Viral Posterior Uveitis

s u r v e y o f o p h t h a l m o l o g y 6 2 ( 2 0 1 7 ) 4 0 4 e4 4 5
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Major review
Viral posterior uveitis
Joanne H. Leea, Aniruddha Agarwal, MDb,

Padmamalini Mahendradas, MSc, Cecilia S. Lee, MDd, Vishali Gupta, MDb,
Carlos E. Pavesio, FRCOphthe, Rupesh Agrawal, MDa,e,f,*
a
Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
b
Department of Vitreoretina and Uveitis, Postgraduate Institute of Medical Education and Research, Chandigarh, India
c
Department of Uveitis and Ocular Immunology, Narayana Nethralaya, Bengaluru, India
d
Department of Uveitis, University of Washington, Seattle, Washington, USA
e
Department of Medical Retina, Moorfields Eye Hospital, NHS Foundation Trust, London, United Kingdom
f
Department of Ophthalmology, National Healthcare Group Eye Institute, Tan Tock Seng Hospital, Singapore, Singapore
article info abstract
Article history: The causes of posterior uveitis can be divided into infectious, autoimmune, or masquerade
Received 11 June 2016 syndromes. Viral infections, a significant cause of sight-threatening ocular diseases in the
Received in revised form 12 posterior segment, include human herpesviruses, measles, rubella, and arboviruses such
December 2016 as dengue, West Nile, and chikungunya virus. Viral posterior uveitis may occur as an
Accepted 13 December 2016 isolated ocular disease in congenital or acquired infections or as part of a systemic viral
Available online 22 December 2016 illness. Many viruses remain latent in the infected host with a risk of reactivation that
depends on various factors, including virulence and host immunity, age, and
Keywords: comorbidities. Although some viral illnesses are self-limiting and have a good visual
viruses prognosis, others, such as cytomegalovirus retinitis or acute retinal necrosis, may result in
posterior uveitis serious complications and profound vision loss. Since some of these infections may
viral posterior uveitis respond well to antiviral therapy, it is important to work up all cases of posterior uveitis to
CMV retinitis rule out an infectious etiology. We review the clinical features, diagnostic tools, treatment
herpetic retinitis regimens, and long-term outcomes for each of these viral posterior uveitides.
polymerase chain reaction ª 2016 Elsevier Inc. All rights reserved.
1. Introduction The incidence of uveitis has been estimated between 17

and 52 cases per 100,000 population per year, with a
Posterior uveitis is an inflammation of the posterior uveal prevalence of 38e714 cases per 100,000 population.242 Uveitis
tract (retina and choroid). According to the International generally has an equal gender distribution,242 with a slight
Uveitis Study Group24 and Standardization of Uveitis female predominance in some studies.55,131,150,153 Uveitis can
Nomenclature working group106 classification, posterior uve- occur at any age, but the mean age of incidence is between 30
itis includes focal, multifocal or diffuse choroiditis, to 40 years in most studies.12,55,131,150,153,188,248 About 60%e
chorioretinitis, retinochoroiditis, retinitis, and neuroretinitis. 80% of uveitis occurs between the ages of 20 to 50 years.242 In
* Corresponding author: Rupesh Agrawal, MD, Department of Ophthalmology, National Healthcare Group Eye Institute, Tan Tock Seng
Hospital, Singapore 308433.
E-mail addresses: [email protected], [email protected] (R. Agrawal).
0039-6257/$ e see front matter ª 2016 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.survophthal.2016.12.008
s u r v e y o f o p h t h a l m o l o g y 6 2 ( 2 0 1 7 ) 4 0 4 e4 4 5 405
terms of anatomic classification, anterior uveitis is the most In recent years, viral retinitis has appeared as a
common form of uveitis, followed by panuveitis, posterior complication of intraocular injections. Several reports have
uveitis, and intermediate uveitis. The prevalence of anterior shown that viral retinitis develops later in patients who
uveitis, panuveitis, posterior uveitis, and intermediate uveitis received intraocular corticosteroid injections, including CMV,
is reported to be 24.5%e52.3%, 11.8%e52.9%, 7.1%e46.0%, herpes simplex virus (HSV), and varicella zoster virus (VZV)
and 6.3%e19.3%, respectively, in several studies.12,55,131, retinitis.51,208,218,232,237 Since the first case of CMV retinitis
150,153,188,248
The causes of posterior uveitis can be infectious following a sub-Tenon injection of triamcinolone acetonide
(bacterial, viral, fungal, and parasitic), noninfectious was reported in 2002 by D’Alessandro and colleagues,51
(autoimmune or associated with a systemic disease), or part of several other studies have appeared (Table 2).51,66,208,232,237,252
a masquerade syndrome.53 A significant proportion of the
cases of posterior uveitis are infectious (Table 1).12,
55,131,150,153,188,248
2.2. Clinical features
The pathophysiology of infectious uveitis is almost always
hematogenous spread of infection from another part of Viral posterior uveitis may present with symptoms of
the body to the highly vascular uvea, with a breach in the decreased visual acuity, visual field defects, floaters,
blood-eye barrier.178 Viral etiologies of infective posterior photopsia, photophobia, and occasionally pain.270 Typical
uveitis include human herpesviruses (HHVs), HIV, measles, signs on examination include subconjunctival hemorrhage,
rubella, arboviruses (dengue, chikungunya, Rift Valley virus, mild anterior segment inflammation with or without
and West Nile virus [WNV]), and other rare causes such as conjunctival injection with diffuse fine keratic precipitates.
influenza, Ebola, and Zika virus (ZIKV). Viral posterior uveitis There may be retrolental cells, ocular hypertension, or
may occur as an isolated ocular disease or as part of a glaucoma.270 Fundus examination may reveal inflammatory
systemic viral illness. infiltrates on the retina either retinitis or retinal vascular
sheathing, macular edema in acute cases, scarring, retinal
pigment epithelium (RPE) hyperplasia, and peripheral retinal
neovascularization in long-standing cases.270
2. Viral posterior uveitis

2.3. Diagnosis
2.1. Risk factors
The diagnosis of viral posterior uveitis is usually clinical.
The most important risk factor associated with viral Characteristic features on the slit lamp and dilated fundus
posterior uveitis is an immunocompromised state, examination are used to diagnose viral posterior uveitis.
particularly in patients with HIV infection and AIDS. Retinal imaging, including fundus photography, fundus
Opportunistic ocular infections are common among AIDS fluorescein angiography (FFA), wide field retinal imaging, and
patients, with cytomegalovirus (CMV) retinitis and herpetic optical coherence tomography (OCT), is useful in establishing
progressive outer retinal necrosis (PORN) being the 2 main the diagnosis and monitoring response to treatment.81 Other
types of viral posterior uveitis.141 Patients with multiple ancillary investigations, including laboratory tests for viral
medical comorbidities that suppress the immune system are serology and imaging, can be used to confirm the diagnosis.270
also predisposed to developing viral retinitis.218 Polymerase chain reaction (PCR) analyses of intraocular
Nonetheless, viral posterior uveitis may also occur in fluid samples are an effective aid for diagnosis50,70,135,229,239,267
apparently immunocompetent individuals. In 2 studies by and subsequent management84,204 of viral posterior uveitis
Rochat and colleagues201 and Guex-Crosier and colleagues80 caused by HSV, VZV, and CMV. The tetraplex PCR analysis of
that evaluated the effects of an individual’s immune status intraocular fluids for HSV, VZV, and CMV is effective in
on the presentation of necrotizing herpetic retinopathies, confirming the etiological pathogen involved in 59e100% of
however, immune dysfunction was found in all apparently cases,28,84,204,211 with PCR having a sensitivity of 80.9%e84.0%
immunocompetent and HIV-negative patients diagnosed with and a specificity of 97.4%e100.0%.50,84,135,211 Serial PCR
herpetic retinitis. All patients may have abnormalities in one analysis may be useful in monitoring viral activity and
or more immunologic parameters, including diminished response to treatment.45,269 Negative PCR is useful in ruling
lymphocytic proliferative response, diminished cutaneous out the disease in challenging cases. The Goldmann-Witmer
anergy, and relative or absolute increase in B-lympho- coefficient analysis of intraocular antibody titers can also be
cytes.80,201 This suggests that most, if not all, patients with used to identify the virus involved204; however, the tetraplex
herpetic retinitis have an underlying immunodeficiency that PCR has a greater sensitivity and specificity than the
predisposes them to infection, even when they appear to be Goldmann-Witmer coefficient analysis in the diagnosis of
immunocompetent.79,200 Although the pathogenesis in these herpes viruses (HSV, VZV, and CMV) involved in posterior
individuals has yet to be established, further studies to uveitis.204 Chorioretinal biopsy is another diagnostic tool that
determine the effect of virulence and host susceptibility in may be useful in confirming the diagnosis and guiding
immunocompetent individuals in whom viral posterior subsequent management in selected cases where both the
uveitis is developed will be valuable in understanding the PCR and Goldmann-Witmer coefficient analyses are negative,
disease pathology. and there is still a high index of suspicion.163,207
406
Table 1 e Epidemiology of uveitis
Author (year) Gender, n (%) Age (years) Anatomic diagnosis, n (%) Posterior uveitis
Laterality, n (%) Infectious status, % Viral

etiology, n (%)
Male Female Range Mean ( SD) Anterior Intermediate Posterior Pan Bilateral Unilateral Infectious Noninfectious
Pathanapitoon 105 (52.5) 95 (47.5) 8e85 38.4 49 (24.5) 17 (8.5) 92 (46.0) 42 (21.0) 48 (52.2) 44 (47.8) NR NR CMV: 54 (58.7)
et al (2008)188 ARN: 7 (7.6)
Kianersi et al (2014)131 915 (45.4) 1101 (54.6) 2e98 33.76 10.56 865 (42.9) 390 (19.3) 432 (21.4) 329 (16.3) 63 (14.6) 369 (85.4) 88.4 11.6 CMV: 4 (0.9)
HIV: 1 (0.2)
Al-Shakarchi (2014)12 159 (50.0) 159 (50.0) NR 36.2 78 (24.5) 20 (6.3) 123 (38.7) 97 (30.5) 63 (51.2) 60 (48.8) 69.9 30.1 ARN: 2 (1.6)
CMV: 1 (0.8)
Liberman et al (2014)150 256 (41.9) 355 (58.1) 3e91 38.0 (median) 247 (40.4) 51 (8.3) 110 (18.0) 203 (33.2) 42 (38.2) 68 (61.8) 40.0 60.0 CMV: 5 (4.5)
HSV: 2 (1.8)
Llorenç et al (2015)153 465 (45.5) 557 (54.5) 1e92 38.0 (median) 534 (52.3) 92 (9.0) 240 (23.5) 156 (15.3) 120 (50.0) 120 (50.0) 47.9 52.1 CMV: 9 (3.8)
ARN: 6 (2.5)
HIV: 5 (2.1)
NNHR: 2 (0.8)
PORN: 1 (0.4)
Venkatesh 489 (61.1) 311 (38.9) 4e81 34.21 13.94 413 (51.6) 131 (16.4) 162 (20.3) 94 (11.8) 84 (51.9) 78 (48.1) 51.2 48.8 HIV: 11 (6.8)
et al (2015)248 CMV: 8 (4.9)
ARN: 2 (1.2)
Dhibi et al (2016)55 390 (43.9) 498 (56.1) 6e94 39.6 11 242 (27.3) 113 (12.7) 63 (7.1) 470 (52.9) 40 (63.5) 23 (36.5) 47.6 52.4 CMV: 1 (1.6)
Summary, n (%) M: 2779 (47.5); F: 3076 (52.5); Range: 1e98; mean: 2428 (41.5) 814 (13.9) 1222 (20.9) 1391 (23.7) 460 (37.6) 762 (62.4) 65.5 34.5 CMV: 82 (67.8)
M:F ratio 1:1.1 36.4 ARN: 17 (14.0)
HIV: 17 (14.0)
HSV: 2 (1.7)
NNHR: 2 (1.7)
PORN: 1 (0.8)
ARN, acute retinal necrosis; CMV, cytomegalovirus; F, female; HSV, herpes simplex virus; M, male; NNHR, nonnecrotizing herpetic retinitis; NR, not reported; PORN, progressive outer retinal necrosis.
Table 2 e Retinitis after intraocular steroid injection
Author (year) Age (years) Gender HIV Indication for Time from Established VA when Treatment Duration of VA at last visit
status corticosteroid corticosteroid diagnosis retinitis follow-up
to retinitis first (months)
(months) diagnosed
D’Alessandro 45 M þ Immune recovery 2 CMV retinitis 20/100 Intravenous ganciclovir 18 “Habitual visual
et al (2002)51 uveitis acuity”
Saidel et al (2005)208 75 M d CME 4 CMV retinitis 20/400 Oral valganciclovir, intravitreal 6 20/400
ganciclovir
Toh et al (2006)237 62 F d Choroidal neovascular 6 HSV-1 retinitis 20/60 Intravenous acyclovir, 3 20/120
membrane oral acyclovir
Furukawa 54 F d CME 3 CMV retinitis 1.0 Intravenous ganciclovir, 14 0.5
et al(2007)66 intravitreal foscarnet, vitrectomy
Vertes et al (2010)252 78 F d CME 3 CMV retinitis 20/40 Intravenous ganciclovir, oral 8 20/25
valganciclovir, intravitreal
ganciclovir, vitrectomy,
peripheral endolaser
Takakura 65 M d VKH with 1.8 CMV retinitis 20/200 Intravitreal ganciclovir, oral 2 20/70
et al (2014)232 steroid-induced valganciclovir
cataracts
37 F d Idiopathic posterior 12 CMV retinitis 20/80 Intravitreal foscarnet, oral 2 20/80
uveitis with CME valganciclovir
63 M d Granulomatous 2 CMV retinitis 20/40 Intravenous ganciclovir, oral 84 20/200
panuveitis with CME prednisone, pars plana
vitrectomy
72 M d BRVO 1 CMV retinitis 20/60 Intravitreal ganciclovir 12 CF
37 F d Chronic idiopathic 2 ARN 20/30 Oral acyclovir, intravitreal 36 20/200
iridocyclitis ganciclovir
Summary; n (%) Range: Male: HIV CME: 5 (50.0); others: Range: 1e12; CMV retinitis: 20/40: 3 Systemic: 3 (30.0); intravitreal: Range: 2e84; 20/40: 1 (10.0);
37e78; female positive: 5 (50.0) mean: 3.7; 8 (80.0); others: (30.0); 20/40 1 (10.0); both systemic and mean: 18.5; 20/40e20/100:
mean: 58.8; ratio 1:1 1 (10.0) median: 2.5 2 (20.0) e20/100: 4 intravitreal: 6 (60.0) median: 10 2 (20.0); 20/100:
median: 62.5 (40.0); 20/100: 7 (70.0)
3 (30.0)
M, male; F, female; CMV, cytomegalovirus; HSV, herpes simplex virus; ARN, acute retinal necrosis; VKH, Vogt-Koyanagi-Harada disease; C/BRVO, central/branch retinal vein occlusion; CME, cystoid
macular edema; VA, visual acuity; CF, counting fingers.
407
408 s u r v e y o f o p h t h a l m o l o g y 6 2 ( 2 0 1 7 ) 4 0 4 e4 4 5
2.4. Treatment HSV-1 retinitis is more common in older patients, whereas

HSV-2 retinitis is more likely to occur in younger
The treatment of viral posterior uveitis263,270 includes sys- patients.71,130,240
temic antivirals given orally or intravenously, intravitreal HSV posterior uveitis typically presents with features of
antivirals or intraocular antiviral implants, and topical and ARN or nonnecrotizing herpetic retinitis (NNHR). In children,
systemic corticosteroids.40 Management of complications is HSV-2 retinitis may be due to a delayed reactivation of
also important to ensure a favorable prognosis. Measures asymptomatic neonatal HSV infection.76 HSV posterior uveitis
include photocoagulation for neovascularization, vitrectomy generally has a good prognosis if there is no evidence of ARN.
for vitreous hemorrhage or retinal detachment,10,245 and Often the lesions can be treated with systemic acyclovir and
intravitreal injection of antivascular endothelial growth factor corticosteroids with complete resolution of inflammation.77,199
agent for choroidal neovascularization or macular edema.
2.7.2. Varicella zoster virus
2.5. Outcomes VZV is a double-stranded DNA virus belonging to the her-
pesviridae family.227 VZV causes 2 disease entitiesea primary
Early diagnosis and management may improve the visual infection known as chickenpox that usually occurs during
prognosis of viral posterior uveitis. If diagnosis or treatment is childhood and a secondary herpes zoster, also known as
delayed serious complications can develop, including cata- shingles, a result of its neurotropic properties that allow viral
racts, band keratopathy, uveitic glaucoma, cystoid macula latency in ganglia and subsequent reactivation later in
edema (CME), and retinal detachment.270 All these can lead to life.227,257,270 Transmission of VZV is by direct contact, drop-
permanent vision loss. Ultimately, the long-term outcomes lets, or airborne particles.257 Symptoms of VZV infection
depend on the type of viral posterior uveitis, severity, dura- include fever, malaise, and diffuse rash and vesicles in
tion, responsiveness to treatment, associated conditions or chickenpox and headache, malaise, and painful vesicles in a
medical comorbidities, and immune status of the patient. unilateral dermatomal distribution in shingles, with the
thoracic, cranial, and cervical dermatomes being most
2.6. Human herpesviruses commonly affected.257
VZV posterior uveitis typically presents with features of
The most frequent causes of viral posterior uveitis come from PORN, ARN, or NNHR. VZV is the most common virus found in
the HHV family, with CMV being the most common, followed atypical necrotizing retinitis.70 VZV accounts for approxi-
by HSV and VZV.131,153,188,248 The family of HHV includes mately half of ARN cases in non-HIV patients, more than one-
HSV-1, HSV-2, VZV, Epstein-Barr virus (EBV), and CMV. HHV is third of ARN cases in HIV patients, and more than 70% of
an important infectious cause of ocular inflammation. PORN cases.264 VZV retinitis may occur during concomitant
Primary infection of the virus is followed by persistence in the chickenpox infection in adults, and is rare in children. It is
latent form. Reactivation of the virus in the eye may occur more common in older patients67 and may precede shingles,
in the form of keratitis, anterior uveitis, or retinitis especially in immunocompromised patients.162
(necrotizing and nonnecrotizing). The severity and outcome of VZV retinitis lesions may occasionally spontaneously
ocular disease is influenced by a multitude of factors, regress270 or may be complicated by retinal tears or detach-
including the host immune response, human leukocyte ment and optic neuropathy.149 Visual prognosis is poor if
antigen (HLA) differences, virulence, and possibly intraocular there is ARN or PORN.
viral load.
2.7.3. Epstein-Barr virus
2.7. Etiologic viruses EBV, also known as HHV-4, is a B lymphotropic, double-
stranded DNA virus in the Herpesviridae family. The sero-
2.7.1. Herpes simplex virus positive prevalence of EBV is more than 90% of the population
HSV-1 and HSV-2, also known as human herpes virus 1 and 2, worldwide.9 EBV is spread by direct contact via saliva,
respectively, are double-stranded DNA viruses that belong to airborne, or blood. EBV infection is lifelong but usually clini-
the Herpesviridae family. Both HSV-1 and HSV-2 cause oro- cally silent in immunocompetent hosts.9 Similar to other
facial infections (cold sores), genital herpes, and encephalitis HHV, EBV may be latent. Reactivation of EBV causes diseases
and can be vertically transmitted from infected mothers to usually of a lymphocytic naturedincluding infectious mono-
neonates.261 As a neuroinvasive and neurotoxic virus, HSV nucleosis, lymphoproliferative disordersdor epithelial, such
persists in the latent state in the dorsal root ganglia after the as nasopharyngeal carcinoma and undifferentiated gastric
initial primary infection and occasionally reactivates.261 HSV carcinoma.9
infection is usually asymptomatic, but symptoms of infection Known ocular complications of EBV include conjunctivitis,
include fever and painful blisters in the skin and mucous episcleritis, keratitis, iritis, optic neuritis, ARN, and retinal
membranes of the mouth and genitals.261 There are 2 forms of vasculitis.90,167,192,258 There have been a few reports of EBV
HSV retinitisenecrotizing and nonnecrotizing. Necrotizing infection associated with posterior uveitis.89,90,
118,133,146,192,213,258
herpetic retinitis caused by both HSV-1 and HSV-2 may be Posterior uveitis associated with EBV typi-
found in patients with concomitant HSV encephalitis or HSV cally presents as chorioretinitis. It can occur at any age, and
meningitis.39,67,130,228 Acute retinal necrosis (ARN) with HSV there is usually a preceding history of EBV infec-
encephalitis is more commonly associated with HSV-1, tion.89,118,133,192,213,258 The demographics and clinical features
whereas HSV meningitis is more often caused by HSV-2.67 of EBV posterior uveitis are found in Table 3.89,118,133,192,213,258
Table 3 e Demographics and clinical characteristics of Epstein-Barr virus chorioretinitis
Author Age Gender Laterality Immuno Method of Symptoms Signs VA at Treatment Complications Duration VA at last
(year) (years) deficiency diagnosis presentation of follow- visit
up
(months)
Kelly et al 17 M U Nil Serology Pain, RAPD, AC/vitreous cells, white OS: CF 1/3 m Oral Atrophic 0.25 6/36
(1989)118 blurred fluffy retinitis, retinal clindamycin, macular scar
vision hemorrhage, vitreous haze, prednisolone,
vascular sheathing, optic disk acetazolomide,
edema topical
dexamethasone
Hershberger 0.8 M B X-linked Serology, Unable to RAPD, posterior synechiae, NR Vitrectomy, bone RD, phthisis NR NR
et al lymphoproliferative retinal fix and rubeosis, hazy vitreous, marrow bulbi
(2003)89 disorder biopsy follow widespread yellow-white transplant
retinal opacification, retinal
hemorrhages, RD, optic nerve
swelling and hemorrhage,
vascular sheathing, atrophic
RPE lesions
Kim et al 65 F B Nil Serology, Sudden ERM, coalescing, yellow OD: 20/200; Oral RPE atrophy 6 OD: 20/80
(2011)133 vitreous decreased lesions at the level of the RPE OS: CF valacyclovir, OS: CF
biopsy vision in the macula prednisone
Peponis et al 67 M B EBV encephalitis CSF PCR Progressive Multiple, well-demarcated OD: 6/60; OS: Ceftriaxone, Nil 2 OD: 6/18
(2012)192 decreased gray-white areas of retinal HM ampicillin, OS: CF
vision atrophy, multifocal acyclovir
chorioretinitis, optic neuritis
Schmoll et al 65 F U Aplastic anemia on Anterior Pain, RAPD, anterior uveitis, OS: PL IV acyclovir, Hypotony, 1 PL
(2013)213 immunosuppressive chamber redness, hypotony, vitritis, focal topical progression of
therapy paracentesis blurred retinitis, localized choroidal dexamethasone, retinochoroiditis
vision effusions, hemorrhagic oral
arteriolitis prednisolone,
oral famciclovir
Weller et al 30 M U Nil Serology Paracentral Intraretinal, white sharp- 20/20 IV/oral acyclovir, Nil 1 20/20
(2015)258 scotoma edged macular lesion, topical
surrounded by several smaller prednisolone
intraretinal white-yellow
spots
Summary; Mean: M: 4 B: 3 (50.0); 2 (33.3) Serology, Blurred RAPD, anterior chamber/ Range: 20/20- IV/oral acyclovir, Progression, RD, Mean: 2.05 Improved:
n, % 40.8; (66.7); F: U: 3 (50.0) aqueous/ vision, vitreous inflammation, PL oral valacyclovir, phthisis, Range: 3
range: 2 (33.3) vitreous scotoma, chorioretinitis, hemorrhage, topical/systemic hypotony, 0.25-6 Stable: 2
0.8e67 PCR, retinal pain, vasculitis, optic neuritis corticosteroids atrophy,
biopsy, CSF redness macular scar
M, male; AC, anterior chamber; B, bilateral; CF, counting fingers; CSF, cerebrospinal fluid; EBV, Epstein-Barr virus; ERM, epiretinal membrane; F, female; HM, hand movement; IV, intravenous; NR, not
reported; NPL, no light perception; OD, oculus dexter; OS, oculus sinister; PCR, polymerase chain reaction; PL, light perception; RD, retinal detachment; RPE, retinal pigment epithelium; RAPD, relative
afferent pupillary defect; U, unilateral.
409
410
Table 4 e Demographics and clinical characteristics of Acute Retinal Necrosis
Author Age Gender, Laterality, Immun Viral Method Previous Symptoms, Signs, n (%) VA at Treatment, Complications, Duration VA at last
(year) (years) n (%) n (%) odeficiency, etiology, of herpes n (%) presentation n (%) n (%) of follow- visit
n (%) n (%) diagnosis infection, n up
(%) (months)
Tran et al Mean: 36; M: 6; F: 5 B: 4 (27.2); U: 7 0 HSV-2: 11 Aqueous or Neonatal NR RPE Range: 20/25 IV acyclovir/ RD: 5 (41.7); ERM: 4 Mean: 14.5; Improved: 5
(2004)240 range: 10 vitreous herpes: 1; abnormalities, eCF; <20/60: 4; foscarnet, (33.3); cataract: 5 range: 5e22 (41.7); <20/60:
e57 biopsy previous ARN: neuroretinal 20/70e20/400: 4; intravitreal (41.7); optic nerve 4 (33.3); 20/70
3 atrophy, >20/400: 4 ganciclovir, oral atrophy: 2 (16.7); e20/400: 4
chorioretinal valacyclovir, CME: 1 (8.3) (33.3); >20/
scars interferon, 400: 4 (33.3)
vitrectomy,
laser
Lau et al Mean: M: 10; F: 12 B: 5 (22.7); U: 0 VZV alone: Vitreous Shingles: 2; Flu-like NR Mean: 0.32 Systemic RD: 14/27 (51.9); Mean: 48; Mean: 0.38
(2006)146 49.53.5; 17 9/18 (50.0); biopsy cold sore: 1; symptoms: 1 0.05 corticosteroid, macular lesion: 7 range: 12 0.17
median: HSV alone: Ramsay Hunt (4.5) laser, IV and oral (25.9); e146
51; range: 4/18 (22.2); syndrome: 1; acyclovir, vitreoretinopathy: 7
18e83 EBV þ VZV: corneal vitrectomy (25.9); optic
3/18 (16.7) dendritic ulcer: neuropathy: 3 (11.1);
1 ERM: 1 (3.7);
cataracts: 1 (3.7);
glaucoma: 1 (3.7)
Muthiah Mean: M: 22 B: 3 (9.7); U: 28 7 (22.6) VZV: 9; Aqueous or Herpes Sudden visual AC activity: 25 Range: 6/5eNPL IV antivirals RD: 9/12 (75.0); 12 Worsened:
et al 54.3; (71.0); F: 9 (90.3) HSV-1: 3; vitreous simplex loss: (85.1); (80.6); vitreous (acyclovir, hypotony, CME, 15/34 (44.1);
(2007)179 range: 13 (29.0) HSV-2: 2; biopsy keratitis: (9.7); photophobia: cells: 26 (83.9); ganciclovir, and rubeosis improved: 9/
e85 HSV-1 þ herpes zoster (54.5); flu-like peripheral cidofovir): 23 34 (26.5)
HSV-2: 1; ophthalmicus: symptoms: retinal (85.2); oral
HSV þ VZV: (20.7); cold (26.1); ocular involvement: antivirals
1 sore: (25.0); pain: (25.8); red 25 (80.6) (acyclovir and
genital ulcers: eye: (16.1) valacyclovir): 4
(4.5); (14.8); systemic
encephalitis: steroids: 16
(15.4); chicken (51.6); aspirin: 2
pox: (70.6); (6.5); laser: 5
Shingles: (29.4)
Hillenkamp Mean: 58 M: 16; F: 11 B: 3; U: 24 NR VZV alone: Vitreous NR NR NR Mean: 1.09 IV acyclovir þ RD: 22/30 (73.0); Mean: 38 Mean: 1.46
et al 21; 23; HSV biopsy 0.83; range: 0.1 oral phthisis: 2/30 53; range: 1 0.88; range:
(2009)90 range: 17 alone: 4; e3.0 prednisolone: e216 0.18e3.0
e96 VZV þ EBV: 32; vitrectomy,
2; VZV þ intravitreal
HSV:1 acyclovir, laser:
10
Meghpara Mean: 42 M: 5; F: 15 B: 5 (25.0); U: 0 VZV: 2; Vitreous Chicken pox: 7 NR Retinal NR IV acyclovir/ RD: 5 (25.0) Mean: 20.4 Improved: 4;
et al 19; 15 (75.0) CMV: 1 biopsy (35.0); cold involvement: foscarnet: 14 20.5; range: worsened: 5
(2010)172 range: 9 sore: 5; <25%: 11 (44.0), (70.0); oral 0.3e57.9
e77 shingles: 2; 25e50%: 8 acyclovir/
genital ulcers: (32.0), >50%: 6 valacyclovir/
1; pharyngeal (24.0); optic famciclovir: 19
herpes: 1 disk swelling: 6 (95.0);
intravitreal
ganciclovir/
foscarnet: 11
(44.0);
ganciclovir
implants: 2
(8.0%); laser: 6
(24.0)
Cochrane Range: 10 M: 25 B: 7 (15.6); U: 13 (28.9) VZV alone: Aqueous Chicken pox: 9 NR NR NR Oral antivirals: RD: 16/52 (30.8); 6 <6/60: 21
et al e94 (55.6); F: 20 38 (84.4) 15; HSV tap, vitreous (20.2); 11 (24.4; 8 with phthisis: 2/42 (4.7) (47.7)
(2012)42 (44.4) alone: 9; biopsy, or Shingles/ valacyclovir); IV
CMV alone: CSF lumbar herpes zoster antivirals: 34;
2; EBV puncture ophthalmicus: intravitreal
alone: 1; 6 (13.3); antivirals
VZVþEBV: encephalitis/ (foscarnet): 21
2; meningitis: 7 (46.7); oral
VZVþCMV: (15.6) steroids: 26
1 (57.8); aspirin:
14/43 (32.6);
laser: 10 (23.2)
Roy et al Mean: M: 38 B: 9 (17.0); U: 2 VZV: 28 Aqueous or Chicken pox: 4 Hazy vision: 53 Retinal Mean: 2.02 Oral steroids, RD: 41 (66.1); Mean: 27; Mean: 1.78;
(2014)205 36.0; (71.7); F: 15 44 (83.0) (45.2); HSV: vitreous (7.5); herpes (100.0); necrosis systemic proliferative range: 6e120 <6/60: 28
range: 6 (28.3) 19 (30.6) biopsy encephalitis: 1 headache/ acyclovir, laser, vitreoretinopathy: 14 (45.1)
e70 periocular pain: vitreoretinal (35.0); optic atrophy:
10 (18.9); viral surgery 10 (29.4); phthisis: 4
fever: 4 (7.5) (11.7); hypotony: 3
(8.8); macular scar: 1
(2.9)
Summary; Mean: M: 122 B: 36 (17.2); U: 22 (12.1) VZV alone: Aqueous or Chicken pox: Vision loss, AC Range: 6/5-NPL Systemic/ RD: 112 (53.6); Mean: 23.7; Majority
n, % 46.0; (58.4); F: 87 173 (82.8) 86 (41.1); vitreous 42 (20.1); ocular pain, inflammation; intravitreal phthisis: 8 (3.8); range: 0.3 worsen or no
range: 6 (41.6) HSV alone: biopsy, CSF shingles: 19 photophobia, retinal antivirals, macular lesion: 13 e216 improvement
e96 53 (25.4); (9.1); cold sore: flu-like necrosis, RPE systemic/topic (6.2); optic
CMV: 4 (1.9); 14 (6.7); herpes symptoms, red abnormality, steroids, aspirin, neuropathy/atrophy:
EBV: 8 (3.8) encephalitis: eye neuroretinal prophylactic 15 (7.2); cataracts:6
13 (6.2); others: atrophy, laser, (2.9); others: CME,
neonatal chorioretinal vitrectomy rubeosis,
herpes, herpes scars vitreoretinopathy
simplex
keratitis,
genital ulcers
AC, anterior chamber; ARN, acute retinal necrosis; B, bilateral; CME, cystoid macular edema; CF, counting fingers; CSF, cerebrospinal fluid; EBV, Epstein-Barr virus; ERM, epiretinal membrane;
F, female; HM, hand movement; HSV, herpes simplex virus; IV, intravenous; M, male; NR, not reported; NPL, no light perception; PCR, polymerase chain reaction; PL, light perception; RD, retinal
detachment; U, unilateral; VA, visual acuity; VZV, varicella zoster virus.
411
The role of EBV as a pathogen in the eye is unclear, as up to 2.8. Acute retinal necrosis
20% of normal cadaver eyes have intraocular evidence of EBV
by PCR.38 Most cases of ARN in which EBV is positive on PCR 2.8.1. Background
are also simultaneously positive for VZV.90,146 There are a few ARN, a severe, sight-threatening ocular emergency, was initially
case reports of ARN that were only positive for EBV on PCR and described in 1971 by Urayama and colleagues246 in healthy
histopathologic evidence in the retinal biopsy young Japanese adults as an acute unilateral panuveitis with
specimen.89,133,213 retinal periarteritis progressing to diffuse necrotizing retinitis
In general, EBV posterior uveitis appears to be as self- with retinal detachment. ARN is rare, with an incidence of 1 of 2
limited as infectious mononucleosis.192,258,270 Treatment of million individuals per year in the UK.42,179 There is a 2-peak age
EBV posterior uveitis is supportive and may include cortico- distributiond20 and 50 years old, and both genders are equally
steroids for intraocular inflammation118 and antivirals such as affected.270 The demographics and clinical features of ARN are
oral valacyclovir 1 g 3 times daily,133 acyclovir 400 mg 5 times found in Table 4.42,90,146,172,179,205,240
daily,258 or famciclovir,213 and monitoring for resolution. The ARN is usually found in immunocompetent individuals,73
visual prognosis in EBV posterior uveitis is generally good. but the risk factors for ARN include a younger age, history of
Vision usually improves and intraocular inflammatory signs previous herpes infections such as chickenpox, shingles and
resolve rapidly, with near complete recovery in the majority of HSV encephalitis, preexisting chorioretinal scar, trauma,
the cases.118,133,192 systemic corticosteroids, and genetics.42,96,146,172,179,205,240
ARN can present without a viral prodrome many years after
2.7.4. Cytomegalovirus the initial primary herpes infection or following herpetic
CMV, or HHV-5, is a double-stranded DNA virus that belongs encephalitis.42,130,205
to the Herpesviridae family. Primary CMV infection is trans-
mitted perinatally, by close contact, including sexual contact, 2.8.2. Causative viruses
or parenterally.270 The seropositive prevalence worldwide is VZV is the leading cause of ARN.146 Patients with ARN caused
between 60% and 100%.197 It is usually asymptomatic in by VZV and HSV-1 tend to be older, whereas HSV-2 is found in
immunocompetent hosts.270 An infectious mononucleosis- younger patients.42,130 Rarely, ARN may be caused by CMV and
like syndrome develops in some patients, whereas more se- EBV.42,90,137,146,172,210
vere diseases may manifest in immunocompromised patients
in the form of encephalitis, pneumonitis, hepatitis, colitis, and 2.8.3. Clinical features
uveitis.197,270 The virus remains latent in mononuclear lym- Symptoms of ARN include redness, blurring of vision, photo-
phocytes in immunocompetent hosts and only reactivates phobia, floaters, ocular pain, and flu-like symptoms or recent
when immunity is suppressed.197,270 history of herpes infection.146,179,205,270 Bilateral involvement
The most frequent ocular manifestation of CMV is CMV occurs in approximately one-third of patients, but some cases
retinitis.108 Rarely, CMV may cause ARN42,172 and optic start off as a unilateral disease with subsequent involvement
neuritis.161 of the second eye.172,205
Characteristic features on examination include prominent
anterior chamber inflammation and vitritis, peripheral
necrotizing retinitis with focal areas of full thickness necrotic
lesions, circumferential extension of necrotic foci, and
occlusive vasculitis with arteriolar narrowing.93
Table 5 e Diagnostic criteria of acute retinal necrosis by
the American Uveitis Society ARN often occurs in 2 phases, the acute herpetic phase
consisting of anterior uveitis and vitritis, peripheral confluent
Clinical characteristics that Characteristics that
necrotizing retinitis with well-demarcated areas of full
must be seen support but are not
required for diagnosis thickness yellow necrotic lesions, hemorrhages, occlusive
vasculopathy, and rapid progression circumferentially toward
One or more focus of retinal Optic neuropathy/atrophy
the posterior pole. The late cicatricial phase consists of
necrosis with discrete borders Scleritis
secondary retinal atrophy, proliferative vitreoretinopathy,
located in the peripheral retina Pain
(primarily involving the area and serous or rhegmatogenous retinal detachment.42,
56,90,146,172,179,205,240
adjacent to, or outside of, the
major temporal vascular arcades). The severity of the disease is classified according to the
Rapid progression of disease amount of surface area affectedemild (less than 25%), mod-
(advancement of lesion borders erate (25%e50%), and severe (more than 50%).172 The severity
or development of new foci of
of retinitis at presentation may be predictive of retinal
necrosis) if antiviral therapy
is not given
detachment risk and final visual outcome. There is a correla-
Circumferential spread of disease tion between mean initial and subsequent visual acuities with
Evidence of occlusive the severity of retinitis.172,205
vasculopathy with arteriolar
involvement 2.8.4. Diagnosis
Prominent inflammatory
Diagnosis of HHV posterior uveitis can be made clinically
reaction in the vitreous and
based on history and signs seen on complete ophthalmologic
anterior chambers
examination and supported with laboratory testing of viral
Table 6 e Antiviral treatment modalities for herpes human virus posterior uveitis
Type of drug Route of Doses Duration Mechanism of action Indications Side effects
administration
Antivirals
Acyclovir induction6,26,56 Intravenous 10 mg/kg every 5 to 10 days A nucleoside analog that ARN, PORN Reversible rise in serum
8 hours or 1500 selectively inhibits creatinine levels, urinary
mg/m2 per day replication of HSV, VZV and calculi, elevation in liver
Acyclovir maintenance6,26,56 Oral 800 mg 5 times 6 weeks EBV. Acyclovir is converted ARN, PORN function tests, central
daily into acyclovir triphosphate, nervous system toxicity
Acyclovir7,258 Oral 400 mg 5 times 4 weeks, then which inhibits viral DNA EBV such as lethargy, delirium,
daily tapered slowly polymerase, resulting in chorioretinitis seizures.
800 mg 5 times 4e8 months chain terminations and NNHR
daily mutations.
Valacyclovir2,6,15,27,60,79,133 Oral 1 g 3 times daily Slowly tapered The L-valyl ester of acyclovir ARN, PORN, Headache, gastrointestinal
or 2 g 4 times over 2e6 months is rapidly converted to NNHR, EBV disturbances, nausea, with
daily acyclovir, producing chorioretinitis similar side effects as
acyclovir blood levels 3e5 acyclovir but to a lesser
times greater, with extent.
bioavailability of 54%
compared with 20% for
acyclovir.
Famciclovir6,15,60,213 Oral 500 mg 3 times Slowly tapered Rapidly converted to a highly ARN, EBV Well-tolerated, similar side
daily over 2e6 months bioavailable penciclovir chorioretinitis effect profile as acyclovir.
which is converted to a
triphosphate that
preferentially inhibits viral
DNA polymerase.
Foscarnet265 Intravitreal 2.4 mg/0.1 mL 2e4 injections A pyrophosphate analog ARN, PORN, EBV Systemic foscarnet may
that selectively inhibits chorioretinitis cause nephrotoxicity,
pyrophosphate binding site hypocalcemia, anemia and,
on viral DNA polymerases of nausea. Risks of intravitreal
HHVs but is not activated by injections include cataract,
thymidine kinase. infection, vitreous
hemorrhage, retinal
detachment.
Ganciclovir134,155,171,193 Intravitreal 4 mg/0.1 mL or 2e4 injections An acyclic analog of the ARN, PORN Greater systemic toxicity
400 mg twice nucleoside guanosine. and cytotoxicity including
per week Differs from acyclovir by the neutropenia, anemia,
lack of hydroxyl group on nephrotoxicity, diarrhea.
the acyclic side chain, with Risks of intravitreal
enhanced activity against injections as previously
CMV, but similar activity described.
against HSV and VZV.
ARN, acute retinal necrosis; CMV, cytomegalovirus; EBV, Epstein-Barr virus; HHVs, human herpesviruses; HSV, herpes simplex virus; NNHR,
nonnecrotizing herpetic retinitis; OD, oculus dexter; OS, oculus sinister; VZV, varicella zoster virus; PORN, progressive outer retinal necrosis.
serology. Viral antibodies may be detected with complement corresponding to areas of retinal necrosis. There may be
fixation test, immunofluorescence, or enzyme-linked immu- subretinal exudates and macular edema.183,230 With resolu-
nosorbent assay (ELISA) techniques.270 PCR analysis of intra- tion, there is marked inner and outer retina thinning within
ocular fluids is particularly useful and commonly done to areas of retinal necrosis and resolution of the hyperreflectivity
confirm the etiological viruses involved in cases of consistent with retinal tissue loss and scar formation, even
ARN.42,90,146,172,179,205,240 Specifically, the diagnosis of ARN can when funduscopy is normal.183,230 This suggests that regres-
be summarized by the diagnostic criteria established by the sion of necrotic lesions does not mean normalization of the
executive committee of the American Uveitis Society93 retinal structure, and retinal breaks may still occur.230 Thus,
(Table 5). OCT is useful to monitor for early signs of retinal detach-
Ocular imaging may be used to determine the extent of ment.183 The necrotizing lesions extending into the macula
disease. FFA may show dye leakage from retinal vessels, are associated with irreversible damage and may lead to poor
choroid, RPE, or optic disk and is useful for confirming the central vision.183 These findings are similar to those observed
diagnosis of co-existing pathologies such as CME, vascular in central retinal artery occlusion as the necrotic lesions likely
occlusion, and retinal or choroidal neovascularization.81,255 reflect ischemic changes caused by obstructive retinal
OCT scan is useful for establishing the extent and depth of vasculitis.230
lesions and monitoring response to therapy. OCT scans may
demonstrate full thickness tissue loss in necrotizing herpetic 2.8.5. Treatment
retinitis and demarcate the extent, depth, and thickness of The goals of treatment in necrotizing herpetic retinitis are to
macular edema or retinal detachment.23,81 eliminate active viral infection in the eye, stop progression of
In the acute phase of ARN, OCT shows inner retina retinal necrosis to avoid complications such as retinal
hyperreflectivity with disorganization of the retinal structure, detachment and optic atrophy, prevent fellow eye
involvement, and mitigate ocular damage from the host im- prophylactic panretinal photocoagulation. Conversely, pro-
mune response. Treatment should begin immediately after a phylactic vitrectomy may select for more severe cases of ARN.
clinical diagnosis is made without waiting for the laboratory Park and colleagues187 critically reviewed the role of laser
results. Details of the various pharmacologic treatment mo- photocoagulation in patients with ARN. Laser treatment does
dalities for HHV posterior uveitis are found in Table 6. not prevent the progression of retinitis but forms a barrier
Antivirals are the mainstay of treatment for ARN. The posterior to the involved retina to form a stronger chorior-
standard of care used to be inpatient hospitalization and in- etinal adhesion posterior to the retinal breaks, hence pre-
duction with intravenous (IV) acyclovir 10 mg/kg every 8 hours venting potential retinal detachment. Though there are a
or 1500 mg/m2 per day for 5 to 10 days, followed by mainte- number of studies showing the benefit of prophylactic laser
nance with oral acyclovir 800 mg 5 times daily for an addi- versus no laser, there are no randomized control trials, and all
tional 6 weeks.6,26,56 Acyclovir is a synthetic acyclic purine- are retrospective studies.187
nucleoside analogue that is viral static and stops viral repli- Although there are several aspects of management of ARN,
cation by inhibiting DNA polymerase.26 There has, however, the long-term outcomes depend on the severity, duration, and
been a shift in recent years toward outpatient management of comorbidities of the patient. Final visual acuity may be poor
HSV- and VZV-associated posterior uveitis with the newer despite optimal treatment, especially in cases where the optic
oral and intravitreal antivirals. Newer oral antivirals such as disk or macula is involved.5,25,90,170
valacyclovir (a prodrug of acyclovir) and famciclovir have
greater bioavailability and systemic concentrations similar to 2.8.6. Outcomes
that of IV acyclovir.6,15,60,102 Thus, they may be used as in- ARN is a severe, blinding disease with poor visual outcomes.
duction agents. A few studies reported that all patients treated Two-third of eyes has a final best corrected visual acuity of 6/
with either oral valacyclovir 1 g 3 times daily or oral famci- 60 or worse.205,240,270 Complications include extension of
clovir 500 mg 3 times daily had complete resolution of retinitis retinal necrosis, involvement of the second eye in more than
without the need for IV acyclovir therapy.6,15,60 To achieve a one-third of untreated cases, retinal detachment (up to 75% of
similar area under the curve as IV acyclovir, oral agents must untreated eyes), optic atrophy, CME, neovascularization, sec-
be used in high doses. There are only data for valacyclovir in ondary vitreous hemorrhage, epiretinal membrane, cataracts,
this regard. Higher oral doses of valacyclovir 2 g 4 times daily and phthisis or hypotony.41,42,56,58,90,146,172,179,184,205,239 Early
are well tolerated and produce a daily area under the curve diagnosis and proper treatment are critical to reduce the
similar to that of IV acyclovir 10 mg/kg every 8 hours.2,79 impact of these complications.
Antiviral agents can also be delivered via intravitreal in-
jections in cases of severe retinitis or that refractory to sys-
temic antiviral therapy. This may be done immediately after 2.9. Progressive outer retinal necrosis
diagnostic sampling of intraocular fluid is taken. Intravitreal
foscarnet 2.4 mg/0.1 mL has been used successfully to treat 2.9.1. Background
ARN caused by HSV and VZV.265 Intravitreal ganciclovir 4 mg/ PORN is a highly destructive and rapidly progressive variant of
0.1 mL may be effective in treating necrotizing herpetic reti- ARN found almost exclusively in immunocompromised in-
nitis in immunocompetent patients.134,155 dividuals such as AIDS patients with low CD4þ T-lymphocytes
Besides antivirals, systemic corticosteroids such as oral count75,94,191,241 or posttransplant recipients.114,128,244 The
prednisone 40e80 mg daily, topical, or intravitreal cortico- demographic factors and clinical characteristics of PORN are
steroids can be added to the treatment regime in cases with found in Table 7.75,114,128,191,241,244 PORN occurs in people be-
significant inflammation, such as severe vitritis, serous retinal tween the ages of 20 to 50 years, has a male predominance,
detachment, and retinitis or vasculitis involving the mac- and is usually bilateral.75,114,128,191,241,244
ula.40,258 This, however, should only be done after initiation of
antiviral therapy, as the corticosteroids may promote viral 2.9.2. Causative viruses
replication.258 PORN is almost exclusively caused by VZV16,75,114,128,191,241,244
Surgery is performed for complications of ARN. Retinal and may be associated with a previous or concurrent history
detachment occurs in up to 3 quarters of ARN cases.25,41,146 of herpetic disease such as herpes zoster.75,114,128,191,241,244
Pars plana vitrectomy, lensectomy, air-fluid exchange, endo-
laser, gas, or silicone oil tamponade is performed for reat- 2.9.3. Clinical features
tachment and recovery of vision.5,25,90,170 Other than PORN may present with acute or progressive blurring of
treatment of retinal detachment that has already occurred, vision, scotoma, and other visual field defects, but there is no
early prophylaxis can also be considered in severe cases, as it pain or photophobia unlike in ARN.75,104,114,128,191,241,244 There
has been found to lower the risk of retinal detachment in eyes is minimal nongranulomatous anterior uveitis and vitri-
where necrotic lesions do not extend beyond the mid- tis.191,241 Extensive multifocal necrotizing chorioretinitis be-
periphery.103 The role of prophylactic panretinal photocoag- gins at the posterior pole and spreads toward the peripheral
ulation or prophylactic vitrectomy in patients with ARN is retina. There are peripheral confluent satellite lesions that
controversial. There is ongoing debate about whether or not coalesce rapidly.114,175,191,241,244 The characteristic macular
prophylactic panretinal photocoagulation provides any pro- lesion is a white, necrotic parafoveal opacification with a
tection. The issue is that there may be a selection bias. Milder central cherry red spot.175,191 There is RPE mottling, but
cases of ARN may get laser because the media is clear and absence of vascular inflammation and minimal hemor-
detach less frequently due to milder disease not prophylactic rhage.128 Optic disk involvement can masquerade as papillitis
Table 7 e Demographics and clinical characteristics of progressive outer retinal necrosis
Author Age Gender Laterality Immuno- Viral Method Previous Symptoms Signs VA at Treatment Complications Duration VA at
(year) (years) deficiency etiology of herpes presen- of last visit
diagnosis infection tation follow-
up
(months)
Pavesio 33 M B HIV þ CD4þ VZV Vitreous Thoracic Acute vision Parafoveal white lesion OD: 6/6; IV acyclovir/ RD 2 OU: NPL
et al count: 1 biopsy shingles loss with central cherry red OS: 1/60 foscarnet,
(1995)191 cell/mm3 spot, optic disk edema, intravitreal
peripheral confluent acyclovir, laser
satellite lesions photocoagulation,
vitrectomy
37 M U (OD) HIV þ CD4þ VZV Vitreous Concurrent Acute vision Mild right anterior OD: PL IV acyclovir, RD 12 “Poor
count: biopsy left loss uveitis, bilateral vitritis, intravitreal visual
14 cells/mm3 CMV retinitis large white macular acyclovir prognosis”
lesion, multiple
peripheral white lesions
Greven 41 M B HIVþ VZV Retinal Herpes Vision loss, Outer retinal and OU: 20/25 Trimethoprim/ Retinal and optic 4 OU: NPL
et al biopsy zoster paracentral choroidal infiltrates sulfamethoxazole, atrophy, RD
(1995)75 dermatitis scotoma IV acyclovir,
pyrimethamine,
pentamidine,
clindamycin, IV
ganciclovir
Kalpoe 24 M B Stem cell VZV Aqueous Cutaneous Acute vision AC cells, yellow OS: 0.2; IV acyclovir, Involvement of 6 OS: 1/300;
et al transplant tap herpes loss chorioretinal dots, OD: 1.0 tobradex, fellow (OD) eye after OD: 0.4
(2005)114 zoster exudative RD; coalescing vitrectomy, IV and 4 weeks
peripheral retinal intravitreal
necrosis foscarnet, laser
Khot 51 M B Stem cell VZV Vitreous Thoracic Left visual RAPD, extensive OU: 6/9 IV foscarnet, RD, optic disk 1 OD: 6/60;
et al transplant biopsy shingles field defect peripheral pigmented prednisolone, IV edema, macular OS: NPL
(2006)128 mottling, hemorrhage ganciclovir/ involvement
cidofovir,
intravitreal
foscarnet, IVIG, oral
valacyclovir
Turno- 41 F B Kidney VZV; Vitreous Mucocutaneous Progressive Mild vitritis, white deep OD: 20/35; IV ganciclovir, RD 1 OD: NPL;
Kre˛cicka transplant BK virus biopsy HSV infections vision loss retinal infiltrate in OS: 20/ intravitreal OS: PL
et al posterior pole, retinal 100 ganciclovir,
(2015)244 atrophy, vascular vitrectomy
sheathing
Tseng 45 M B HIVþ VZV Aqueous Cutaneous Progressive Multifocal, patchy OD: HM; Oral/IV/intravitreal Obliterative 1 OU: NPL
et al tap herpes zoster vision loss choroidal, and deep OS: PL ganciclovir, vasculitis, CRVO
(2015)241 retinal opacification sulfamethoxazole,
with dot and blot trimethoprim,
hemorrhage HAART, aspirin, IV
valganciclovir/
famciclovir, laser
Summary; Mean: M: 6 B: 6 (85.7); HIV: 4; VZV Vitreous Herpes zoster Vision loss, Minimal AC/vitreous Range: Systemic/ RD: 5 (71.4); optic Mean: Worsened:
n, % 38.9; (85.7); U: 1 (14.3) Transplant: 3 biopsy, scotoma, inflammation, 6/6-PL intravitreal disk involvement, 3.9; 7
range: F: 1 aqueous tap, visual field multifocal white-yellow antivirals, laser, CRVO, involvement range:
24e51 (14.3) retinal defect choroidal and retinal vitrectomy of fellow eye 1e12
biopsy lesions, hemorrhage
415
AC, anterior chamber; ARN, acute retinal necrosis; B, bilateral; CMV, cytomegalovirus; CRVO, central retinal vein occlusion; F, female; HAART, highly active antiretroviral therapy; HSV, herpes simplex
virus; HM, hand movement; IV, intravenous; IVIG, intravenous immunoglobulin; M, male; NR, not reported; NPL, no light perception; OD, oculus dexter; OS, oculus sinister; OU, oculus uterque; PORN,
progressive outer retinal necrosis; RD, retinal detachment; U, unilateral; VZV, varicella zoster virus.
or neuroretinitis with the presence of relative afferent pupil- 2.9.6. Outcomes

lary defect.191 PORN has a poor visual prognosis with rapid and profound
vision loss. Two-thirds of eyes progress to no light percep-
2.9.4. Diagnosis tion.57,75,128,191,241,244 PORN tends to have a worse prognosis
Diagnosis of PORN is based on the diagnostic criteria than ARN because PORN does not respond as well to antiviral
described by Engstrom and colleagues57 which includes clin- therapy. Complications of PORN include retinal detachment in
ical history and fundoscopic findings of well-demarcated, 70% of cases, optic disk edema or atrophy, vitreous
multifocal, coalescing, and deep or full thickness areas of hemorrhage, macular edema, and involvement of the fellow
predominantly posterior retinal necrosis in immunocompro- eye.73,75,114,128,191,241,244
mised patients, supported with laboratory testing of VZV
and HIV serology, and PCR analysis of intraocular fluids
for VZV. 2.10. Cytomegalovirus retinitis
In PORN, although it may appear clinically as an outer
retinal necrosis, OCT shows widespread full thickness 2.10.1. Background
neurosensory retina loss, particularly as the disease pro- CMV retinitis is a form of opportunistic viral posterior uveitis
gresses.23,241 Similarly to ARN, OCT findings in acute PORN are that occurs mostly in severely immunocompromised AIDS
similar to those in central retinal artery occlusion. At pre- patients195 or, rarely, in those on immunosuppressive therapy
sentation, there is extensive perifoveal retinal thickening with after organ transplantation or who are on systemic cortico-
hyperreflectivity corresponding to the retinal edema and steroids.4,100,105,108,139,140,189,214 75%e85% of AIDS patients with
posterior shadowing.11 At resolution, however, there is total CD4þ counts less than 50 cells/mL have CMV reti-
loss of identifiable retina layers corresponding to areas of nitis.97,100,105,195,254 CMV retinitis is the most frequent
retinal necrosis unlike a diffuse retinal thinning seen in cen- manifestation of CMV disease among AIDS patients and
tral retinal artery occlusion.11 accounts for 75%e85% of all CMV end-organ disease.108
Rarely, CMV retinitis may occur in immunocompetent
2.9.5. Treatment individuals, although these patients usually have some degree
As PORN tends to progress rapidly, early initiation of aggres- of immune dysfunction, such as advanced age, diabetes
sive systemic and intravitreal antiviral therapy (a combina- mellitus, corticosteroid, and noncytotoxic immunosuppres-
tion of ganciclovir, acyclovir, cidofovir, and foscarnet) is sive medication use.214
important to arrest the progression of retinitis, induce CMV retinitis can occur at almost any age, but is most
remission, prevent involvement of the fellow eye, and main- common between the ages of 30 and 60. Most patients are
tain useful vision.114,191,241 males.4,100,105,108,140,189,214 CMV retinitis usually begins as a
Similarly to ARN, antivirals are the mainstay of treatment. unilateral disease, but progresses to involve the contralateral
Acyclovir, ganciclovir, foscarnet, and cidofovir block the eye within 6 months in about 20% of cases, presumably from
replication of VZV by selectively inhibiting viral DNA poly- hematogenous spread.119,140 The disease follows a chronic
merase.244 Systemic antiviral therapy includes IV foscarnet clinical course.214 The demographics and clinical character-
24 mg/mL 3 times daily,114 IV ganciclovir 5 mg/kg/ istics of CMV retinitis can be found in
24 h,128,241,244 IV cidofovir128 or IV acyclovir.191 PORN may have Table 8.4,100,105,108,140,189,214
a poor response to IV acyclovir therapy alone.241 A combina-
tion therapy of IV ganciclovir and foscarnet, intravitreal gan- 2.10.2. Clinical features
ciclovir combined with IV acyclovir or foscarnet, or CMV retinitis is asymptomatic in 50% of cases, and symptoms
intravitreal ganciclovir with foscarnet results in better visual include blurred vision, floaters, scotomata, and ocular
outcomes.241 Intravitreal ganciclovir 4 mg/0.1 mL171,193,241,244 discomfort.4,100,105,108,140,189,214,270 Acute complaints such as
or intravitreal foscarnet 1.2 mg/0.05 mL114,128 has been effec- pain, redness, and photophobia are typically absent.214
tive in treating PORN in immunosuppressed patients. When CMV retinitis presents with mild anterior segment
response to treatment is observed, patients may also be given inflammation, including keratic precipitates, anterior cham-
maintenance of oral valacyclovir 1 g 3 times daily,128 ber cells, and minimal vitritis.189 The distinguishing feature is
valganciclovir, or famciclovir.241 Oral prednisolone a single focus of full thickness yellow-white necrotizing
128
40 mg/day may be given to reduce intraocular inflammation granular retinitis in the peripheral retina with a perivascular
such as vitritis. distribution that expands centrifugally.100,214,270 There may be
Surgery may be performed for complications of PORN. vitritis, retinal hemorrhage, and vasculitis, usually in the form
Panretinal photocoagulation can be performed for extensive of retinal arteritis,4,100,105,108,140,189,214 which have been
full thickness necrosis,114,241 although prophylactic described as a “pizza pie retinopathy.”189 CMV posterior uve-
photocoagulation in preventing retinal detachment is not itis may also present as an optic neuritis.161
useful in most patients.241 Retinal detachment may be treated There are 2 stages in CMV retinitis. The first stage is an
by vitrectomy with silicon oil tamponade.244 active retinitis. Three patterns of active retinal lesions have
In AIDS patients, highly active antiretroviral been described: fulminant/edematous, indolent/granular, and
therapy (HAART) may benefit by lowering the HIV viral load exudative.254 The fulminant/edematous form consists of large
and maintaining high CD4þ T-cell counts.241 Maintenance areas of retinal hemorrhage in a background of confluent
therapy is necessary despite immune recovery after retinal necrosis.254 The indolent/granular pattern consists of
HAART.241 granular satellite lesions with little or no hemorrhage.254 The
Table 8 e Demographics and clinical characteristics of cytomegalovirus retinitis
Author (year) Age Gender Laterality Immunodeficiency Method Symptoms Signs VA at Treatment Complications Duration VA at last
(years) of presentation of follow- visit
diagnosis up
(months)
Kuo et al Mean: 50; M: 13; F: B: 12; U: 6 Immunosuppressive NR Blurred Necrotizing >20/50: 11 IV ganciclovir, Involvement of 12 >20/50: 17
(2004)140 Median: 58; 5 drugs: 18 vision, retinitis, (37%); >20/ ganciclovir second eye, RD, IRU, (58%); >20/200:
range: 14 floaters, intraretinal 200: 5 (20%) implant, posterior 13 (45%)
e74 scotoma hemorrhage, intraocular subcapsular
with granular or foscarnet, sub- cataract, CME, ERM,
edematous Tenon optic atrophy
borders corticosteroid
Jabs et al Mean: 41 M: 224; B: 97; U: HIVþ: 271; CD4þ <50: Clinical NR Necrotizing NR Ganciclovir Progression of NR NR
(2004)108 F: 47 174 34.0%; CD4þ 50e99: retinitis, implant: 42.2%; retinitis,
12.7%; CD4þ 100 atrophic and systemic involvement of
e199: 17.5%; CD4þ gliotic scar ganciclovir: 17.5%; second eye, RD, IRU
200: 35.8% Intravitreal
injection: 3.0%;
HAART: 79.8%
Pathanapitoon Mean: 49; M: 11; F: B: 4; U: 14 Immunosuppressive Aqueous NR Focal NR Systemic/ ERM, RD, traction Mean: 24; NR
et al (2013)189 range: 29 7 drugs: 11; primary PCR hemorrhagic intraocular range: 3
e65 immunodeficiency: 1 retinitis, ganciclovir, e60
granular vitrectomy
retinitis, ARN,
vitritis, retinal
arteritis, frosted
branch angiitis
Schneider et al Mean: 71.0; M: 4; F: 1 B: 1; U: 4 Immunosuppressive Aqueous/ Progressive Slowly OS: PL IV ganciclovir, oral Retinal Mean: OS: HM
(2013)214 median: drugs: 2 vitreous vision loss, progressive OD: HM valganciclovir, neovascularization, 13.2; OD: HM
74; range: PCR, floaters, granular OS: 20/25 intravitreal vitreous range: 7 OS: 20/20
48e83 retinal scotoma retinitis, OD: 20/30 foscarnet, hemorrhage, RD, e21 OD: 20/30
biopsy occlusive OS: 5/200 panretinal phthisis OS: HM
panretinal photocoagulation,
vasculitis, vitrectomy
retinal
hemorrhages,
optic neuritis
Jabs et al Median: M: 196; B: 88; U: HIVþ: 250; median Clinical NR Full thickness Mean: 20/42 HAART, oral RD, IRU, visual field Mean: 60; >20/40: 27.8%;
(2013)106 40.0; range: F: 54 162 CD4þ count: 20 necrotizing valganciclovir, IV loss, second eye range: 20.4 >20/200: 12.4%
34e45 retinitis ganciclovir/ involvement e90
cidofovir/
foscarnet,
intravitreal
ganciclovir/
foscarnet,
ganciclovir
implant
417
(continued on next page)
418
Table 8 e (continued )
Author (year) Age Gender Laterality Immunodeficiency Method Symptoms Signs VA at Treatment Complications Duration VA at last
(years) of presentation of follow- visit
diagnosis up
(months)
Agarwal et al Mean: M: 6; F: 4 B: 8; U: 2 Immunosuppressive Clinical, Blurred Vascular Mean: Intravitreal IRU, posterior Mean: 9.46 Mean:
(2014)4 33.7 15.7; drugs: 8 vitreous vision, sheathing, CMV 0.51 0.41; ganciclovir subcapsular 12.42 0.43 0.52;
range: 11 PCR floaters lesions range: 0e1.9 cataracts, RD, CME, range: 0e1.9
e63 ERM
Huang et al Mean: 38 M: 58; F: B: 37; U: 30 HIVþ: 67; mean CD4þ NR Ocular Perivascular <0.05: 23; 0.05 HAART, IV Macular necrosis, Range: 5 No
(2015)100 9; range: 18 9 count: 31.7 33.9 discomfort, yellowish white e0.3: 31; >0.3: ganciclovir/ RD, cataracts, IRU e44 improvement:
e60 blurred necrotic retinal 44 foscarnet, oral/ 26 (33.3%);
vision, infiltration with intravitreal improved: 39
visual field granular ganciclovir (50.0%); <0.05:
defects, borders, 28.9%
floaters intraretinal
hemorrhages,
retinal
vasculitis, optic
neuritis
Summary; n, % Mean: 47.1; M: 512 B: 247 HIVþ: 588 (92.0); Clinical, Blurred Necrotizing Range: 20/20- HAART, systemic/ Progression, second Mean: Majority no
range: 11 (80.1); F: (38.7); U: immunosuppressive aqueous/ vision, retinitis, retinal PL intraocular eye involvement, 23.7; improvement
e83 127 392 (61.3) drugs: 39 (6.1) vitreous floaters, hemorrhage, valganciclovir, RD, IRU, CME, ERM, range: 3
(19.9) PCR scotoma, vasculitis, optic ganciclovir, cataracts, phthisis, e90
ocular neuritis cidofovir, neovascularization,
discomfort foscarnet, optic atrophy
vitrectomy,
corticosteroid
ARN, acute retinal necrosis; B, bilateral; CMV, cytomegalovirus; CME, cystoid macular edema; EBV, Epstein-Barr virus; ERM, epiretinal membrane; F, female; HAART, highly active antiretroviral
therapy; HM, hand movement; HSV, herpes simplex virus; IV, intravenous; IRU, immune recovery uveitis; M, male; NPL, no light perception; NR, not reported; OD, oculus dexter; OS, oculus sinister; PL,
light perception; PORN, progressive outer retinal necrosis; RD, retinal detachment; RPE, retinal pigment epithelium; U, unilateral.
exudative pattern, also known as frosted branch angiitis, has optic atrophy, and rhegmatogenous retinal detachment in up
extensive vascular sheathing.154,189 The second stage is to one-third of eyes.100,209 The strongest predictor for retinitis
widespread necrosis and retinal tears. In quiescent disease, progression, involvement of the contralateral eye, and risk of
there is retinal atrophy with fibrosis, calcification, and scle- retinal detachment is low CD4þ T-cell counts less than
rotic vessels.270 50 cells/mL.108 CMV necrotizing retinitis can be differentiated
from ARN by increased rates of neovascular complications
2.10.3. Diagnosis and decreased rates of retinal detachment.214
CMV retinitis is diagnosed clinically on indirect ophthalmos- Immune recovery uveitis is a HAART-dependent, nonin-
copy with concurrent documentation on digital fundal fectious inflammatory response that occurs in up to 63% of
photography, as described by Newman and colleagues,181 and patients with treated CMV retinitis and increased CD4þ
supported by clinical history, systemic review, laboratory, and counts.100,121,254 Complications include epiretinal membrane,
ancillary tests. PCR analysis of CMV DNA in intraocular fluid CME, neovascularization, cataracts, and severe proliferative
samples aids with the diagnosis, subsequent management, vitreoretinopathy.100,121,254 The risk of immune recovery uveitis
and monitoring of treatment response.84,135,229 increases with the severity of CMV retinitis and use of cidofovir
during treatment.225 This risk is reduced by delaying HAART
2.10.4. Treatment therapy until induction of CMV antiviral therapy begins.
The mainstay of treatment in CMV retinitis is the reversal of
immunodeficiency. In the setting of HIV/AIDS, initiation of
HAART, or checking for antiviral resistance if CD4þ counts is 2.11. Nonnecrotizing herpetic retinitis
low despite HAART, is an aspect of management. In iatro-
genically immunosuppressed patients, immunosuppression 2.11.1. Background
should be minimized as much as possible. Since CMV retinitis NNHR is a relatively new disease entity first reported in 2003
is found mostly in AIDS patients (and recently in by Bodaghi and colleagues.27 Five of 37 patients included in
immunocompetent individuals as well66,252), the use of the initial report had PCR-confirmed herpetic infections
HAART to treat the coexisting HIV infection lowers the masquerading as atypical posterior uveitis.27 A viral etiology
progression of CMV retinitis and incidence of subsequent must be excluded in cases of sight-threatening and atypical
visual loss.100,108,120,260 Anti-CMV therapy may be posterior uveitis that is unresponsive to conventional corti-
discontinued in patients with sustained immune recovery to costeroid treatment.27 The demographics and clinical features
CD4þ counts 100 cells/mL.105,260 of NNHR are found in Table 9.7,27,259,262 NNHR can occur in any
Antivirals such as ganciclovir, valganciclovir, cidofovir, age group, with slightly more males affected than females.
and foscarnet are used in the treatment of CMV retinitis Most cases tend to be unilateral and chronic.
because these antivirals competitively inhibit CMV DNA po-
lymerase.95,100,166,254,270 Ganciclovir was also available as a 2.11.2. Causative viruses
surgically implanted delivery device, Vitrasert (Bausch & VZV accounts for up to three-quarter of NNHR cases, followed
Lomb, Rochester, NY, USA), that released a sustained con- by HSV in the remaining cases.7,27,259,262
centration of the drug into the vitreous cavity and had a low
risk of complications.115,164 This device was used for patients 2.11.3. Clinical features
who could not tolerate systemic ganciclovir or foscarnet270; Patients may present with symptoms of blurred vision or
however, because of lack of demand, the ganciclovir implant ocular pain.262 There is mild anterior chamber inflammation
is no longer available. with vitritis. Fundus examination may reveal peripheral reti-
Since CMV retinitis is a manifestation of a systemic dis- nitis, diffuse occlusive retinal vasculitis, peripheral neo-
ease, antiviral therapy has to be given systemically. Studies vascularization, intraretinal or vitreous hemorrhage, retinal
from the Studies of Ocular Complications of AIDS have edema, and papillitis but no signs of retinal necrosis.7,27,259,262
demonstrated that mortality is significantly increased in HIV/ In patients with atypical ARN or NNHR, the retinal lesions
AIDS patients with CMV retinitis, if the CMV retinitis is tend to progress slowly and generally do not completely
treated locally alone by intravitreal injections or ganciclovir destroy the involved retina.259
implant.1
2.11.4. Diagnosis
2.10.5. Outcomes Diagnosis of NNHR is made based on the clinical features
The natural course of CMV retinitis includes regression, described by Bodaghi and colleagues,27 in patients with
complications like retinal detachment, or recurrence. Most atypical posterior uveitis that is PCR positive for HSV or VZV in
studies demonstrate improvement or stabilization of vision the intraocular fluids and remain unresponsive to conven-
and ophthalmic findings in majority of patients, with many tional therapy with systemic corticosteroids and immuno-
achieving complete remission.270 modulatory therapy.7 Viral serologies are measured by
Complications of CMV retinitis are severe and may result in ELISA.27 Tetraplex PCR analysis is done using aqueous or vit-
profound vision loss and blindness.120 Complica- reous samples to identify the herpes virus involved.7,27,259,262
tions4,97,100,105,108,140,189,214 include extension of retinitis
(although less rapidly than in HSV or VZV retinitis), involve- 2.11.5. Treatment
ment of second eye, epiretinal membrane, CME, retinal neo- NNHR does not respond to conventional therapy with sys-
vascularization, posterior subcapsular cataracts, phthisis, temic corticosteroids or immunosuppressive therapy, but a
Table 9 e Demographics and clinical characteristics of nonnecrotizing herpetic retinitis

Author Age (years) Gender Laterality Immunodeficiency Viral Method of Previous
(year) etiology diagnosis herpes
infection
Bodaghi et al Mean: 53.2; M: 1; F: 4 B: 4; U: 1 HIV; immunosuppressive VZV: 3; Aqueous Herpetic

(2003)27 range: 29e82 drugs/corticosteroids: 5 HSV-1: 2 tap keratitis
Wickremasinghe 48 M U NR VZV Vitreous Herpetic

et al (2009)262 biopsy anterior
uveitis for 15
years
76 M U NR VZV Vitreous Herpetic

biopsy anterior
uveitis for
2 months
Wensing Mean: 55; M: 6; F: 3 B: 2; U: 7 Immunosuppressive VZV: 7; PCR and Herpetic

et al (2011)259 range: 19e81 drugs/corticosteroids: 3 HSV: 2 GWC encephalitis
Albert et al 19 F B NR HSV-1 Aqueous NR

(2015)7 tap
11 M U Tetralogy of VZV Vitreous NR

Fallot biopsy
Summary; n, % Mean: 43.7; M: 10 B: 7 Immunodeficiency: 8 VZV: 13 Aqueous Herpes

range: 11e82 (55.6); F: (38.9); U: (72.2); HSV: tap, keratitis,
8 (44.4) 11 (61.1) 5 (27.8) vitreous anterior
biopsy uveitis,
encephalitis
AC, anterior chamber; B, bilateral; CF, counting fingers; CME, cystoid macular edema; F, female; GWC, Goldmann-Witmer coefficient; HSV,
herpes simplex virus; KPs, keratic precipitates; M, male; NR, not reported; OD, oculus dexter; OS, oculus sinister; OU, oculus uterque; RD,
retinal detachment; PCR, polymerase chain reaction; U, unilateral; VA, visual acuity; VZV, varicella zoster virus.
favorable response may be achieved with systemic be considered for patients who present with recurrent intra-
antivirals.7,27 ocular inflammation.7
Antivirals should be started immediately after identifica- Most patients may be treated with corticosteroids before
tion of the virus. The use of antivirals stabilizes intraocular diagnosis and identification of a viral etiology. Oral steroids
inflammation, allows eventual tapering of corticosteroids and should not be stopped but progressively tapered to avoid re-
discontinuation of immunosuppressive therapy.27 Systemic currences.27 Oral prednisone 10e20 mg/day or topical corti-
antivirals include oral acyclovir 800 mg 5 times daily or oral costeroids7,259,262 and immunosuppressive treatment (such as
valacyclovir 2e3 g/day (depending on the creatinine clear- cyclosporine A)7,27 are progressively tapered over a few
ance), tapered and maintained for 7e8 months.7,27,259,262 Re- months.27,262 Laser photocoagulation of the ischemic
lapses may be treated with oral acyclovir until resolution of zones7,259 or pars plana vitrectomy can be performed for
the retinitis.7 Long-standing preventive antiviral therapy may retinal detachment or diagnostic purposes.259
Symptoms Signs VA at Treatment Complications Duration of VA at last visit

presentation follow-up
(months)
NR Mild to moderate Case 1: OD Oral valacyclovir, NR Mean: 11.2; Case 1: OD 20/30

vitritis, diffuse 20/60 low-dose steroids range: 6e16
retinal vasculitis, Case 2: Case 2: OU 20/40
papillitis, macular OU 20/60
edema; Case 3: Case 3: OU 20/30
granulomatous OU 20/40
anterior uveitis; Case 4: Case 4: OD CF, OS 20/
unilateral glaucoma OD CF, 40
OS 20/50
Case 5: Case 5: OU 20/60
OD 20/
200, OS
20/100
Blurred Sectorial iris 6/12 Oral acyclovir, NR 7 6/12
vision, pain atrophy, mutton fat topical prednisolone,
KPs, 1þ AC cells, timolol
flare, multiple
discrete arteriolar
sheathing
Blurred Localized corneal 6/18 Oral acyclovir, Persistent stromal 1 6/12
vision stromal edema, KPs, topical steroid corneal edema
iris atrophy 1/2 þ AC
cells, vitreous cells,
arteriolar sheathing
NR Vasculitis: 3; NR Oral valacyclovir, RD: 1; CME: 2; retinal 6 0.3e0.8
papillitis: 2; vitritis, corticosteroids, atrophy
panuveitis without vitrectomy, laser
any distinct features
NR Severe bilateral OU 20/20 Oral corticosteroid, Multiple recurrences 132 OU 20/20
occlusive vasculitis, laser of occlusive
vitreous/intraretinal photocoagulation, vasculitis with
hemorrhage, immunosuppressive hemorrhage, CME
peripheral drugs, vitrectomy,
neovascularization oral acyclovir
NR Inferior occlusive OD 20/50 Vitrectomy, CME, recurrence of 168 OD 20/200
retinal vasculitis, photocoagulation, anterior uveitis,
optic disk/retinal oral acyclovir, band keratopathy,
neovascularization, topical posterior
severe vitritis corticosteroids subcapsular cataract
Blurred Vitritis, retinal Range: 20/ Oral (val)acyclovir, Recurrences, CME, Mean: 54.2; range: 1 Improved: 6;
vision, pain vasculitis, papillitis, 20e20/200 topical/systemic RD, band e168 worsened: 1
hemorrhages, steroids, vitrectomy keratopathy,
neovascularization cataracts
2.11.6. Outcomes 2.12. Other herpetic posterior segment manifestations

NNHR has a good visual prognosis, and a majority of cases
show improvement in visual acuity and stabilization or The most frequent findings in congenital HSV retinitis are
resolution of uveitis.7,27,259,262 There was severe visual loss in multifocal, confluent patches of white retinal opacification, at
one patient from multiple complications.7 Wensing and times presenting as ARN.76 In acquired infections, typical
colleagues259 noted that the presence of occlusive vasculitis features include vascular sheathing, arteriolar attenuation,
was associated with a worse visual acuity at follow-up. hemorrhage, retinal and optic disc edema, multifocal cho-
Complications of NNHR include multiple recurrences of rioretinitis, and yellowish exudative plaques in the macula
anterior uveitis or retinal vasculitis, CME, retinal detach- and posterior pole.39,77,228,270
ment, retinal atrophy, band keratopathy, and In congenital VZV infections, posterior segment findings
cataracts.7,27,259,262 include discrete white chorioretinal scars.34 In acquired
infections there may be focal, yellow-gray chorioretinitis, juxtafoveal opacification of the superficial retina, cherry red
perivasculitis, or ARN features of diffuse necrotizing retinitis spot, and intraretinal hemorrhages. Patients were diagnosed
with macular extension, hemorrhage, retinal tears, edema, with ischemic maculopathy based on FFA changes, which
and vascular sheathing.107,117 A hemorrhagic variant of VZV show enlargement of the foveal avascular zone and mild
retinitis was reported, with dense vitreous hemorrhage, per- staining of the juxtafoveal vessels.46
ipapillary edema and hemorrhage, and intraretinal
whitening.149 2.13.3. Diagnosis
Features of EBV posterior uveitis include relative afferent Diagnosis of HIV retinitis is made based on positive HIV
pupillary defect, mild anterior chamber inflammation, vitritis, serology by ELISA for antibodies to the p24 antigen, signs on
chorioretinitis, yellow-white fluffy retinal opacifications, fundus examination, and exclusion of other etiologies.270
multifocal choroiditis, localized choroidal effusions, hemor- The CD4þ T-lymphocyte count has been used to predict
rhage, vasculitis, and optic neuritis.89,116,118,133,185,192,213,226,258 the onset of certain ocular infections.49,243 Studies have found
Other reported findings associated with EBV infection that a CD4þ count of less than 50 cells/mL is associated with
include subretinal fibrosis and uveitis syndrome and punctate CMV retinitis and PORN.97,100,105,191,195,254
outer retinitis with retinal pigment epithelial clumping and
depigmentation.185,198 2.13.4. Treatment
HIV retinitis responds to antiretroviral therapy such as zido-
2.13. Human immunodeficiency virus vudine, saquinavir, and nelfinavir mesylate, but not to other
antivirals such as ganciclovir or acyclovir commonly used to
2.13.1. Background treat other types of viral retinitis.148,254
HIV is a single-stranded RNA retrovirus that causes AIDS. HIV HAART, a combination of nucleoside reverse transcriptase
is spread by sexual contact, blood, or vertical transmission inhibitors, nonnucleoside reverse transcriptase inhibitors,
from mother to child. AIDS is a multisystemic disease asso- and protease inhibitors, is a therapy used in AIDS patients to
ciated with progressive failure of the immune system that can lower the plasma levels of HIV RNA and increase CD4þ T-
cause opportunistic infections and viral-induced cancers.222 lymphocyte counts, thereby improving the overall immune
Ocular disease occurs in up to 70% of AIDS patients function of the patient43,83 and salvage the vision of AIDS
throughout the natural history of HIV infection.36,47 HIV itself patients by stopping the progression of ophthalmic opportu-
is an extremely rare infectious cause of posterior uveitis. nistic infections.99
There have been few reports of posterior uveitis occurring in Any infection or intraocular lymphoma should be treated
AIDS patients in the absence of other viral etiologies.148 AIDS with specific antimicrobial or antineoplastic therapy. Inflam-
patients are at risk of other opportunistic ocular infections matory complications such as severe vitritis, CME, or posterior
secondary to their immunosuppressed state. The 2 most synechiae should be treated with corticosteroids, in
common viral posterior uveitis in AIDS patients are CMV conjunction with a cycloplegic agent.47
retinitis and PORN, and rarely, HSV-related ARN.47e49,141,145,254
HIV-related uveitis can also be the result of drug toxicity or 2.13.5. Outcomes
Immune recovery uveitis.47 The prognosis of HIV retinitis depends upon the location of the
lesions and the CD4þ counts. The few complications reported
2.13.2. Clinical features include epiretinal membrane formation and CME, but there
HIV retinitis may present with symptoms of blurred vision, were no cases of retinal detachment, neovascularization,
floaters, photophobia, tearing, and foreign body sensation. vascular occlusion, or optic nerve involvement.148
Levinson and colleagues148 reported in 1998 that several
patients infected with HIV were found to have slowly pro- 2.14. Measles
gressive mid-peripheral multifocal retinal infiltrates, diffuse
or located in clusters, with irregular faint yellow-white or 2.14.1. Background
translucent discrete foci, lacy inflammation in between, Measles is a single-stranded, enveloped (nonsegmented) RNA
minimal anterior chamber inflammation, vitritis or vascu- Morbillivirus from the Paramyxoviridae family.98 Measles is an
litis, and no retinal hemorrhage or necrosis. There was no airborne disease that spreads via direct contact with secre-
evidence of opportunistic infections. The median CD4þ tions. It usually presents with fever, cough, coryza, and Koplik
count at presentation was 272 cells/mL.148 Vrabec and spots before the onset of rash.194
colleagues254 also describe HIV retinitis as a peripheral Posterior uveitis associated with measles can occur in both
multifocal retinitis with low-grade vitritis, retinal vasculitis, congenital and acquired infections, although it is more com-
and no hemorrhage. Besides HIV retinitis, AIDS patients mon in the latter.270 It may occur concomitantly with measles
commonly present with features of CMV retinitis, PORN, or encephalitis, also known as subacute sclerosing pan-
ARN.49,141,145,254 encephalitis (SSPE).17,18,216,238,268,270,271 Ocular involvement
Retinal vascular changes, including cotton wool spots, occurs in up to 50% of SSPE cases.18,216,268 SSPE is a condition
intraretinal hemorrhages, and microaneurysms, are the most that mainly affects children and young adults.17,216,238,268,271
common manifestations of HIV retinopathy. These are caused SSPE is characterized by a history of primary measles infec-
by noninfectious microvasculopathy of HIV disease that may tion, several asymptomatic years, followed by a gradual,
result in ischemic maculopathy.46 Visual symptoms are usu- progressive psychoneurological deterioration consisting of
ally bilateral and abrupt in onset. On examination, there is behavioral changes, myoclonic seizures, ocular abnormalities,
Table 10 e Demographics and clinical characteristics of measles retinopathy
Author Age Gender Laterality Immuno- Associated Method Symptoms Signs VA at Treatment Complications Duration VA at
(year) (years) deficiency conditions of presen- of last visit
diagnosis tation follow-
up
(months)
Scheie 6 F B Nil Measles Clinical Blurred vision Blurred optic disk OU: HM ACTH, cortisone, Retinitis 54 OD: 6/9;
et al margins, diffuse tetracycline pigmentosa, OS: 6/12
(1972)212 retinal edema, visual field
attenuated defect
arterioles, scattered
retinal
hemorrhages,
macular star
Tomoda 10 M B Nil Measles CSF, EEG Visual loss Macular NR Corticosteroids, NR 12 NR
et al at 8 months, degeneration, interferon alpha
(1997)238 SSPE chorioretinitis
Nguyen 9 M B Nil SSPE Serology, Neurologic RAPD, optic disk OD: 20/800; Isoprinosine NR NR NR
et al CSF, EEG symptoms edema, multifocal, OS: 20/30
(1999)182 translucent
pigment, epithelial-
level lesions
Serdaroglu 17 M B Nil Measles at CSF, EEG Visual disorder, Yellow-white OD: CF 3 m; Oral corticosteroid, Macular 6 Died
et al 1.5 years, poor memory, jerky retinitis-like lesion OS: 20/200 IVIG, isoprinosine pigment
216
(2005) SSPE movements with hemorrhage mottling
14 M B Nil Measles CSF Blurred vision, Macular retinitis, OD: 20/400; Beta interferon, Hypopigmented/ 18 OU:
at 2 years headache macular edema, OS: 20/200 isoprinosine hyperpigmented 20/20
yellow-white mottling
lesions
Babu 20 M B Nil SSPE Serology, Sudden painless Macular gray-white OD: 20/400; Sedatives, NR 3 Died
et al CSF, EEG vision loss retinal lesions with OS: 20/30 antiepileptics
(2007)17 geographic borders,
yellow exudates,
optic disk pallor
25 M B Nil Measles at Serology, Progressive vision Macular RPE OD: 20/200 Antiseizure, NR 6 No
7 years CSF, EEG loss atrophy OS: 20/800 isoprinosine, improvement
interferon
Yuksel Mean: M: 19; B: 22; Nil SSPE CSF, EEG Alternating Retinal edema, NR NR NR NR NR
et al 6.6 2.5 F: 6 U: 3 exotropia vessel tortuosity,
(2011)271 RPE changes, optic
disk edema, optic
atrophy,
chorioretinitis
Yimenicioglu 15 M B Nil Measles at 8 CSF, EEG Decreased vision, Atrophic macular NR Isoprinosine, Nil 1 NR
et al months, SSPE amnesia pigmentary vitamin A/C/E
(2012)268 changes, active
macular retinitis,
hyperpigmentation
423
and coma.17,194,268 The prevalence has declined since the
M, male; NR, not reported; OD, oculus dexter; OS, oculus sinister; OU, oculus uterque; PL, light perception; RPE, retinal pigment epithelium; RAPD, relative afferent pupillary defect; SSPE, subacute
ACTH, adrenocorticotropic hormone; B, bilateral; CF, counting fingers; CSF, cerebrospinal fluid; EEG, electroencephalogram; F, female; HM, hand movement; IVIG, intravenous immunoglobulin;
last visit
introduction of the measles vaccine.21,30
VA at
Majority
The demographics and clinical characteristics of measles
worsen
OD: PL;
OS: CF;
or die
retinopathy are found in Table 10.17,18,182,212,216,238,268,271
died
(months) Measles retinopathy mainly affects younger patients and
Complications Duration
follow-
males. It is usually bilateral, and patients are often

up
of
3
immunocompetent.17,18,182,212,216,238,268,271
range:
Mean:
1e54
12.9;
2.14.2. Clinical features
Measles posterior uveitis may present with symptoms of
macular scar
Macular scar
pigmentosa,
painless visual loss. Fundus findings include optic disk
Retinitis
swelling, arteriolar attenuation, diffuse retinal edema, scat-
tered hemorrhages, and exudative stellate macular le-
sions.212,270 Upon resolution, there is optic disk pallor,
Treatment
peripapillary vascular sheathing, and secondary pigmentary

interferon alpha,
interferon alpha,
corticosteroids
retinopathy with a “salt and pepper” appearance.212

Isoprinosine,
isoprinosine,
prednisone,
Acyclovir,
In SSPE, visual symptoms and retinopathy precede the

ribavirin
onset of neurological findings by weeks to years. The most

characteristic fundus lesion in SSPE is focal necrotizing reti-
nitis or chorioretinitis that starts in the macula and progresses
OD: PL; OS: 20/400
toward peripheral retina. It preferentially affects the retina

presen-
Range: 20/30-PL
tation
VA at
with secondary involvement of the RPE and

choroid.17,18,182,216,238,268,271 Ground-glass whitening of the
retina with ill-defined margins and RPE mottling occur. Other
findings include optic nerve involvement, such as papil-
attenuated vessels,
ledema and optic atrophy, and retinal changes such as retinal

hemorrhage, optic
edema, vasculitis,
retinal occlusive
retinitis, retinal
Chorioretinitis,
folds, edema, hemorrhage, serous detachments, and occlu-

optic atrophy,
Signs
hemorrhages
sive vasculitis.17,18,271 There is minimal vitreous inflamma-

disk edema
Diffuse RPE
alteration,
vasculitis,
tion.17 The lesions usually resolve rapidly with varying

degrees of scarring and depigmentation.238,268,271
neurological signs
Symptoms
2.14.3. Diagnosis
Sudden blurred
Diagnosis of measles posterior uveitis is clinical and

Vision loss,
confirmed by positive measles serology with complement

vision
fixation, enzyme immunoassay, immunofluorescent and

hemagglutination inhibition tests, or positive measles anti-
diagnosis
Age Gender Laterality Immuno- Associated Method
bodies in the cerebral spinal fluid in cases of SSPE.270 FFA may

Measles, SSPE Serology,
CSF, EEG
CSF, EEG
of
show early hypofluorescence which changes into hyper-

fluorescence at later stages, compatible with chorioretinal
deficiency conditions
inflammation, diffuse leakage secondary to widespread

Measles with
symptoms at
4 years, SSPE
retinal edema, and zones of atrophy, RPE mottling, or occlu-

neurologic
sive vasculitis.18,212,268 OCT shows signs of necrotizing reti-

sclerosing panencephalitis; U, unilateral; VA, visual acuity.
nitis with focal areas of moth-eaten disorganization in the

macula.18
2.14.4. Treatment
Nil
Nil
There is no definitive treatment for measles retinopathy or

SSPE.182,216 SSPE can be managed with medications if treat-
F: 7 (20.6) U: 3 (8.8)
ment is started early; however, no cure for SSPE exists, and the
(91.2);
B: 31
condition is often fatal. Various treatment regimens have

B
been tried with little success, including IV IgG, plasma ex-

(79.4);
change, cytarabine, amantadine, and interferons. The most

M: 27
promising results to date use a combination of isoprinosine

(years)
(inosiplex), an antiviral agent, and intraventricular, intra-

range: 6
39
Mean:
thecal, or intracameral interferon alpha as an immunomod-

16.2;
e39
ulator, with stabilization or improvement in some

cases.17,18,147,182,216,238 The role of corticosteroids in the man-
Summary;
(2012)18
Author
agement of measles posterior uveitis is controversial, and

(year)
et al
n, %
Baillif
there is lack of any evidence or published literature about

administering corticosteroids to prevent vision loss.
Table 11 e Demographics and clinical characteristics of rubella retinopathy
Author Age Gender Laterality Immuno- Associated Method Symptoms Signs VA at Treatment Complications Duration VA at
(year) (years) deficiency conditions of presentation of follow- last
diagnosis up visit
(months)
Kresky Mean: M: 3 B Nil Congenital Serology Hearing loss Abnormal areas of OU: 20/20; NR Strabismus, NR NR
et al 4.5 rubella depigmentation and OD: 20/80; nystagmus, nuclear
(1967)138 hyperpigmentation in OS: 20/40 cataracts
macula, “salt and
pepper” retinitis
Collis 1.4, 1.1 NR B Nil Congenital Serology Blindness, hearing Hazy cornea, NR NR Cataracts, iris 17, 13 NR
et al rubella loss pigmentary retinopathy, atrophy
(1970)45 diffuse black granular
pigmentation
Orth 11 M B Nil Congenital NR Profound deafness, Macular pigment OD 20/20; NR Disciform scar, band NR NR
et al rubella sudden vision loss mottling, loss of foveolar OS 3/400 keratopathy,
(1980)186 reflex, yellow fibrotic snowflake cataracts
scar, punctate
hemorrhage
11 M U Hearing loss, Diffuse pigment OS 20/400 Disciform scar
decreased vision epithelial mottling, salt
and pepper appearance,
yellow fibrotic macular
scar
12 M B Deaf, vision loss Salt and pepper OD 20/400; Nil
pigmentary mottling, OS 20/20
loss of macular ring and
foveolar reflex, serous
RD, subretinal
hemorrhage
Hayashi 50 M B Betame- Acquired Serology Decreased visual Localized dark-gray NR Nil Atrophic RPE 3 “normal”
et al thasone rubella acuity atrophic lesions at
(1982)86 for 20 days posterior pole, diffuse
RD, anterior uveitis
Hirano 7 F B Nil Congenital NR Sudden visual loss Rubella retinopathy NR NR Neovascular 10 NR
et al rubella maculopathy
(2000)92 12 F B Nil Congenital NR Visual loss Rubella retinopathy, NR NR Nil 10 NR
rubella neovascular
maculopathy
Wang 36 M B Nil Congenital NR Decreased visual Diffuse mottling with OD: 20/200; Photodynamic Subfoveal choroidal 5 OD: 20/60
et al rubella acuity, central RPE clumping, OS: 20/25 therapy neovascularization,
(2002)256 scotoma, submacular hemorrhage (verteporfin) subretinal fibrosis
metamorphopsia
Khurana 39 F B Nil Congenital NR Congenital hearing Granular, pigmentary OU 20/20 Nil Nil 4 20/20
et al rubella loss, no visual mottling, punctuate
(2006)129 problems hypopigmentation and
hyperpigmentation
consistent with “salt and
pepper” retinopathy
425
2.14.5. Outcomes
AC, anterior chamber; B, bilateral; F, female; KPs, keratic precipitates; M, male; NR, not reported; OD, oculus dexter; OS, oculus sinister; OU, oculus uterque; PDT, photodynamic therapy; RAPD, relative
OD: 20/60
VA at
In measles retinopathy, permanent ocular damage due to
Majority
improve
visit
last
remain
stable
complications of retinitis pigmentosa, macular scarring, and
or
RPE mottling is developed in some patients.18,212,216 Even with
of follow-
(months)
Complications Duration
range: 2e17
2 return of useful vision, the visual fields usually remain con-
Mean: 8;
up
stricted to less than 15 degrees.212,270
neovascularization
“Salt and pepper”
Salt and pepper 2.15. Rubella
disciform scar,
retinopathy,
corticosteroids, pigmentary
2.15.1. Background
choroidal
fundus
Rubella, also known as German measles or 3-day measles, is a

single-stranded RNA Rubivirus from the Togaviridae family.
Treatment
Rubella virus is spread via airborne inhalation of aerosols or

vertical transmission from mother to child.20 Rubella usually
Prednisone
presents with fever, coryza, Forchheimer spots, cervical

PDT
Nil,
lymphadenopathy and a scarlatiniform rash that fades after 3

days.20
presentation
Retinopathy caused by rubella is usually associated with

VA at
RAPD, fine KPs, AC cells, OD: 20/200
congenital rubella syndrome, characterized by a triad of

20/20e20/
Salt and pepper fundus, Range:
auditory, ocular (cataracts, microphthalmos and pigmentary

400
retinopathy) and cardiac defects.20 Pigmentary retinopathy

secondary to rubella was first observed by Mitchell in 1941 as a
hemorrhage, vasculitis,
neuroretinitis, macular
mild vitritis, resolving
pale fundus with scattered irregular spots of pigment.74

star, retinal edema,
yellow fibrotic scar,

vasculitis, papillitis
Pigmentary retinopathy is developed in about 20%e60% of

Signs
retinal edema,
children with congenital rubella syndrome.44,138,186 Like

afferent pupillary defect; RD, retinal detachment; RPE, retinal pigment epithelium; U, unilateral; VA, visual acuity.
papillitis
measles, the prevalence of congenital rubella syndrome and

rubella-related posterior uveitis has decreased since the
introduction of the rubella vaccine.144
Vision loss, scotoma,
Rubella retinopathy is a bilateral disease that usually oc-

Sudden vision loss,
Symptoms
metamorphopsia,
preceding flu-like
curs in immunocompetent children or young adults with a

history of congenital rubella syndrome. The demographics
hearing loss
and clinical characteristics of rubella retinopathy can be

illness
found in Table 11.44,52,86,92,129,138,186,256

diagnosis

Method
Congenital rubella causes a progressive pigmentary retinop-

of
Serology
Serology
athy that is characterized by a “salt and pepper” fundus. It

often occurs in the posterior pole and macula, consisting of
Age Gender Laterality Immuno- Associated
deficiency conditions
black, irregular pigmentary lesions, areas of depigmentation

Congenital:
and hyperpigmentation, waxy disk, coarse macular mottling,

acquired:
Acquired
11 (84.6);
and hemorrhage.44,92,129,138,186,256,270 Morlet described 3 types

2 (15.4)
rubella
of fundus featuresegross and generalized pigmentary

changes, peripheral pepper-like pigmentary changes, and
diffuse strange, moth-eaten areas with a waxy disk.129,138
Cortico-
steroid
Rubella retinitis, a rare feature of acquired rubella infection

Nil,
Nil
in adults,86 may present as a diffuse chorioretinitis with dark

gray atrophic lesions at the posterior pole and diffuse retinal
detachment, normal retinal vessels and optic disk, and
(84.6);
(15.4)
B: 11
absence of hemorrhage.86 There has also been a report of

U: 2
U
rubella neuroretinitis, characterized by diffuse retinal edema,

macular star, vasculitis, and papillitis.52
(75.0);
(25.0)
M: 9
F: 3
M
2.15.3. Diagnosis
(years)
1.1e50
range:
Mean:
Diagnosis of rubella retinopathy is difficult because of a lack

28
17.8;
pathognomonic signs. Serological diagnosis is based on the

presence of rubella IgM antibodies or detection of an IgG in-
Damasceno
Summary;
(2010)52
Author
crease of fourfold or more, with hemagglutination inhibition,

(year)
et al
n, %
complement fixation, ELISA, or immunofluores-

cent44,52,86,138,270 in the absence of other possible causes.
Fundus autofluorescence imaging is a sensitive and noninva- Dengue fever is usually characterized by fever, arthralgia,
sive method that supports the diagnosis of rubella retinopathy headache, and rash.82,136,151,234
when stippled fluorescence is highlighted in the fundus.72 In The first case of dengue fever-related posterior uveitis was
some cases, FFA shows transmission and blockage of choroid described by Deutman and colleagues54 in 1979 among tour-
fluorescence with subretinal neovascularization and multi- ists who returned from dengue endemic countries. Since 2000,
focal leakage into the subretinal space.86,270 There is no pub- more cases have been reported, especially in the Southeast
lished literature to support the role of PCR in the diagnosis of Asian countries.37,68,82,111,136,151,223,231,234 Dengue-related pos-
rubella posterior uveitis. terior uveitis is acute, bilateral in 75% of cases, and occurs in
immunocompetent individuals.37,82,111,136,151,223,231,234 The
2.15.4. Treatment demographics and clinical features of dengue posterior uveitis
There is no definite treatment for rubella retinopathy. Rubella are found in Table 12.37,82,111,136,151,223,231,234
retinopathy is usually just monitored as the retinopathy is
generally benign and does not affect vision unless choroidal 2.17.2. Clinical features
neovascularization develops in the macula.129,256 Systemic Symptoms of dengue-related posterior uveitis include blur-
corticosteroids may be beneficial in instances where there is ring of vision, paracentral scotoma, metamorphopsia,
severe inflammation.52 Photodynamic therapy may be effec- floaters, red eyes, and systemic symptoms of dengue fever
tive for choroidal neovascularization secondary to rubella such as fever, petechial rash, and myalgia. There is no pain,
retinopathy, with a resulting improvement of visual acuity.256 photophobia, or tearing. Ocular symptoms frequently occur 1
week after the onset of dengue fever.37,82,111,136,151,223,231,234
2.15.5. Outcomes Dengue-related posterior uveitis may present as chorior-
The long-term prognosis of rubella retinopathy is excel- etinitis or a hemorrhagic retinopathy. On examination, there
lent.44,92,138 Rubella retinopathy is usually benign, nonpro- is minimal anterior chamber inflammation and vitritis. In
gressive, and does not interfere with vision.129 Rare dengue chorioretinitis, the characteristic feature is a chorior-
complications include subretinal or choroidal neo- etinitis with maculopathy. The macular region is often
vascularization, macular hemorrhage, and disciform scarring, involved. There may be focal chorioretinitis or choroiditis,
which may lead to a significant reduction in visual retinal edema, vascular sheathing, retinal hemorrhages,
acuity.92,186,256 foveolitis, cotton wool spots, and neuro-
retinitis.68,111,136,151,223,231,234 Foveolitis is a newly described
manifestation specific for dengue fever and is described as a
2.16. Vector borne diseases
discrete, round yellow-orange lesion localized to the fovea.111
Hemorrhagic retinopathy associated with dengue hemor-
Vector borne diseases contribute to some of the most serious
rhagic fever is related to the induced thrombocytopenia.37,82
epidemics in the world and are of great public health impor-
The onset of visual symptoms is usually observed within 1
tance. Disease transmission by hematophagous arthropods
day from the resolution of fever and at the nadir of the
was first reported by Manson in 1877. Since the discovery of
thrombocytopenia. Fundoscopic examination shows multiple
filariasis being spread by Culex mosquitoes in 1877, other
dot and blot hemorrhages within the vascular arcades and
diseases such as malaria (1898), yellow fever (1900), and
macula.37,82
dengue (1903) have been shown to have similar transmission
modes.78 Although malaria is the most important vector borne
2.17.3. Ocular imaging findings
disease because of its global distribution and numerous
On FFA, there may be extensive retinal vasculitis, choroidal
deaths, arboviruses are the most abundant.78
hyperfluorescence, blocked fluorescence, or capillary non-
There is insufficient evidence to suggest if the associated
perfusion.136,151 Similarly, on indocyanine green angiography,
retinitis, choroiditis, or optic nerve involvement in these
there may be early diffuse choroidal hypercyanescence with
vector borne diseases are related to live viruses or a secondary
late silhouetting of the larger choroidal vessels151 or hypo-
immunologic process.
fluorescent spots corresponding to yellow subretinal lesions
seen clinically and additional spots in areas without clinically
2.17. Dengue virus evident dots.123 On OCT scan, there are 3 patterns of mac-
ulopathyediffuse retinal thickening, CME, and foveoli-
2.17.1. Background tis.32,234,235 In diffuse retinal thickening, there is increased
Dengue fever is caused by 4 closely related, but antigenically central or paracentral fovea thickness associated with loss of
distinct, Flavivirus serotypes, and transmitted by the mos- foveal dimple.235 CME is characterized by large intraretinal
quito, Aedes aegypti. Dengue is endemic in Southeast Asia, ovoid areas of hyporeflectivity with reflective septa separating
Central America, and South America. Globally, approximately the cystoid cavities.235 Foveolitis is characterized by an area of
50e100 million cases of dengue fever and 500,000 cases of thickening and high reflectivity at the subfoveal outer retina
dengue hemorrhagic fever occur each year, although the layer. There may be a tented elevation and separation of the
public health impact of dengue is likely to be greatly highly reflective layer with accumulation of subretinal fluid
underestimated.78 (area of low reflectivity) within cystic.235 Serial OCT imaging
Dengue infection produces a clinical spectrum of disease, demonstrates spontaneous rapid resolution of edema, but
ranging from a nonspecific viral illness to severe and fatal patients may complain of persistent central or paracentral
dengue hemorrhagic fever or dengue shock syndrome. scotoma after resolution of the disease.234
428
Table 12 e Demographics and clinical characteristics of dengue posterior uveitis
Author Age Gender Laterality Immuno- Method of Symptoms Signs VA at Treatment Complications Duration of VA at
(year) (years) deficiency diagnosis presentation follow-up last visit
(months)
Lim Mean: 35.8; M: 1; F: 5 B: 5; U: 1 Nil Serology Blurring of vision, Maculopathy with Range: 20/30-HM Corticosteroids RPE discoloration Mean: 2.4; Partial
et al range: 24e61 scotoma choroidopathy: small, (topical, periocular, range: 0.5e4 recovery: 3;
(2004)151 intraretinal, whitish oral) stable: 2
lesions, localized retinal
and RPE disturbance,
hemorrhages, vascular
sheathing
Siqueira 32 F B Nil Serology Blurred vision Peripheral vascular OD: 20/100; OS: 20/200 Oral antiplatelet Vitreous 24 “Poor”
et al sheathing, preretinal (acetylsalicylic acid), hemorrhage,
(2004)223 hemorrhage, cotton vitrectomy, panretinal preretinal
wool spots in macula photocoagulation neovascularization
Chlebicki Mean: 34; M: 1; F: 3 B: 4 Nil Serology, Reduced visual Blot hemorrhages NR Supportive, platelet Metamorphopsia 2 6/6: 3;
et al range: 21-49 PCR acuity, within the vascular transfusion partial
(2005)37 metamorphopsia arcades recovery: 1
Teoh Mean: 29.8; M: 3; F: 1 B: 4 Nil PCR, Sudden painless Focal macular OD: 20/400; OS: CF 1 ft Supportive, oral Paracentral scotoma Mean: 5.3; NR
et al range: 20e40 serology blurring of vision chorioretinitis, macular OU: 20/20 prednisone, IV range: 3e6
(2006)234 edema, vasculitis, flame OD: 20/20; OS: 20/400 methylprednisolone
hemorrhage OD: 20/40; OS: 20/200 OD: 20/30;
OS: 20/60
Gupta Mean: 29; M: 1; F: 2 B: 2; U: 1 Nil Clinical, Sudden, painless Retinal/subhyaloid OU: CF 0.5 m Oral steroids, Nil Range: 1.5e3 OU: 6/12
et al range: 14e45 serology vision loss hemorrhages in macular OD: 6/36; OS: 6/24 observation OU: 6/12
(2011)82 area and vascular OS: CF 2 m NR
arcades, retinal edema,
small whitish dot-like
retinal lesions
Juanarita 24 F B Nil Serology Sudden painless Multiple retinal OD: 6/30; OS: 6/120 Supportive Multiple retinal 1 OD: 6/7.5;
et al vision loss hemorrhages at macula, yellowish deposits OS: 6/120
(2012)111 elevation of fovea, at fovea
subretinal fluid
Tabbara 32 M: 2 B: 2 Nil Serology Blurred vision, Multifocal OD: 20/100; OS: 20/40 Supportive CME, nummular 1.5 OD: 20/50;
(2012)231 floaters chorioretinitis, retinal pigmented scars OS: 20/25
45 vasculitis, cotton wool OD: 20/30; OS: 20/40 2 OD: 20/20;
spots, flame-shaped OS: 20/30
hemorrhages, CME
Koh et al Mean: 27 9; M: 7; F: 4 B: 5; U: 6 Nil Serology Blurring of vision: 7; Retinal hemorrhage: 15; Median: 6/7.5; range: 6/ Supportive, oral/ Optic atrophy, Range: Range:
(2013)136 range: 14e40 floaters: 2; redness: cotton wool spots: 15; 6-CF topical/IV persistent scotoma 0.4e12 6/6-NPL;
1 RPE change: 5; optic disk corticosteroids 6/12 or
swelling: 3; foveolitis: 3; better:
hyperemia: 2 95.2%
Summary; Mean: 32.1; M: 15 B: 24 Nil Serology, Blurred vision, Chorioretinitis, Range: 6/6-CF Supportive, Neovascularization, Mean: Majority
n, % range: 14e61 (46.9); (75.0); PCR, clinical floaters, redness, maculopathy, corticosteroids vitreous 5.5; improved
F: 17 (53.1) U: 8 (25.0) metamorphopsia hemorrhages, vasculitis, hemorrhage, range:
retinal edema, cotton nummular scars, 0.4e24
wool spots, foveolitis persistent scotoma
B, bilateral; CME, cystoid macular edema; CF, counting fingers; F, female; HM, hand movement; IV, intravenous; M, male; NR, not reported; NPL, no light perception; OD, oculus dexter; OS, oculus
sinister; OU, oculus uterque; PCR, polymerase chain reaction; RPE, retinal pigment epithelium; U, unilateral; VA, visual acuity.
2.17.4. Diagnosis neuritis.33,143,158,159,174,177,180,203 It may morphologically mimic

Dengue fever can be confirmed with serological tests such as herpetic viral retinitis, but the clinical history (symptoms of
serum PCR and dengue antibodies using ELISA, antibody fever, joint pain, and rash) can be used to distinguish between
capture, monoclonal antibody, or hemagglutination.190 There the 2.158 It may also resemble WNV retinitis; however, pe-
is also thrombocytopenia in the full blood count.64 Thrombo- ripheral fundus lesions and linear chorioretinal streaks seen
cytopenia has been found to have a predictive value for in WNV retinitis are not present in chikungunya retinitis.31
spontaneous ocular bleeds.190 Dengue posterior uveitis is
diagnosed based on clinical history, signs, and positive 2.18.3. Ocular imaging findings
dengue serology. FFA may show early hypofluorescence with late hyper-
fluorescence with disk leakage and capillary nonperfusion
2.17.5. Treatment corresponding to the areas of retinitis.33,158,159,177 On OCT
Treatment of dengue fever and dengue retinitis is mainly scan, areas of retinitis are seen as hyperreflective with after
supportive, with fluid correction for electrolyte imbalance and shadowing, whereas serous retinal detachment is seen as a
hypotension, and management of complications. There is no hyporeflective area.158,177
specific antiviral available for dengue, but systemic cortico-
steroids such as IV methylprednisolone or oral prednisone 2.18.4. Diagnosis
may be used to control the inflammation.82,136,151,234 In The gold standard of diagnosis of chikungunya is a viral cul-
dengue hemorrhagic retinopathy, other than supportive care, ture inoculation of mosquito cell cultures or mammalian cell
platelet transfusion may be given to correct severe cultures196; however, this is not normally done, and nearly all
thrombocytopenia.37 studies reporting ocular manifestations of chikungunya fever
used reverse transcriptase PCR assay or chikungunya ELISA
2.17.6. Outcomes IgM antibodies instead.33,143,158,159,174,177,180,203
Dengue posterior uveitis is a self-limiting condition with
spontaneous recovery or recovery after treatment within 6 2.18.5. Treatment
months.136 It has a good visual prognosis. Ocular complica- There is no established treatment for ocular manifestations of
tions associated with dengue fever are rare but may result in chikungunya fever. Antipyretics such as acetaminophen,
permanent visual impairment. Complications include neo- nonsteroidal antiinflammatory drugs, chloroquine, and hy-
vascularization, vitreous hemorrhage, nummular scars, dration are given for supportive management.158 Systemic
persistent scotoma, and optic neuropathy with impaired color corticosteroids have been used to treat inflammation and
vision.136,151,223,231,234 optic neuritis caused by chikungunya virus infec-
tion.33,143,158,159,174,177,180,203 It is important to institute early
therapy once there is onset of optic disk involvement, as a
2.18. Chikungunya virus delay in treatment could result in poor visual outcomes.174
There is no specific antiviral available for chikungunya virus.
2.18.1. Background Some patients have been empirically treated with acyclovir,
Chikungunya virus is a single-stranded RNA Alphavirus from although its efficacy is doubtful.158,177,180
the Togaviridae family that is transmitted by Aedes mosqui-
toes. Chikungunya is relatively uncommon and poorly docu- 2.18.6. Outcomes
mented, but is endemic in India, Asia, and Africa. More than Majority of patients with chikungunya posterior uveitis
266,000 people were infected during the 2007 outbreak in recover well with good visual outcome. Complications include
Réunion and 1,400,000 cases were reported in India in 2006.196 retinal detachment, central retinal artery occlusion, and optic
Chikungunya fever is a self-limiting condition that pre- nerve involvement (papillitis, neuroretinitis optic atrophy, or
sents with fever, skin rash, and myalgia. The characteristic edema), which may result in severe vision loss in the
feature of chikungunya is a debilitating and prolonged minority.33,143,158,159,174,177,180,203
arthralgia that primarily affects the peripheral small joints.196
Ocular manifestations of chikungunya virus range from
conjunctivitis to retinitis and optic neuritis.143,157 Chikungu- 2.19. Rift Valley fever
nya posterior uveitis is an acute disease that affects immu-
nocompetent individuals.33,143,158,159,174,177,180,203 The 2.19.1. Background
demographics and clinical features of Chikungunya posterior Rift Valley fever (RVF) virus is a single-stranded RNA Phlebo-
uveitis are found in Table 13.33,143,158,159,174,177,180,203 virus belonging to the Bunyaviridae family. Since the first
report of a RVF outbreak in Kenya in 1930, several epidemics
2.18.2. Clinical features have occurred in Africa, including the largest outbreak in
Chikungunya posterior uveitis usually presents with fever, Egypt in 1977 involving 18,000 cases and 598 fatalities, and
headache, arthralgia, and skin rash a few weeks before the others in Kenya and Somalia from 1997 to 1998, as well as
onset of visual symptoms (blurring of vision, diplopia, scoto- Saudi Arabia in 2000.8
mata, redness, and retro-orbital pain).33,143,158,159,174,177,180,203 RVF is an arboviral disease that affects livestock as well as
On examination, there may be mild vitritis, areas of retinitis humans.219 In humans, it is usually asymptomatic or causes
with or without macular star, retinal hemorrhages, retinal an acute, self-limiting, influenza-like febrile disease. In 1%e
edema, multifocal choroiditis, neuroretinitis, and optic 3% of cases, however, it can cause serious morbidity and
430
Table 13 e Demographics and clinical characteristics of chikungunya posterior uveitis
Author Age (years) Gender Laterality Immuno- Method of Symptoms Signs VA at Treatment Complications Duration VA at last
(year) deficiency diagnosis presentation of follow- visit
up
(months)
Lalitha Mean: 44.8; M: 21; B: 7; U: 30 Nil Clinical, Blurring of Retinitis with vitritis: 2; Range: 20/20-PL; 20/20 Topical/systemic RD, CRAO, optic Range: 0.5e3 Improved: 11;
et al range: 22e57 F: 16 serology vision optic neuritis: 4; e20/120: 24; <20/200: 7; corticosteroids neuritis/atrophy same: 12; worse: 3
(2007)143 multifocal choroiditis <HM: 3
with CME: 2; exudative
RD: 2; neuroretinitis: 1;
CRAO: 1
Chanana 16 M B Nil Serology Decreased Macular choroiditis with OD: 20/400; OS: 20/40 Oral prednisolone Nil 1.5 OD: 20/120; OS: 20/
et al vision submacular exudates 30
(2007)33
Mittal Mean: M: 9; F: 5 B: 5; U: 9 Nil Serology Blurred vision: Papillitis: 8; Range: 6/6-CF; 6/6e6/12: IV methylprednisolone, Optic atrophy, disk 0.75 Improved: 10; >6/
45.8 15.6; 3; 6/18e6/60: 5; <6.60: 11 oral prednisolone
et al 19; impaired neuroretinitis: 3 pallor/edema 12: 12
(2007)174 range: 22e68 color vision:
19; pain: 3;
diplopia: 1;
redness: 1
Mahendradas Mean: 43; M: 2; F: 1 B: 1; U: 2 Nil Serology Blurring Viral retinitis: 3; vitritis, OU: 20/2000 Systemic acyclovir, oral Serous RD 1.5 OD: 20/20; OS: 20/
et al range: 32e55 of vision hyperemic disk, area of prednisolone 40
(2008)158 confluent retinal opacity OS: 20/20000 OS: 20/60
in posterior pole, retinal OD: 20/200 OD: 20/40
and macular edema,
hemorrhage
Murthy 35 M B Nil Serology Decreased RAPD, retinitis, OD: CF 2 m; OS: 20/20 IV/oral acyclovir, Nil 5 OD: 20/120; OS: 20/
et al (2008)177 (aqueous vision hemorrhages in intravitreal ganciclovir, 20
tap positive posterior pole, oral steroids
for HSV) hyperemia and blurring
of disk margins
(neuroretinitis)
Mahesh 48 F B Nil Serology Decreased Optic disk edema, OD: 20/80; OS: 20/60 Symptomatic, oral Nil 2 OD: 20/30; OS: 20/
et al (2009)159 (ELISA vision intraretinal prednisolone 20
and PCR) hemorrhages,
peripapillary cotton
wool spots, retinitis with
macular star
Rose et al Mean: 35.6; M: 7; F: 1 B: 3; U: 5 Nil Clinical, Sudden Papillitis: 7; Range: 6/6-PL IV methylprednisolone, Nil 1 Improved >6/12: 9
(2011)203 range: 22e45 serology blurring of neuroretinitis: 1; RAPD, oral prednisolone
vision, disk edema,
scotoma hemorrhage
Nair et al 65 M B Nil PCR Decreased Neuroretinitis, cotton OD: 20/200; OS: 20/400 Oral steroids, oral Nil 0.75 NR; “partial
(2012)180 vision wool spots, acyclovir resolution”
hemorrhages, grade 2
vitreous haze
Summary; n, % Mean: 41.7; M: 42 B: 20; U: 46 Nil Clinical, Blurring of Vitritis, retinitis, Range: 20/20-PL Corticosteroids, RD, optic atrophy, Mean: Improved: 37;
range: 16e68 (63.6); serology, vision, pain, multifocal choroiditis, acyclovir CRAO 1.8; range: (56.1)
F: 24 ELISA, PCR diplopia, neuroretinitis, retinal 0.5e3
(36.4) scotoma, edema, hemorrhage
redness
B, bilateral; CME, cystoid macular edema; CF, counting fingers; CRAO, central retinal artery occlusion; ELISA, enzyme-linked immunosorbent assay; F, female; HM, hand movement; HSV, herpes
simplex virus; IV, intravenous; M, male; NR, not reported; OD, oculus dexter; OS, oculus sinister; OU, oculus uterque; PCR, polymerase chain reaction; PL, light perception; RAPD, relative afferent
pupillary defect; RD, retinal detachment; U, unilateral; VA, visual acuity.
Table 14 e Demographics and clinical characteristics of Rift Valley retinitis
Author Age (years) Gender Laterality Method of Symptoms Signs VA at presentation Treatment Complications Duration of VA at last visit
(year) diagnosis follow-up
(months)
Freed 38 M U Serology Blurred vision, Dense white NR Aureomycin Persistent 2.5 NR

et al retro-orbital elliptical macular central
(1951)62 pain mass, slightly scotoma
raised, well
demarcated,
small
thrombosed
inferior temporal
capillary
localized to
macula
Schrire Mean: 35.8; M: 6 U: 6 Serology Central scotoma, Large yellowish OS: CF 1 m NR Persistent Mean: 1.0; OS: 6/36
(1951)215 range: 28e50 decreased macular central range: 0.8e2
vision, floaters swelling, small scotoma
hemorrhage
Large elevated OS: CF 1 m OS: CF 1 m
yellowish
macular mass
Small macular OS: 6/12 OS: 6/12
exudate with
central
hemorrhage
Large OS: 6/18 OS: 6/12
paramacular
exudate
Large OD: 6/18 OD: 6/6
paramacular
exudate
Vitreous haze, RD OD: CF 1 m OD: PL
Siam 50 M U Serology Reduced vision Vitreous OD: CF 0.5 m NR NR 1 NR
et al turbidity,
(1980)220 extensive
exudate-like
lesion in macular
area, edema,
hemorrhages
51 M U Serology Reduced vision Scattered, OD: 6/60
paramacular
exudate-like
lesions
431
432
Author Age (years) Gender Laterality Method of Symptoms Signs VA at presentation Treatment Complications Duration of VA at last visit
(year) diagnosis follow-up
(months)
Siam Mean: 48.4; M: 7 B: 4; U: 3 Serology Reduced vision Para/macular OD: CF 0.5 m NR Para/macular Range: 1.5e6 OD: CF 0.5 m
et al range: 26e55 exudate-like OD: 3/60 scar, occlusive OD: 6/9
(1980)221 lesions, OD: 2/60 vasculitis, OD: 6/60
hemorrhage, OD: 1/60; OS: 2/60 optic atrophy OD: 1/60;
retinal edema, OS: 6/36
vasculitis, OD: 1/60; OS: 6/9 OD: 6/36;
peripapillary OS: 6/9
choroidal OD: 1/60; OS: CF 0.5 m OD: 6/36;
ischemia, KPs, OS:
vitreous haze CF 0.5 m
OU: NPL OU: NPL
Al-Hazmi Mean: M: 111; B: 69; Serology Blurred vision, Macular retinitis: Range: 20/80-PL Supportive care Chorioretinal 9 Improved: 14;
et al 53.2 15.64; F: 32 U: 74 floaters, scotoma 151; paramacular with IV fluid, scar, vascular worsened: 17;
(2005)8 range: 14e80 retinitis: 61; antimicrobials, occlusion, same: 79
retinal blood transfusion, optic atrophy
hemorrhage: 85; hemodialysis, or
vitreous mechanical
inflammation: ventilation
55; optic disk
edema: 32;
retinal vasculitis:
15
Summary; Mean: 46.1; M: 127 B: 73 Serology Blurred vision, Para/macular Range: 6/9-PL Supportive Para/macular/ Range: 1e9 Improved: 22;
n, % range: 14e80 (79.9); (45.9); scotoma, exudative chorioretinal worsened:
F: 32 U: 86 floaters, retinitis, retinal scar, vascular 18; same: 83
(20.1) (54.1) retro-orbital hemorrhage, occlusion, optic
pain vasculitis, atrophy,
retinal/optic disk persistent
edema, vitreous central scotoma
inflammation
B, bilateral; CF, counting fingers; F, female; IV, intravenous; KPs, keratic precipitates; M, male; NPL, no light perception; NR, not reported; OD, oculus dexter; OS, oculus sinister; OU, oculus uterque; PL,
light perception; RD, retinal detachment; U, unilateral; VA, visual acuity.
mortality from severe manifestations such as meningoen- Since the spread of WNV in the Western Hemisphere after a
cephalitis or hemorrhagic fever.8,219 1999 outbreak in New York, there have been more than 16,000
Ocular complications of RVF range from blurred vision to cases and 660 deaths in North America.87
macular exudates, retinitis, and vasculitis. Most cases are Majority of WNV infections are asymptomatic or present
unilateral and affect males, although there are no updated with a mild, self-limited febrile illness with fever, headache,
reports in the literature after 2005. The demographics and myalgia, vomiting, and chills. Neurologic disease, including
clinical characteristics of Rift Valley retinitis are found in meningitis, encephalitis, and a poliomyelitis-like syndrome,
Table 14.8,62,215,220,221 develops in an estimated 1% of cases.87
WNV posterior uveitis is associated with WNV meningo-
2.19.2. Clinical features encephalitis.14,85 WNV chorioretinitis tends to occur in older
Systemic symptoms of RVF include pyrexia of unknown patients, those with coexisting diabetes mellitus, with higher
origin, headache, joint pain, and myalgia that occur 1 week likelihood of presenting with encephalitis.85 Diabetes mellitus
before the onset of ocular symptoms such as blurring of has been reported as a potential risk factor for multifocal
vision, scotoma, floaters and retro-orbital pain.8,62,215,219e221 chorioretinitis in WNV infection.88,122,126,127 The demographic
The most common fundus findings are progressive macular factors and clinical characteristics of WNV chorioretinitis are
or paramacular necrotizing retinitis consisting of white found in Table 15.13,14,19,69,88,122,126,127,218,224
exudate-like lesions, accompanied by retinal edema, hemor-
rhages, occlusive vasculitis, optic disk edema, and vitreous 2.20.2. Clinical features
haze.8,62,215,220,221 Nongranulomatous anterior uveitis was al- WNV posterior uveitis may present with symptoms of blurring
ways accompanied by posterior uveitis (panuveitis).8 of vision, visual field defect, floaters, diplopia, eye redness, or
pain about 1 to 2 weeks after the onset of fever, headache,
2.19.3. Ocular imaging findings myalgia, and nausea.19,87 The most common ocular manifes-
In the acute phase, FFA shows obscuration of background tation of WNV infection is bilateral multifocal chorioretinitis,
fluorescence, delayed peripapillary choroidal filling corre- found in more than 80% of patients The characteristic feature
sponding to the area of lesion, widespread vascular occlusion of WNV chorioretinitis is a curvilinear clustering of whitish
with extensive leakage, and late staining of retinal lesions. yellow chorioretinal scars with a “target-like” appearance,
After resolution, there may be a window defect at areas of following the course of the retinal nerve fibers.19,126 Other
scarring, residual delay in peripapillary choroidal filling, and features include occlusive retinal vasculitis, optic neuritis or
residual sheathed vessels.8,221 edema, retinal hemorrhages, and no or minimal anterior and
vitreous inflammation.13,14,19,69,85,88,122,126,127,217
2.19.4. Diagnosis
Diagnosis of RVF posterior uveitis is made based on the pre- 2.20.3. Ocular imaging findings
senting history, ocular signs, and positive serology of RVF Affected eyes are classified as active chorioretinitis or inactive
antibodies in ELISA, hemagglutination inhibition or comple- chorioretinitis with or without residual active lesions, based
ment fixation tests that show a 4-fold or higher rise in paired on ophthalmoscopic and FFA findings.122 Active chorioretinal
acute and convalescent samples.8,219e221 lesions appear as circular, deep, creamy lesions on ophthal-
moscopy with early hypofluorescence and late staining on
2.19.5. Treatment FFA. Inactive chorioretinal lesions appear partially atrophic
There is no established treatment for RVF infection, and and partially pigmented with central hypofluorescence and
management is mainly supportive with IV fluids, antimicro- peripheral ring-like hyperfluorescence.13,19,69,89,122,127,217,224
bials, blood transfusion, hemodialysis, or mechanical Indocyanine green angiography shows well-delineated hypo-
ventilation.8 fluorescent choroidal lesions, more numerous than those
appreciated by FFA or clinically.125,126,218,224 On OCT scan
2.19.6. Outcomes there may be inner retinal edema in active inflammation and
The visual prognosis of RVF posterior uveitis is poor, with retinal atrophy in the late stage.218,224
40%e50% of cases having a permanent loss of visual acuity
after resolution of retinitis.8,219,221 Most active retinal lesions 2.20.4. Diagnosis
spontaneously resolve within 12 weeks. The most common WNV posterior uveitis is diagnosed based on clinical history,
complications of RVF retinitis include chorioretinal (macular signs, and positive serology. The most common method used
or paramacular) scarring in about half of cases, vascular oc- for detecting WNV is detection of WNV IgM ELISA antibodies,
clusion and optic atrophy, leading to a persistent central which has a sensitivity approaching 100% at titres greater
scotoma and permanent vision loss.8,62,215,220,221 Up to 70% of than 1:30.13,14,19,69,88,122,125e127,224
patients remain legally blind.8
2.20.5. Treatment
2.20. West Nile virus Currently, there is no proven treatment for WNV infection.
Management of WNV infection and chorioretinitis is mainly
2.20.1. Background supportive. Topical prednisolone may be given to reduce the
WNV is a single-stranded RNA Flavivirus from the Flaviviridae inflammation. Khairallah and colleagues122 treated all of their
family that is transmitted by infected mosquitoes. WNV can hospitalized patients with ribavirin, according to its proven
be found in North America, Europe, Africa, Asia, and Australia. in vitro activity against WNV infection, although its efficacy
434
Table 15 e Demographics and clinical characteristics of West Nile virus chorioretinitis
Author Age Gender Laterality Associated Method Symptoms Signs VA at Treatment Complications Duration VA at last
(year) (years) conditions of presentation of follow- visit
diagnosis up
(months)
Bains et al 62 F B WNV infection Serology Floaters Deep, flat, creamy OD 20/25; OS Topical Chorioretinal scars 0.5 OD 20/25; OS
(2003)19 whitish yellow 20/40 prednisolone 20/30
outer chorioretinal
lesions, moderate
vitritis, small
intraretinal
hemorrhages
Hershberger 61 F B WNV infection Serology Blurred AC cells and flare, OD 20/30; OS Topical Chorioretinal scars 1 NR
et al vision creamy/partially 20/25 prednisolone
(2003)88 atrophic
nummular
chorioretinal
lesions
56 M B WNV Serology Floaters Optic disk edema, OU 20/25 Topical Chorioretinal scars 4 NR
meningoencephalitis retinal prednisolone
hemorrhages,
small white deep
chorioretinal
lesions
Anninger 55 F B WNV Serology Blurred Diffuse creamy OD 20/80; OS Nil Visual field loss, 6 OU 20/25
et al meningoencephalitis vision yellow 20/50 optic neuritis
(2003)13 chorioretinal
lesions
Anninger 55 F B WNV Serology Visual field Pale optic nerves, OD 20/80; OS Nil Optic atrophy 12 OD 20/60; OS:
et al meningoencephalitis loss, blurred vitreous cavity 20/40 “recovered”
(2004)14 vision, ocular cells, diffuse
pain creamy yellow
chorioretinal
lesions
Khairallah Mean: 53; M: 20; F: B: 23 WNV infection/ Serology Floaters: 8; Bilateral multifocal Mean: 20/32; Ribavirin Chorioretinal scars NR Mean: 20/25
et al range: 22 9 meningoencephalitis blurred chorioretinitis: 23; range: 20/20
(2004)122 e74 vision: 6; retinal e20/100
redness: 6; hemorrhages: 21;
visual field vascular
defect: 1; sheathing: 4; optic
diplopia: 1 disk swelling: 2
Khairallah Mean: M: 7; F: 5 B: 12 WNV infection Serology Floaters: 4; Multifocal Mean: 20/25; NR NR NR NR
et al 47.2; blurred chorioretinitis range: 20/20
(2006)126 range: 29 vision: 2; with linear e20/50
e62 redness: 2 clustering of
noncontiguous,
contiguous, or
confluent lesions
Garg et al 44 F B WNV CSF Vision loss Arterial OD 20/30; OS NR NR NR NR
(2006)69 meningoencephalitis attenuation, CF
intraretinal
hemorrhages,
cotton wool spots,
ischemic
whitening of
macula
68 F B WNV infection Serology Blurred Arterial OD 20/60; OS
vision attenuation, 20/25
scattered
chorioretinal
lesions,
intraretinal
hemorrhages
57 M B WNV CSF Vision loss Arterial OD 20/25; OS Panretinal Tractional RD, 18 OD 20/100;
meningoencephalitis attenuation, HM photocoagulation, vitreous OS 20/200
intraretinal vitrectomy hemorrhage
hemorrhages,
ischemic
whitening of
macula, cotton
wool spots, retinal/
disk
neovascularization
Khairallah Median: 57 M: 17; F: NR WNV Serology NR Chorioretinal NR NR CME 24 NR
et al 15 meningoencephalitis: lesions
(2007)127 27
Seth et al 81 M B WNV encephalitis Serology Decreased Mild vitritis, round, OD: NR; OS 20/ Intravitreal Chorioretinal 59 OS: HM 2 ft
(2007)217 vision cream-colored 400 bevacizumab for scars, CNV
chorioretinal CNV
lesions
Sivakumar Mean: 37; M: 22; F: B: 14; U: 23 WNV Serology Decreased Areas of discrete, Mean logMAR: Oral prednisolone Retinal atrophy, Range: 2e6 Mean
et al median: 15 meningoencephalitis: vision, ocular superficial, white 1.26 vascular occlusion, logMAR: 1.00;
(2013)224 35; range: 2 pain retinitis, neovascularization improved: 16;
9e65 multifocal same: 28;
choroiditis, retinal worsened: 2
edema, vasculitis,
retinal
hemorrhages,
optic disk
hyperemia,
neuroretinitis,
serous RD
435
has not been established. Complications of WNV may be
AC, anterior chamber; B, bilateral; CF, counting fingers; CME, cystoid macular edema; CNV, choroidal neovascularization; CSF, cerebrospinal fluid; F, female; HM, hand movement; M, male; NR, not
Duration VA at last managed with panretinal photocoagulation for neo-
improved
visit
vascularization, vitrectomy for vitreous hemorrhage or retinal
Majority
detachment, and intravitreal injection of antivascular endo-
thelial growth factor agent for macular edema.3,13,14,
19,69,88,122,126,127,217
of follow-
(months)
Range: 0.5
up
2.20.6. Outcomes
e59
WNV chorioretinitis is a self-limiting disease and usually has

neovascularization
hemorrhage, CNV,
Complications
good visual prognosis. Visual acuity returns to the baseline in

most patients, with up to half of patients having a final best
Chorioretinal
atrophy, RD,
scars, optic
corrected visual acuity of 6/12 or better.13,14,19,69,88,122,126,127,217

vitreous
Visual prognosis tends to be better in patients with focal

retinitis and worse in patients with occlusive vasculitis.224
Complications of WNV chorioretinitis include significant vi-
photocoagulation,
reported; OD, oculus dexter; OS, oculus sinister; OU, oculus uterque; RD, retinal detachment; U, unilateral; VA, visual acuity; WNV, West Nile virus.
sual field loss, chorioretinal scarring, optic atrophy, retinal

Treatment
prednisolone,
detachment, vitreous hemorrhage, choroidal neo-

Range: 20/20- Topical/oral
vitrectomy
vascularization, and severe ischemic maculopathy.3,13,

14,19,31,69,88,122,126,127,217,224
presentation
2.21. Zika virus

VA at
2.21.1. Background
HM
Zika virus (ZIKV), a neurotropic mosquito-borne Flavivirus

related to the dengue, yellow fever, and WNVs, was first
edema, vasculitis,
retinal/optic disk
identified in monkeys in 1947 and further isolated in humans

lesions, retinal
hemorrhages,
neuroretinitis
White-yellow
chorioretinal
Signs
in 1952. ZIKV is mostly transmitted by Aedes mosquitoes.

serous RD,
Direct interhuman transmission by sexual intercourse, verti-

cal, perinatal, and breast milk transmission has also been
reported.63,249,251 Since the ZIKV emergence in Brazil in April,
Method Symptoms
2015, it is estimated that more than one million Brazilians

visual field
were infected. Nearly, 80% of patients with ZIKV infection are

diplopia,
Floaters,
redness,
blurred
defect,
asymptomatic or oligosymptomatic.63,249,251
vision,
pain
Six months following the onset of the ZIKV outbreak, a 20-

fold annual increase of microcephaly cases was observed,
diagnosis
Serology,
with a prevalence of 99.7 per 10,0000 live births, leading the

of
Brazilian Ministry of Health to confirm a relation between

(58.0); F: U: 23 (28.4) meningoencephalitis CSF
ZIKV and microcephaly. Up to 34.5% of infants born with

presumed ZIKV-associated microcephaly have sight-
threatening ocular lesions. Majority of the children affected
Associated
conditions
B: 58 (71.6); WNV infection/
were female, and bilateral findings were present in 70% of

cases.63,249,251

Several infants with microcephaly were found to have mild to
Gender Laterality
gross macular pigment mottling, foveal reflex loss, well-

demarcated circular areas of neuroretinal or chorioretinal
atrophy with a predilection for the posterior pole and macula,
50 (42.0)
posterior pole pigmentary clumping, and optic nerve hypo-

M: 69
plasia with a double-ring sign, pallor, and increased cup-to-

disk ratio.63,109,169,249e251 In addition, there may also be
pigmentary and hemorrhagic retinopathy, extensive vascular

(years)
range: 9
Age
tortuosity, vascular absence, early abnormal vascular termi-

Summary; n, Mean:
56.4;
e74
nation, and torpedo maculopathy.173 Other ocular abnormal-

ities that have been reported include lens subluxation and iris
coloboma, but no infants had vasculitis or active uveitis.169
Author
These ocular findings can contribute to the diagnosis of

(year)
ZIKV congenital infection in children with

microcephaly.63,109,169,249e251
It remains unclear, however, whether the ocular lesions and optic neuritis.142,206 Other ocular conditions associated
are a direct result of ZIKV or caused by microcephaly (sec- with H1N1 include uveal effusion syndrome202 and orbital
ondary to ZIKV), but there could be a dual-mechanism inflammatory syndrome.22 Visual loss may also be caused by
involved. Ongoing registry studies are under way to confirm simultaneous retinal and lateral geniculate body
the causative association between ZIKV and infarction.29
microcephaly.109,176 No proven treatment exists for influenza retinopathy.
Although posterior uveitis in acquired ZIKV infection has Treatment of influenza posterior uveitis with systemic corti-
not been reported, uveitis may be a potential manifestation of costeroids has been shown to reduce the inflammation.233
acquired ZIKV infection. At least one case of ZIKV anterior Frosted branch angiitis and macular edema may be treated
uveitis has been reported, in which the anterior chamber with oral prednisone.110 The long-term outcomes are gener-
paracentesis PCR tested positive for ZIKV RNA, with signs of ally favorable in majority of the reported cases and H1N1
conjunctival hyperemia, punctate keratitis, non- posterior uveitis carries a better visual prognosis than other
granulomatous keratic precipitates, and anterior chamber viruses that cause acute retinitis.59,110,200,233 Complications
cells.65 are few and include involvement of the fellow eye.200
2.21.3. Diagnosis 2.22.2. Coxsackie B virus

Although ZIKV infection in infants could not be tested by Group B coxsackieviruses are single-stranded RNA Enterovirus
reverse transcriptase PCR, small head circumference and ce- from the Picornavirus family. These viruses cause a number of
rebral calcifications or lissencephaly were characteristic diseases ranging from asymptomatic, nonspecific febrile ill-
findings on computed tomography. In addition, the affected nesses, rashes, and upper respiratory tract disease to aseptic
mothers had dengue-like symptoms in the first or second meningitis and myocarditis.101
trimester of pregnancy, and both the mothers and infants had Posterior uveitis caused by coxsackieviruses is extremely
negative serology for toxoplasmosis, rubella, CMV, and HIV, rare. There have been few reports of chorioretinitis linked to
thus fulfilling the Brazilian Ministry of Health’s clinical criteria coxsackievirus, first described by Hirakata and colleagues in
for ZIKV-related microcephaly.63,173,249e251 1990.91 Symptoms include a viral prodrome consisting of
Recently, cerebrospinal fluid of infants with microcephaly fever, arthralgia, sore throat, headache, and diarrhea preced-
has been tested for ZIKV using the IgM antibody capture ing ocular symptoms such as blurring of vision, meta-
enzyme-linked immunosorbent assay (MAC-ELISA) test,250 morphopsia, and photopsia. On fundus examination, there
following the Centers for Disease Control and Prevention was a unilateral retinal vasculitis, papillitis, and chorior-
protocol as described by Martin and colleagues.165 etinitis in one case caused by coxsackievirus B3,61 and cream-
colored parafoveal spots at level of the RPE with similar
2.21.4. Treatment and outcomes confluent spots in the midperiphery in another case caused by
As yet, there are no data on treatment and long-term out- coxsackievirus B4.113 In both cases, there was complete reso-
comes of ZIKV posterior uveitis. There is currently no vaccine lution of the lesions with excellent visual outcomes.61,113
for ZIKV. Environmental modifications and efforts to eradicate Unilateral acute idiopathic maculopathy has also been
mosquitoes are important to reduce and prevent ZIKV-related associated with Coxsackie virus.112 Unilateral acute idiopathic
microcephaly and ocular manifestations, as well as reduce the maculopathy is a rare cause of unilateral, sudden, painless
infection rates of other vector borne diseases such as dengue vision loss in young immunocompetent adults. A viral pro-
fever, chikungunya, and WNV. In areas where ZIKV is preva- drome is common and 50% of patients had positive titres for
lent, clinicians should perform ophthalmologic examination Coxsackie virus.112 Initially there are irregular, circular areas
on all microcephalic babies.109 Further long-term follow-up of white-gray macular discoloration, serous macular detach-
studies have to be done to determine the optimal management, or exudative neurosensory retinal detachment.112
ment and visual prognosis of ZIKV posterior uveitis. Several FFA studies showed findings of irregular RPE hyper-
fluorescence and hypofluorescence. Following resolution,
2.22. Other rare viruses there is a bull’s eye pattern of pigmentary disturbance at the
macula, well-circumscribed areas of RPE atrophy, and pro-
2.22.1. Influenza A (H1N1) virus gressive hyperplasia with late staining on FFA. Indocyanine
Influenza H1N1 virus is a more recent variant strain of influ- green angiography showed “moth-eaten” choroidal vascula-
enza that is most closely related to the swine influenza A vi- ture, and OCT showed partially reversible disruption of the
ruses. H1N1 virus was the most common cause in a human outer photoreceptor layer. Nearly, all patients experienced
influenza pandemic in 2009. Symptoms of H1N1 include fever, spontaneous visual recovery, with improvement between 20/
cough, sore throat, diarrhea, and vomiting.152 Ocular 20 and 20/30 at final follow-up.112
involvement is rare and has been associated with H1N1
infection as well as influenza vaccination.124,160,233 2.22.3. Ebola virus
Ocular symptoms include pain, redness, and decreased Ebola virus disease (EVD) is a severe hemorrhagic fever caused
visual acuity.200 On examination,59,200 there may be dense by 5 species of RNA Ebolaviruses from the Filoviridae family.
anterior chamber inflammation, vitritis, peripheral retinal Ebola virus infects human monocytes and causes a loss of
necrosis, choroiditis, submacular hemorrhages, macular endothelial barrier function. The first reported cases of EVD
edema, neuroretinitis, vaso-occlusive retinal vasculitis,35 occurred in 1976. The current epidemic in West Africa that
frosted branch angiitis,110 exudative retinal detachment,233 began in December, 2013, is the largest known. As of February,
2016, over 28,500 cases have been reported, with a fatality may be useful, especially in cases of atypical clinical pre-
ratio of 50%e65%.168,236,247,253 sentations. The treatment of viral posterior uveitis is complex
EVD cases may be asymptomatic or manifest as high fever, and requires careful monitoring to provide the appropriate
diarrhea, myalgia, arthralgia, and conjunctival injection. Fatal balance of symptomatic treatment, systemic or ocular anti-
cases present with shock and coagulopathy. Late complica- viral medication, corticosteroids, and management of com-
tions in survivors include auditory, arthritic, cardiac, and plications to ensure optimal long-term visual outcomes.
ocular disease (including vision loss, conjunctivitis, and uve-
itis) that develop during convalescence.168,236,247,253
Hypertensive uveitis characterized by ocular pain, photo-
phobia, hyperlacrimation, foreign body sensation, red eye, 4. Method of literature search
and progressive visual loss develops in as many as 20% of
convalescent patients, who may be asymptomatic for up to 2 A search of Medline, using PubMed and Google Scholar was
months. The presence of blurred vision, photophobia, red or performed. Keywords that were included for the search were:
itchy eye, or fever during acute EVD was associated with un- “viruses,” “viral posterior uveitis,” “herpetic retinitis,” “acute
derlying uveitis during convalescence. Vitreous opacities, retinal necrosis,” “progressive outer retinal necrosis,” “CMV
multiple, peripheral chorioretinal scars with hypopigmented retinitis,” “HIV retinitis,” “measles retinopathy,” “rubella reti-
halos, and small intraretinal hemorrhages were seen on pos- nopathy,” “dengue posterior uveitis,” “chikungunya posterior
terior segment examination. Uveitis was diagnosed as poste- uveitis,” “Rift Valley retinitis,” “West Nile Virus chorioretinitis,”
rior uveitis and panuveitis in up to 26% and 25% of patients “Zika posterior uveitis,” “Ebola posterior uveitis,” “polymerase
with ocular symptoms, respectively.132,168,236,247,253 chain reaction.” Articles were selected based on clinical
Ebola virus is detected by ELISA, reverse transcriptase PCR importance. Additional references of key articles were also
assay, or viral culture from the serum, semen, conjunctival included. Articles with non-English abstracts were excluded.
swab, or aqueous humour samples. Ebola viral load at the time
of EVD diagnosis is a key independent predictor of ocular
symptoms and uveitis in patients during convales-
cence.132,168,247,253 Posterior uveitis caused by Ebola virus can references
be treated with topical, oral, or periocular corticosteroids,
mydriatics, and management of intraocular pressure with
ocular hypotensive agents.132,236,247,253 The mainstay of man- 1. Mortality in patients with the acquired immunodeficiency
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agement of EVD is supportive (IV fluids, antipyretics, antibi-
cytomegalovirus retinitis. Studies of ocular complications of
otics, and blood transfusion) with isolation and strict barrier AIDS research group, in collaboration with the AIDS Clinical
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trials. This includes direct antiviral agents (favipiravirda
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RNA-dependent RNA polymerase inhibitordand BCX4430),
4. Agarwal A, Kumari N, Trehan A, et al. Outcome of
monoclonal antibodies (ZMapp), type I interferons, RNA cytomegalovirus retinitis in immunocompromised patients
interferenceebased drugs (TKM-Ebola and AVI-7537), and without human immunodeficiency virus treated with
anticoagulant drugs (rNAPc2). So far, there is no conclusive intravitreal ganciclovir injection. Graefes Arch Clin Exp
evidence of efficacy in clinical trials with the above drugs, and Ophthalmol. 2014;252(9):1393e401
further testing is required.156,266 5. Ahmadieh H, Soheilian M, Azarmina M, Dehghan MH,
Mashayekhi A. Surgical management of retinal detachment
In a study done by Tiffany and colleagues,236 the visual
secondary to acute retinal necrosis: clinical features,
acuity did not change during the follow-up period in majority surgical techniques, and long-term results. Jpn J
of uveitis patients, worsened unilaterally in 4, and improved Ophthalmol. 2003;47(5):484e91
in 9 of 58 patients. Complications of Ebola posterior uveitis 6. Aizman A, Johnson MW, Elner SG. Treatment of acute retinal
include recurrence of anterior uveitis that may evolve into a necrosis syndrome with oral antiviral medications.
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s u r v e y o f o p h t h a l m o l o g y 6 2 ( 2 0 1 7 ) 4 0 4 e4 4 5

Available online at www.sciencedirect.com

journal homepage: www.elsevier.com/locate/survophthal

Viral posterior uveitis

Joanne H. Leea, Aniruddha Agarwal, MDb,

article info abstract

1. Introduction The incidence of uveitis has been estimated between 17

2. Viral posterior uveitis

Laterality, n (%) Infectious status, % Viral

2.4. Treatment HSV-1 retinitis is more common in older patients, whereas

or neuroretinitis with the presence of relative afferent pupil- 2.9.6. Outcomes

Table 9 e Demographics and clinical characteristics of nonnecrotizing herpetic retinitis

Bodaghi et al Mean: 53.2; M: 1; F: 4 B: 4; U: 1 HIV; immunosuppressive VZV: 3; Aqueous Herpetic

Wickremasinghe 48 M U NR VZV Vitreous Herpetic

76 M U NR VZV Vitreous Herpetic

Wensing Mean: 55; M: 6; F: 3 B: 2; U: 7 Immunosuppressive VZV: 7; PCR and Herpetic

Albert et al 19 F B NR HSV-1 Aqueous NR

11 M U Tetralogy of VZV Vitreous NR

Summary; n, % Mean: 43.7; M: 10 B: 7 Immunodeficiency: 8 VZV: 13 Aqueous Herpes

Symptoms Signs VA at Treatment Complications Duration of VA at last visit

NR Mild to moderate Case 1: OD Oral valacyclovir, NR Mean: 11.2; Case 1: OD 20/30

2.11.6. Outcomes 2.12. Other herpetic posterior segment manifestations

(continued on next page)

and coma.17,194,268 The prevalence has declined since the

males. It is usually bilateral, and patients are often

peripapillary vascular sheathing, and secondary pigmentary

retinopathy with a “salt and pepper” appearance.212

In SSPE, visual symptoms and retinopathy precede the

onset of neurological findings by weeks to years. The most

toward peripheral retina. It preferentially affects the retina

with secondary involvement of the RPE and

ledema and optic atrophy, and retinal changes such as retinal

folds, edema, hemorrhage, serous detachments, and occlu-

sive vasculitis.17,18,271 There is minimal vitreous inflamma-

tion.17 The lesions usually resolve rapidly with varying

Diagnosis of measles posterior uveitis is clinical and

confirmed by positive measles serology with complement

fixation, enzyme immunoassay, immunofluorescent and

bodies in the cerebral spinal fluid in cases of SSPE.270 FFA may

show early hypofluorescence which changes into hyper-

inflammation, diffuse leakage secondary to widespread

retinal edema, and zones of atrophy, RPE mottling, or occlu-

sive vasculitis.18,212,268 OCT shows signs of necrotizing reti-

nitis with focal areas of moth-eaten disorganization in the

There is no definitive treatment for measles retinopathy or

condition is often fatal. Various treatment regimens have

been tried with little success, including IV IgG, plasma ex-

change, cytarabine, amantadine, and interferons. The most

promising results to date use a combination of isoprinosine

(inosiplex), an antiviral agent, and intraventricular, intra-

thecal, or intracameral interferon alpha as an immunomod-

ulator, with stabilization or improvement in some

agement of measles posterior uveitis is controversial, and

there is lack of any evidence or published literature about

(continued on next page)

stricted to less than 15 degrees.212,270

Salt and pepper 2.15. Rubella

Rubella, also known as German measles or 3-day measles, is a

Bodaghi et al Mean: 53.2; M: 1; F: 4 B: 4; U: 1 HIV; immunosuppressive VZV: 3; Aqueous Herpetic