Romanian Journal of Ophthalmology, Volume 61, Issue 2, April-June 2017.

pp:90-94

REVIEW

Pseudophakic bullous keratopathy

Pricopie Stefan*, Istrate Sanziana*, Voinea Liliana*, Leasu Costin*, Paun Vanessa*, Radu Ciuluvica**
*Ophthalmology Department, Bucharest Emergency University Hospital, Bucharest, Romania
**Anatomy Department, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania

Correspondece to: Istrate Sanziana, MD, PhD,

Ophthalmology Department, Bucharest Emergency University Hospital, Bucharest,
169 Splaiul Independentei Street, District 5, Bucharest, Romania,
Mobile phone: +40726 535 515, E-mail: [email protected]

Accepted: May 1st, 2017

Abstract
Pseudophakic bullous keratopathy is characterized by corneal stromal edema with
epithelial and subepithelial bullae due to cell loss and endothelial decompensation
through trauma during cataract surgery. Patients present decreased vision, tearing, and
pain caused by ruptured epithelial bullae. Cataract affects approximately 20 million
people worldwide, and this complication can occur in 1 to 2% of the cataract surgeries.
This study reviewed the bullous keratopathy etiopathogenesis and the clinical and
surgical treatment available for this corneal disease.
Keywords: corneal disease treatment, corneal surgery, bullous keratopathy, cataract
extraction

Introduction keratopathy are associated with pain,

photophobia, and reflex lacrimation [1].
The cornea is a complex structure that is
responsible for most of the refraction of the eye Corneal Pathophysiology
and, because of its highly exposed position, has a The average central thickness of the normal
protective role, acting as a physical barrier to adult human cornea is approximately 550µm for
trauma and infection [1,2]. One of the most Caucasians and it remains constant between the
important property of the cornea is its second and sixth decades, but varies with the
transparency, which is a result of a number of time of day and race [3].
factors: the absence of blood vessels, the The cornea consists of five layers from
regularity and smoothness of the covering anterior to posterior: epithelium, Bowman’s
epithelium, the regular arrangement of the layer, stroma, Descemet’s membrane, and
extracellular and cellular components in the endothelium. The composition of the stroma is
stroma, which is dependent on the state of not uniform; the anterior stroma contains a
hydration and metabolism of the stromal higher ratio of dermatan sulfate to keratan
elements [2]. sulfate, making the posterior stroma more likely
The cornea has one of the body’s highest to swell with excess water in states of
density of nerve endings, with a subepithelial endothelial dysfunction [4].
and a deeper stromal plexus, both supplied by Immunohistochemical studies showed
the 1st division of the trigeminal nerve. This is deposits of a specific extracellular matrix
the reason why disease processes like bullous component, such as fibrilin-1 which belongs to

Romanian Society of Ophthalmology

90 © 2017
doi:10.22336/rjo.2017.17
 Romanian Journal of Ophthalmology 2017; 61(2): 90-94

the family of extracellular matrix proteins can lead to thermal damage to adjacent corneal
associated with elastic microfibrils and tenascin- tissue. Damage to the endothelium can be caused
C, which is a glycoprotein that has great by high irrigation or aspiration rates that can
importance in healing and is found in the result in turbulent flow with lens particles
posterior collagen layer or in the subepithelial connected with it [10].
fibrotic areas of corneas with bullous Also, the duration of phacoemulsification
keratopathy [6]. used during the surgery is very important
Growth factors and cytokines influence cell because the ultrasound energy is associated with
proliferation, inflammation, scarring, and the production of free radicals, which are
fibrosis. Elevated levels of interleukin-2 (IL-2), reactive species with one or more unpaired
interleukin-8 (IL-8), growth factor insulin (IGF- electrons in their outer orbits and can damage
1), transforming growth factor (TGF- β) and the corneal endothelium by oxidative stress [10].
bone marrow factor - 4 (BMP-4) were found in Other etiologies include endothelial
corneas with bullous keratopathy. The dystrophies such as Fuchs dystrophy, tumors of
interactions between growth factors and the anterior chamber such as myxoma,
extracellular matrix degrading matrix congenital abnormalities, like microcornea, acute
metalloproteins are important and can be a and neovascular glaucoma, herpetic endotheliitis
mechanism for the loss of corneal transparency or surgeries that can lead to endothelial cell loss
[6]. like trabeculectomy, intraocular lens scleral
Corneal deturgescence is maintained by fixation, anterior chamber lens implants for
endothelial cell sodium/ potassium-activated aphakic correction and high ametropia, after
adenosine triphosphatase) and by tight junctions argon laser, radial keratotomy [6].
between the endothelial cells that limit the Bullous keratopathy may occur in around 1
ingress of fluid. By removing fluid from the to 2% of the patients undergoing cataract
stroma and limiting its entry, endothelial cells surgery, which is about two to four million
maintain the ordered arrangement of collagen patients worldwide [6].
and preserve the cornea’s transparency. In states
of deficient endothelial cell density, a lack of Treatment options
tight junctions between the endothelial cells The clinical treatment for corneal edema
allows the increased entry of fluid into the should be based on topical hypertonic agents
stroma. The endothelial cells that remain may such as sodium chloride (5%), anti-inflammatory
have a higher concentration of Na+, K+-ATPase drugs, topical and/ or systemic antiglaucoma
as a compensatory mechanism to increase fluid medications, because increased IOP can
removal [4]. compromise endothelial cell function,
The normal endothelial cell density is corticosteroids, lubricants and sometimes, due to
greater than 3500 cells/ 𝑚𝑚𝑚𝑚2 in children and the pain experienced by the patients, therapeutic
gradually declines with age to approximately contact lenses to improve symptoms [10].
2000 cells/ 𝑚𝑚𝑚𝑚2 in older people, with an According to a study conducted in 2015,
average of 2400 cells/ 𝑚𝑚𝑚𝑚2 for adults [5]. After systemic L-cysteine facilitated corneal edema
this, the average cell loss is about 0.6 percent per remission when administered in the
year with the development of edema when the postoperative period in patients after cataract
cell density drops below 700 cells/ 𝑚𝑚𝑚𝑚2 . surgery, thus advocating its concurrent use in
patients developing bullous keratopathy.
Etiopathogenesis An increased expression of several
The main cause of bullous keratopathy is proinflammatory mediators at the protein level
the loss of endothelial cells due to surgical in the corneal epithelium was demonstrated in
trauma, especially in cataract surgery at sixth patients with pseudophakic corneal edema.
decade patients, with or without lens These cytokines and MMP, which are a family of
implantation [6,7]. extracellular proteinases that degrade the
The localized increase of temperature extracellular matrix proteins, participate in the
associated with the phacoemulsification probe pathologic processes in the pseudophakic
corneal edema and specifically contribute to the

91
Romanian Society of Ophthalmology
© 2017
Romanian Journal of Ophthalmology 2017; 61(2): 90-94

continuous degradation of Bowman’s layer and Corneal collagen cross linking (CXL)
recurrent erosions of the corneal epithelium. with Riboflavin and ultraviolet A (UVA)
The MMPs have a pivotal role in a number radiations is a photochemical process that was
of pathologic processes, including angiogenesis introduced by Seiler and Spoerl at the University
and wound healing, where matrix degradation of Dresden for the treatment of corneal ectatic
takes place. MMP are activated by the “cysteine disorders such as keratoconus and post LASIK
switch”. All modes of activation lead to a ectasias [13].
dissociation of Cys73 from the zinc atom with Corneal CXL is considered a new tool in the
concomitant exposure of the active site. struggle for the temporary reduction in corneal
Based on the presumption that high L- edema in patients with bullous keratopathy. It
cysteine levels may act as regulatory substrate has been found to improve corneal transparency,
for MMPs, more studies should be conducted in corneal thickness, and ocular pain after surgery
order to establish the adjuvant role of systemic [12].
L-cysteine in pseudophakic bullous The proposed mechanism of action is that
keratopathies [7]. riboflavin absorbs UVA light, which results in the
The use of conjunctival flaps is effective production of free oxygen radicals. These highly
but has been limited by its unacceptable reactive oxygen radicals then induce the cross-
cosmetic outcome [6]. linking of corneal stromal collagen and
strengthen the cornea [13].
Corneal transplantation is still the gold- Different studies showed that corneal CXL
standard treatment for bullous keratopathy significantly improves corneal transparency,
patients, as it provides symptomatic relief and corneal thickness, and ocular pain one month
visual rehabilitation [8]. Some limitations such postoperatively. This symptomatic relief
as visual acuity recovery occur because of the probably resulted from CXL-induced stromal
high astigmatism and, although the cornea is the compaction and reduced bullae formation.
most commonly transplanted tissue in the body However, it did not seem to have a long-lasting
and corneal grafts high success rate, there is also effect in decreasing pain and maintaining corneal
the risk of rejection [6,9]. transparency [12,14].
In 1999, Pires et al. successfully used
Penetrating keratoplasty refers to a full amniotic membrane (AM) to control pain in
thickness corneal transplant. In conventional patients with BK. They attributed their results to
posterior lamellar keratoplasty (LK) and the various protease inhibitors located in the
newer endothelial keratoplasty (EK) procedures, stromal matrix of the AM, which are important
only the inner layers of the cornea are for promoting epithelial healing and reducing
transplanted and there are multiple variants of stromal ulceration and inflammation [16].
this procedures that include deep lamellar EK, AM facilitates re-epithelialization by
Descemet’s stripping (automated) EK (DSEK or providing a suitable substrate and a normal
DSAEK), Descemet’s membrane EK, and basement membrane, by promoting epithelial
Descemet’s membrane automated EK [11]. cell migration and adhesion. AM is also believed
The posterior lamellar keratoplasty to produce several growth factors that support
technique requires surgical skill and hinders any epithelial cells. When the amniotic membrane is
necessary action in the anterior chamber, but it applied to the cornea, keratocyte derived
has the advantage of a lower risk of rejection and fibroblasts and myofibroblasts are known to
preservation of the receptor surface. It is a migrate from the corneal stroma into the
promising technique, but the endothelial cell loss amniotic stroma. This contributes to the
is bigger than in penetrating keratoplasty [6]. subepithelial fibrosis and also anchors the
In developing countries with a shortage of amnion epithelial sheet to the corneal surface
donor corneas and long waiting lists of patients [15].
awaiting corneal transplantation, patients need Amniotic membrane transplant is effective
to be provided with relief of symptoms and, if in controlling pain in patients with pseudophakic
possible, temporary improvement in vision [12]. bullous keratopathy and does not induce
neovascularization, but is not the first treatment

92
Romanian Society of Ophthalmology
© 2017
 Romanian Journal of Ophthalmology 2017; 61(2): 90-94

option because of the cost and needed time increased scarring associated may also result in
[6,15]. an increased stability of the epithelium and a
deep ablation has a superior effect on decreasing
Anterior stromal puncture (ASP) is a pain by the ablation of the neural plexus in the
simple and popular interventional option in the cornea [19].
management of pseudophakic bullous The same reasoning as in PTK is used also
keratopathy with low cost and rare for automated lamellar keratectomy but, in
complications [6,15,17]. this case, a traditional microkeratome is used for
Immunohistochemical studies have the removal of the corneal tissue. It is a fast
demonstrated an increased expression of procedure, which can be an important factor for
extracellular matrix proteins important for the some elderly patients who present difficulties in
adhesion of basal epithelial cells such as undergoing longer surgeries while remaining in
fibronectin, laminin, and type IV collagen at dorsal decubitus [6].
stromal puncture sites. The secretion of these
basement membrane components would
increase the epithelial adhesion in the
Conclusions
underlying stroma, which is associated with
Although corneal transplantation is the
subepithelial fibrosis, thus creating a barrier to
treatment with the best results in improving
liquid penetration into the subepithelial space
pain and visual acuity, what has to be kept in
and decreased subepithelial bubble formation
mind is the research for alternative treatments
[6,15].
for the patients with no visual potential or those
Hsu et al. were able to clinically correlate
who are waiting for an available cornea. For this
an improvement in pain symptoms with varying
group of patients, clinical therapy, use of
degrees of subepithelial fibrosis and epithelial
therapeutic contact lens, systemic L-cysteine,
attachment [18].
anterior stromal puncture, conjunctival flaps,
amniotic membrane transplantation,
Phototherapeutic keratectomy (PTK)
phototherapeutic keratectomy, and automated
can improve pain by reducing corneal thickness
lamellar keratectomy can significantly improve
and this would help the remaining endothelial
the quality of life.
cells maintain corneal hydration [6].
Several studies reported PTK to be elective
in the management of patients with bullous References
keratopathy from a variety of etiologies; they
reported that the bullae resolve and pain is 1. Kansky JJ, Bowling B. Clinical Ophthalmology - A
abolished in a large proportion of patients systemic approach, Seventh edition, 2011, Elsevier
Saunders, 168-172.
treated with a superficial ablation [19,20]. 2. Forrester JV, Dick AD, McMenamin PG, Roberts F,
The main sensory nerve plexus in the Pearlman E. The Eye - Basic science in practice, Fourth
cornea, which is derived from the nasociliary edition, 2016, Elsevier, 15-22.
branch of the ophthalmic division of the 3. Jackson TL. Moorfields Manual of Ophthalmology,
Second edition, 2014, JP Medical Publishers, 157-159.
trigeminal nerve, is located in the stroma, in the
4. Fernandez MM, Afshari NA. Endothelial Keratoplasty:
immediately subepithelial region, with a lower From DLEK to DMEK. Middle East African Journal of
density plexus deeper in the stroma [19]. The Ophthalmology. 2010 Jan-Mar; 17(1):5–8.
rationale for this treatment is the ablation of doi: 10.4103/0974-9233.61210.
these nerve plexuses thereby reducing corneal 5. American Academy of Ophthalmology. External disease
and cornea. 2014-2015; 34.
sensation and, in addition, corneal scarring 6. Gonçalves Domingues E, Fields F, Paris F, Pereira
induces an increase of extracellular proteins Gomes JA, Costa de Farias C. Bullous keratopathy:
such as laminin, fibronectin, type IV collagen and etiopathogenesis and treatment. Arq.
hemidesmosomes which promote a greater Bras. Oftalmol. Nov./Dec. 2008; 71(6) supl.0.
7. Iancu R, Voinea L, Ciuluvica R, Golu A, Dinu I, Leasu C,
adhesion between the epithelium and
Pricopie S, Gradinaru S. The effect of systemic L-
stroma [6,19]. cysteine in myopic patients with corneal edema after
Deep PTK appears to be more successful in cataract surgery. 2015.
comparison with superficial PTK because of the

93
Romanian Society of Ophthalmology
© 2017
Romanian Journal of Ophthalmology 2017; 61(2): 90-94

8. Siu GD, Young AL, Jhanji V. Alternatives to corneal

transplantation for the management
of bullous keratopathy. Current opinion in
ophthalmology. Jul. 2014; 25(4):347-52.
9. Abud TB, Di Zazzo, Kheirkhah A, Dana R. Systemic
Immunomodulatory Strategies in High-risk Corneal
Transplantation. Journal of Ophthalmic & Visual
Research. 2017 Jan-Mar; 12(1):81-92.
10. Feinbaum C. A new treatment modality with the Hyper
CL soft contact lens. Ophthalmology Times Europe. May
2015.
11. Reinhart JW, Musch DC, Jacobs SD, Lee WB, Kaufman
SC, Shtein RM. Deep Anterior Lamellar Keratoplasty as
an Alternative to Penetrating Keratoplasty. American
Academy of Ophthalmology. Jan. 2001; 118(1):209–
218.
12. Ritu A, Manudhane A, Saran R, Goyal J, Gupta D. Role of
Corneal Collagen Cross-Linking in Pseudophakic
Bullous Keratopathy. American Academy of
Ophthalmology Annual Meeting. November 2012,
Chicago, Illinois.
13. Khan MS, Basit I, Ishaq M, Shakoor T, Yakub A, Intisar
R. Corneal Collagen Cross Linking (CXL) in treatment of
Pseudophakic Bullous Keratopathy. Pakistan Journal of
Medical Sciences. 2016 Jul-Aug; 32(4):965–968.
14. Santhiago MR, Berti TB, Thomaz S, Netto MV. Collagen
crosslinking with riboflavin and ultraviolet-A in eyes
with pseudophakic bullous keratopathy. Journal of
Cataract and Refractive Surgery. February 2010;
36(2):273-276.
15. dos Santos Paris F, Domingues Gonçalves E, Silveira de
Queiroz Campos M, Hideo Sato E, Dua HS, Pereira
Gomes JA. Amniotic membrane transplantation versus
anterior stromal puncture in bullous keratopathy: a
comparative study. Brazilian Journal of Ophthalmology.
May 2010.
16. Pires RT, Tseng SC, Prabhasawat P et al. Amniotic
membrane transplantation for symptomatic bullous
keratopathy. Arch Ophthalmol. 1999; 117:1291–7.
17. Gomes JA, Haraguchi DK, Zambrano DU, Izquierdo
Júnior L, Cunha MC, de Freitas D. Anterior stromal
puncture in the treatment of bullous keratopathy: six-
month follow-up. Cornea. 2001 Aug; 20(6):570-2.
18. Hsu JK, Rubinfeld RS, Barry P, Jester JV. Anterior
stromal puncture. Immunohistochemical studies in
human corneas. Archives of Ophthalmology. Aug. 1993;
111:1057–63.
19. Maini R, Sullivan L, Snibson GR, Taylor HR, Loughnan
MS. A comparison of different depth ablations in the
treatment of painful bullous keratopathy with
phototherapeutic keratectomy. The British Journal of
Ophthalmology. Aug. 2001; 85:912–915.
20. Thomann U, Meier-Gibbons F, Schipper I.
Phototherapeutic keratectomy for bullous keratopathy.
The British Journal of Ophthalmology. 1995; 79:335–8.

94
Romanian Society of Ophthalmology
© 2017