary glaucoma - Kelsey A. Green, Nicholas Volpe, Paul A. Knepper
open-angle glaucoma - Haiyan Gong, David L. Swain 17. Structure-function relationships in the optic nerve head and
3. Intraocular pressure control through linked trabecular meshwork the consequences of regional pressure disturbances - Chandraku-
and collector channel motion - Murray Johnstone mar Balaratnasingam, William H. Morgan, Min H. Kang, Geoffrey
4. IOP homeostasis – Why most people do not ever develop Chan, Dao-Yi Yu
glaucoma - Ted S. Acott, Mary J. Kelley, Kate E. Keller, Janice A. 18. The role of blood flow in glaucoma - Scott Wentz, Casey Seizys,
Vranka, Diala W. Abu-Hassan, Xinbo Li, Mini Aga, John M. Bradley Giovanna Guidoboni, Julia C. Arciero, Katherine Hutchins, Brent
5. The multiple-hit theory on the pathogenesis of primary Siesky, Alon Harris
open-angle glaucoma - Paul A. Knepper, Kelsey A. Green, John R. 19. Optic nerve blood flow in primary open-angle glaucoma -
Samples Kelsey A. Green, Michael Giovingo, Paul A. Knepper
6. Dynamic mechanobiology of conventional outflow - W. Daniel 20. Microvascular disease in glaucoma - Paul A. Knepper, William
Stamer, Pedro Gonzalez, Mortimer M Civan, Malik Y. Kahook M. Norkett, Kelsey A. Green, Christopher Wanderling, Paulius V.
7. Molecular differences in segmental regions of the trabecular Kuprys, Michael Giovingo, Angelo P. Tanna, Louis R. Pasquale
meshwork - Janice A. Vranka, Ted S. Acott 21. Laser alteration of the collector channels ostia. Pivotal
8. Biomechanics and the aqueous humor outflow pathway - Vijay K. paradigm shift from laser photocoagulation to laser photostimula-
Raghunathan, Joshua T. Morgan, Paul Russell tion - Giorgio Dorin, Jeffrey K. Luttrull, John R. Samples
9. Uveoscleral outflow - Sruthi Sampathkumar, Carol B. Toris 22. The 810 Nm I.R. Diode Laser in the pivotal paradigm shift from
10. Autophagy in outflow pathway physiology and pathophysiolo- laser photocoagulation to laser photostimulation - Giorgio Dorin
gy - Paloma B. Liton 23. Special consideration for pediatric glaucoma - Peter A. Netland,
11. The interleukin-20 (IL-20) story - Kate E. Keller, Mary K. Wirtz John R. Samples
12. Biomarkers in primary open-angle glaucoma - Kelsey A. Green, 24. Novel surgical methods for addressing glaucoma - Arsham
Paul A. Knepper Sheybani, Ike K. Ahmed, John Samples
13. Family studies of primary open-angle glaucoma - Mary K. Wirtz, 25. Medical device basics - Royce DuBiner, Lane Womack
John R. Samples Index of authors
Available at www.kuglerpublications.com
Also available: Glaucoma Research and Clinical
Advances - 2018 to 2020
Edited by: J.R. Samples & P.A. Knepper
Volume 2 of the New Concepts in Glaucoma Series
Volume 2 of the Glaucoma Research and Clinical Advances series continues our
desire to address glaucoma with a combination of science and speculation. As
science expands, the emphasis is on data, interpretation, and dogma. We disagree;
open minds open new approaches. Using methodologies that are primarily
molecular and genetic, we seek to refine the causes of glaucoma as well as how
it is best treated, especially incorporating thoughts and hypotheses about new
methods of treatment. Glaucoma is a complex disease, and genetics proves that
a variety of proteins are culpable at one level. At another level, however, there are
likely final common pathways and numerous feedback loops which have defied
explanations to date.
ISBN: 978-90-6299-271-3
Publication details: 2018. xxvi and 358 pages. Hardbound. US letter format, with
many full color figures.
Table of Contents Indre Bielskus, Michael C. Giovingo, Nicholas J. Volpe

Foreword 14. Proteins in perfused and non-perfused areas of the trabecular
About the authors meshwork: potential drug candidates - Julia A. Staverosky, Ted S.
1. Do you hear me now? Mechanisms of cellular communication in Acott, Janice A. Vranka
the trabecular meshwork -Kate E. Keller 15. Modulation of intraocular pressure by ATP sensitive potassium
2. The innate immune system in primary open-angle glaucoma - channel openers - Uttio Roy Chowdhury, Peter I. Dosa, Michael P.
Paul A. Knepper, Nicholas M. Pfahler, Kevin Carey, Indre Bielskus Fautsch
3. Phagocytic activity in the trabecular meshwork - Paloma B. Liton 16. Development of the nitric oxide-donating prostaglandin analog
4. How fibronectin fibrillogenesis can regulate aqueous humor latanoprostene bunod, a novel intraocular pressure lowering drug
outflow -Jennifer A. Faralli, Jennifer Peotter, Donna M. Peters - Megan E. Cavet, Jason L. Vittitow
5. Cell-derived matrices as a model to study ocular hypertension 17. Targeting the adenosine A1 receptor in the eye with trabode-
-VijayKrishna Raghunathan noson, an adenosine mimetic - Cadmus C. Rich, David S. Albers,
6. Bioengineered human trabecular meshwork membrane James A. Gow, Rudolf A. Baumgartner
constructs: opportunities and challenges - Karen Y. Torrejon, 18. Laser trabeculoplasty renewed - Stephen S. Bylsma, Ted S.
Matthew D. Kerr Acott, Mary J. Kelley, John R. Samples
7. Is there a final common pathway affected in POAG? - Brian S. 19. Micropulse cyclophotocoagulation: an update on a novel
McKay, R. Rand Allingham, W. Daniel Stamer glaucoma treatment - Michael C. Giovingo, Krishna B. Patel,
8. Genetics of primary angle-closure glaucoma: genes and Elizabeth A. Martin, Mitchell J. Greenberg, John R. Samples, Paul A.
mechanisms - Eranga N. Vithana, Monisha E. Nongpiur, Tin Aung Knepper, Thomas D. Patrianakos
9. Genetics of POAG in Greece - Anastasios G. P. Konstas, John R. 20. Panmacular subthreshold diode micropulse laser (SDM) as neu-
Samples, Mary K. Wirtz roprotective therapy in primary open-angle glaucoma - Jeffrey K.
10. Blood flow parameters of the optic nerve - Priyanka Parekh, Luttrull, John R. Samples, David Kent, Bryant J. Lum
Alon Harris, Josh Gross, Alice C. Verticchio Vercellin, Brent Siesky 21. The development of SIBS and the InnFocus MicroShunt® -
11. Systemic manifestations of microvascular disease in primary Leonard Pinchuk, Isabelle Riss, Juan F. Batlle, Yasushi P. Kato, John
open-angle glaucoma - Nicholas M. Pfahler, Michael M. Miazga, B. Martin, Esdras Arrieta, Paul Palmberg, Richard K. Parrish, II,
Indre Bielskus, Elani Kaufman, Jack G. McGuire, Thomas Cronin, Yongmoon Kwon, Jean-Marie Parel
James Haney, Ryan McCarty, Michael C. Giovingo, Nicholas J. 22. What is the ideal conjunctival bleb? Learning from minimally
Volpe, Angelo P. Tanna, Paul A. Knepper invasive glaucoma filtration
12. Imaging of the narrow angle - Marisse Masis, Shan C. Lin Surgery - Dao-Yi Yu, Stephen John Cringle, William H. Morgan,
13. The link between Alzheimer’s disease and primary open-angle Er-Ning Su
glaucoma - Paul A. Knepper, Nicholas M. Pfahler, Jack G. McGuire, 23. Trabecular Meshwork Study Club Abstracts 2017
Available at www.kuglerpublications.com
ISBN 978-90-62992-76-8
9 789062 992768

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What is the purpose of this book series?

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What information can be accessed on the website for this book series?

ISBN 978-90-62992-76-8

New Concepts in Glaucoma Website

Published by Kugler Publications

Kugler Publications/Amsterdam/The Netherlands

New Concepts in Glaucoma Surgery Series - Volume 1

© 2020 Kugler Publications, Amsterdam, The Netherlands

Cover design by: Willem Driebergen, Rijnsburg, The Netherlands

About the editors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . viii

About the authors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . x

1. Anatomy of the conventional aqueous outflow pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

2. Patents in an age of innovation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

4. In defense of the trabeculectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

5. On the use of curcumin as a multimodal antifibrotic agent for glaucoma surgery . . . . . . . . . . . . . . . . . . 71

6. The future of MIGS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85

7. Gonioscopy-assisted transluminal trabeculotomy (GATT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .95

8. Hydrus® microstent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107

10. Ab interno trabecular meshwork incision, ablation, and disruption . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137

12. XEN: the evolution of the stent and technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167

14. Laser trabeculoplasty and micropulse: evolution from trabecular photocoagulation,

15. Cyclophotocoagulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211

17. Mixing and combining MIGS procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245

18. Trabeculectomy with suprachoroidal derivation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249

19. Modern retinal laser for neuroprotection in open-angle glaucoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255

21. Special considerations for pediatric glaucoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289

Iqbal Ike K. Ahmed, MD, FRSC (C)

Iqbal Ike K. Ahmed, MD, FRCSC

Ike Ahmed is a fellowship-trained glaucoma, cataract, and anterior segment surgeon

Alyssa Francesca Ahorro, BA 

Henny J.M. Beckers, MD, PhD, FEBOphth 

Michael S. Berlin, MD, MSc 

Stephen John Cringle, BSc, PhD 

Antonio Maria Fea, MD, PhD 

Haiyan Gong, MD, PhD, FARVO 

Davinder S. Grover, MD, MPH 

Leon W. Herndon, Jr., MD 

David Kent, FRCOphth 

Paul A Knepper, MD, PhD 

Nils A. Loewen, MD, PhD 

William Morgan, MBBS, PhD, FRANZCO 

Peter A. Netland, MD, PhD 

William D. Noonan, MD, JD 

Leonard Pinchuk PhD, DSc (h.c.), NAE 

Steven R. Sarkisian, Jr., MD 

Ingeborg Stalmans, MD, PhD 

Er-Ning Su, MD, PhD 

Marc Töteberg-Harms, MD, FEBO 

Jithin Yohannan, MD, MPH 

Dao-Yi Yu, MD, PhD 

Department of Ophthalmology, Boston University School of Medicine, Boston, MA, USA

New Concepts in Glaucoma Surgery Series: Volume 1, pp. 1-38

Fig. 4. Drawing of the aqueous outflow pathway and

Fig. 5. Light micrograph of the trabecular meshwork

Fig. 18. Diagrammatic representation of the distal portion of

into CCs in POAG compared to normal eyes.59,60

Fig. 19. Neoprene cast of Schlemm’s canal and limbal vessels

4. In vivo assessment of structure 4.2.1. Introduction

Alyssa Francesca Ahorro, BA

Henny J.M. Beckers, MD, PhD, FEBOphth

Michael S. Berlin, MD, MSc

Stephen John Cringle, BSc, PhD

Antonio Maria Fea, MD, PhD

Haiyan Gong, MD, PhD, FARVO

Davinder S. Grover, MD, MPH

Leon W. Herndon, Jr., MD

David Kent, FRCOphth

Paul A Knepper, MD, PhD

Nils A. Loewen, MD, PhD

William Morgan, MBBS, PhD, FRANZCO

Peter A. Netland, MD, PhD

William D. Noonan, MD, JD

Leonard Pinchuk PhD, DSc (h.c.), NAE

Steven R. Sarkisian, Jr., MD

Ingeborg Stalmans, MD, PhD

Er-Ning Su, MD, PhD

Marc Töteberg-Harms, MD, FEBO

Jithin Yohannan, MD, MPH

Dao-Yi Yu, MD, PhD