Received: 12 August 2018 Revised: 7 October 2018 Accepted: 11 October 2018

DOI: 10.1111/ceo.13417

REVIEW

Demystifying viral anterior uveitis: A review

Nicole Shu-Wen Chan MBBS1 | Soon-Phaik Chee FRCOphth MMed(S'pore)1,2,3,4

1
Singapore National Eye Centre, Singapore,
Singapore A viral aetiology should be suspected when anterior uveitis is accompanied by ocu-
2
Singapore Eye Research Institute, Singapore, lar hypertension, diffuse stellate keratic precipitates or the presence of iris atrophy.
Singapore The most common viruses associated with anterior uveitis include herpes simplex
3
Department of Ophthalmology, Yong Loo Lin virus, varicella-zoster virus, cytomegalovirus and rubella virus. They may present
School of Medicine, National University of
as the following: Firstly, granulomatous cluster of small and medium-sized keratic
Singapore, Singapore, Singapore
4
precipitates in Arlt's triangle, with or without corneal scars, suggestive of herpes
Duke-NUS Medical School, Singapore,
Singapore simplex or varicella-zoster virus infection. Secondly, Posner-Schlossman syndrome
Correspondence with few medium-sized keratic precipitates, minimal anterior chamber cells and
Dr Soon-Phaik Chee, Singapore National Eye extremely high intraocular pressure; this is mainly associated with cytomegalovi-
Centre, 11 Third Hospital Avenue, Singapore rus. Thirdly, Fuchs uveitis syndrome, with fine stellate keratic precipitates diffusely
168751, Singapore.
Email: chee.soon.phaik@singhealth.com.sg
distributed over the corneal endothelium, with diffuse iris stromal atrophy but with-
out posterior synechiae, is associated mainly with rubella or cytomegalovirus infec-
tion. In rubella, the onset is in the second to third decade. It presents with posterior
subcapsular cataract, may have iris heterochromia and often develops vitritis with-
out macular oedema. Cytomegalovirus affects predominantly Asian males in the
fifth to seventh decade, the keratic precipitates may be pigmented or appear in
coin-like pattern or develop nodular endothelial lesions, but rarely vitritis. Eyes
with cytomegalovirus tend to have lower endothelial cell counts than the fellow
eye. As their ocular manifestations are variable and may overlap considerably, viral
AU can pose a diagnostic dilemma. Thus, quantitative polymerase chain reaction
or Goldmann-Witmer coefficient assay from aqueous humour samples are preferred
to confirm the aetiology and determine the disease severity as this impacts the
treatment.

KEYWORDS

cytomegalovirus, herpes simplex virus, rubella virus, varicella-zoster virus, viral

anterior uveitis

1 | INTRODUCTION vision. Concomitant scleritis or posterior segment involve-

Anterior uveitis (AU) is the most common type of intraocu-
lar inflammation. It may be acute (of sudden onset, lasting
for <3 months), recurrent (episodes separated by quiescence
lasting >3 months) or chronic (persistent for >3 months).1
Acute AU usually presents with unilateral eye pain, redness,
blurring of vision, photophobia and tearing, while chronic
AU may be asymptomatic or present with mild blurring of
ment should be excluded.
AU may be infectious, non-infectious, which includes
immune-mediated conditions, and secondary to masquerade
syndromes. The most common AU is HLA-B27-associated
AU which typically presents as unilateral acute non-
granulomatous inflammation with a marked fibrinous reac-
tion and hypopyon. Intraocular pressure (IOP) is often
reduced.

© 2018 Royal Australian and New Zealand College of Ophthalmologists

320 wileyonlinelibrary.com/journal/ceo Clin. Experiment. Ophthalmol. 2019;47:320–333.
CHAN AND CHEE
In contrast, viral AU should be suspected with elevated
IOP or iris atrophy. Viral clinical phenotypes include2: AU
with granulomatous keratic precipitates (KPs) with or with-
out corneal scars; Posner-Schlossman syndrome (PSS)-like
uveitis; and Fuchs uveitis syndrome (FUS)-like uveitis.
Steroid-recalcitrant AU also has a high likelihood of viral
infection (67%).3 The most commonly implicated viruses are
Herpes simplex virus (HSV), varicella-zoster virus (VZV),
cytomegalovirus (CMV) and rubella virus (RV). As they
have variable ocular manifestations and may present simi-
larly, viral AU can pose a diagnostic dilemma. This review
focuses on the clinical manifestations of viral AU, as well as
clinical clues and patterns that suggest a viral aetiology and
help in differentiating one virus from another.
2 | CL IN IC A L F E A T U RE S OF VI RA L
A NT E RI O R U VE IT IS
2.1 | Phenotypes of viral anterior uveitis
2.1.1 | Granulomatous keratic precipitates with or without
corneal scars
Unlike the endothelial dusting seen in non-granulomatous
inflammation, viral AU presents with granulomatous
FIGURE 1 Fuchs uveitis syndrome. (Top left) fine stellate keratic precipitates are diffusely distributed over the entire endothelium in Fuchs uveitis
syndrome (FUS). (Top right) the cataract is typically posterior subcapsular in FUS. (Bottom left) diffuse iris stromal atrophy creates a moth-eaten appearance
of the brown-coloured iris. (Bottom right) the same eye (bottom left) status post cataract surgery. The previously brown iris now appears darker in colour due
to progressive stromal atrophy exposing the posterior pigment epithelium
321
inflammation with individual small, medium or large KPs.
Although active keratitis may not be present during an epi-
sode of viral AU, corneal scars are important clues that sug-
gest possible previous viral keratitis, likely caused by HSV
or VZV infection in the absence of a history of trauma.
2.1.2 | Fuchs uveitis syndrome
FUS is a chronic low-grade inflammatory disorder predomi-
nantly involving the anterior uvea and vitreous and is mostly
unilateral (90%).4 Fuchs first described the entity of hetero-
chromia, cyclitis with KPs, and cataract associated with vit-
reous involvement.5 Although historically referred to as
"Fuchs heterochromic iridocyclitis,” the term “FUS” may be
preferred as heterochromia may not always be present and
“cyclitis” does not adequately describe the involvement of
other structures from the corneal endothelium to the vitreous
and optic disc.
As it is less aggressive than other uveitides, majority of
patients are asymptomatic for a long period of time. It com-
monly presents in the third and fourth decade of life, with no
gender predilection,6 for the evaluation of floaters from vitri-
tis, or blurring of vision when complicated by the presence
of a posterior subcapsular cataract (in over 80%) (Figure 1).
322
Aetiology
FUS likely represents a final common pathway of low-grade
immunoreactivity. RV is the main etiologic agent in Europe
(90%-100%) and the United States,7–9 as confirmed by ele-
vated titres of oligoclonal RV-specific antibodies in the
aqueous humour of affected eyes.8,10 In East Asia, CMV is
the predominant cause and is especially common in Singa-
pore, Taiwan and Japan.2 Other reported infectious aetiol-
ogies include HSV,11 toxocariasis12 and toxoplasmosis.13
Clinical signs
Ocular inflammation is usually mild with a low-grade ante-
rior chamber inflammation and absent ciliary injection.
Unlike the typical inferior distribution of KPs in other uvei-
tides, the fine white stellate KPs are diffusely distributed
over the entire endothelium in FUS (Figure 1).
It is believed that certain signs of this syndrome vary
depending on the aetiology. As RV is the most common
cause in Western populations, the features originally
described by Fuchs5 likely describe the FUS caused by
RV. CMV was not identified as a cause of FUS until in
recent years when it was reported more frequently in Asia.
The clinical signs of CMV-associated FUS therefore differ
in some aspects from those in RV-associated FUS (see
Table 1).17
Heterochromia is more apparent in light-coloured irides
and may be noticed by the patient decades before visual
symptoms develop. The affected eye is usually hypochromic
due to diffuse pigment loss,18,19 but may be hyperchromic
when anterior stromal atrophy exposes the darker iris pig-
mented epithelium (Figure 1). In brown irides, the iris
appears more black than brown as a result of the atrophy. As
heterochromia depends on the initial amount of pigment and
the degree of atrophy, its frequency varies widely (12.7%-
82%)18,20,21 and is often absent in heavily pigmented eyes.
Structural changes in the iris occur earlier than hetero-
chromia. Atrophy affects all layers of the iris19,22,23 and
radial markings at the pupillary border become less promi-
nent.6 The iris loses its normal corrugated texture18,22 and
may develop a moth-eaten appearance (Figure 1).22,23
Advanced, patchy atrophy of the posterior pigment epithe-
lium can cause irregular transillumination defects.6,22,23 In
later stages of the disease, loss of iris tone from diffuse atro-
phy and loss of sphincter muscle may cause flattening or
even concavity of the iris, resulting in a widened iridocor-
neal angle and increased anterior chamber depth.24
With generalized iris atrophy, both normal and abnormal
vasculature appear more prominent, and fragile vasculature
in the trabecular meshwork or iridocorneal angle are easily
visualized on gonioscopy.25 These vessels are prone to
bleeding, giving rise to a filiform haemorrhage and
hyphaema formation after anterior chamber paracentesis
(Amsler's sign26), a characteristic27 but not pathognomonic
finding. Hyphema has also been described to occur
CHAN AND CHEE
spontaneously,22 likely after trivial self-injury such as eye-
rubbing.
Koeppe nodules (20%-30%)4 on the pupillary margin are
typically small and translucent and are easily missed, espe-
cially in pale irides. Synechiae formation may rarely occur
transitorily in the area of the Koeppe's nodules, leaving typi-
cal radial pigmented lines on the anterior surface of the
lens.4 Small, refractile iris crystals representing Russell bod-
ies are also typical of FUS.28
Vitritis is seen in almost all cases of RV-associated
FUS29 but is rare in CMV infection. Although the vitritis
may even be so significant as to obscure the view of the fun-
dus, visual acuity remains good as there is no associated
cystoid macular oedema, unlike in intermediate uveitis.
Toxoplasmosis-like scars (56.5%),30 non-specific chorioret-
inal scars and histoplasmosis-like scars21 have been reported.
Glaucoma is the most serious vision-threatening compli-
cation. In a cohort study of 103 patients with FUS, 26.2%
had glaucoma, of which half were diagnosed at presentation.
Most patients have open angle glaucoma that is usually
refractory to medical and even to surgical therapy.31
2.1.3 | Posner-Schlossman syndrome
PSS is characterized by recurrent, acute attacks of mild uni-
lateral AU with a single or couple of granulomatous KPs
accompanied by markedly elevated IOP,32 which may cause
mild ocular discomfort with mild blurring of vision and
haloes. It occurs more frequently in the third decade of life
in European populations,33 but presents later in the Far East
(mean age 33-59 years old).2,34–36 Regardless of age, males
are at higher risk of developing PSS (50.5%-71.4%).2,33,35
Aetiology
Bloch-Michel et al first demonstrated local production of
CMV-specific antibodies in the aqueous humour.37 Although
HSV38 and other organisms have been proposed by isolated
cases studies, CMV appears to be a major cause of
PSS.2,3,34,36,39–42 The proportion of CMV positivity in PSS
varies globally; studies in Singapore2 and Thailand3 found
52% and 26.4% of eyes with PSS to be CMV-positive, while
smaller studies in France and Iran reported lower rates of
71%41 and 40%,39 respectively; possibly reflecting the differ-
ent rates of endemic infection.
Clinical signs
Despite the low-grade anterior chamber inflammation and a
single or a few granulomatous KPs, the presenting IOP is
uniformly high (mean 43-49 mmHg).2,35,39 Diffuse iris stro-
mal atrophy may be present (38.8%).2
Clinical features that favour CMV as the aetiology of
PSS include being male, corneal endotheliitis, coin-shaped
lesions, linear KPs and diffuse iris atrophy.36,43 The endo-
thelial cell count (ECC) is usually reduced compared to the
TABLE 1 Clinical manifestations of herpes simplex virus, varicella-zoster virus, cytomegalovirus and rubella virus.2,14–16 This table summarizes and compares the clinical features of the four most common aetiologies of
viral anterior uveitis, which are helpful in helping the ophthalmologist arrive at the likely diagnosis
Cytomegalovirus (CMV)
Chronic Rubella virus
CHAN AND CHEE

Chronic CMV anterior CMV-associated Fuchs

Herpes simplex virus (HSV) Varicella-zoster virus (VZV) Posner-Schlossman syndrome uveitis uveitis syndrome (FUS) RV-associated FUS
Patient demographics
Age <50 years old(mean 43  15 y) > 60 years old (mean age 20-50 y old 40-60 y old 40-60 y old 20-40 y old (mean age
53  23 y) 35  12 y)
Immunocompromised (of any
age)
Gender No predilection No predilection Males Males Males No predilection
Population No predilection No predilection No predilection Western Asian (particularly Chinese Western
and Japanese)
Laterality Mostly unilateral (bilateral in 18%) Unilateral Unilateral Unilateral Unilateral Mostly unilateral (bilateral in
14%)
Course Acute, recurrent Acute, recurrent Acute, recurrent Chronic Chronic Chronic
Intraocular pressure Acute spikes Acute spikes Very high (up to 50 mmHg) Very high (up to Very high (up to 50 mmHg); May be complicated by persistent
during acute episodes 50 mmHg); persistently persistently elevated elevation (25%)
elevated (73.3%)
Dermal manifestations Grouped vesicles occurring at the Vesicular rash involving the CN V1 None None None None
border of the eyelids with diffuse dermatome
oedema; Rarely, in a dermatomal
distribution (zosteriform herpes
simplex)
Conjunctival injection Moderate to severe Moderate to severe Mild Mild Mild None
Corneal manifestations
Corneal sensation May be reduced May be reduced (more profound Intact Intact Intact Intact
and diffuse hypoaesthesia than
HSV)
Epithelial keratitis Dendritic ulcers (usually branching, Pseudodendritic ulcers (less regular None None None None
with well-developed terminal branching, few terminal
bulb) dilatations)
Stromal keratitis Disciform keratitis; Interstitial Nummular keratitis; Limbal Immune ring keratitis None
keratitis; Immune ring keratitis keratitis; Immune ring keratitis
Corneal scars Present (33%) Present (25%) Rare None
endotheliitis May be present May be present May be present May be present May be present;  nodular None
endothelial lesions
Keratic precipitates
Size Small to medium Small to medium KPs Medium to large (39%) Small Fine and stellate (44%) Fine and stellate; may not be
stellate
Distribution Central, paracentral, diffuse, or in Central, paracentral, diffuse, or in Single or a few in number in the May have coin-like Diffusely distributed; May Diffusely distributed
Arlt's triangle; Arlt's triangle; Located in the central or peripheral cornea; lesions have coin-like lesions
Located in the same distribution as same distribution as the inflamed May have coin-like lesions
the inflamed cornea cornea
323
 324

TABLE 1 (Continued)

Cytomegalovirus (CMV)
Chronic Rubella virus
Chronic CMV anterior CMV-associated Fuchs
Herpes simplex virus (HSV) Varicella-zoster virus (VZV) Posner-Schlossman syndrome uveitis uveitis syndrome (FUS) RV-associated FUS
Colour White; White; White or grey White or grey; may be White or grey; May be White; never pigmented
May be pigmented May be pigmented brown pigmented
Endothelial cell Normal Normal Reduced Reduced Reduced Normal
densities
Anterior chamber Moderately severe generally less Severe inflammation. Generally Minimal Minimal Mild Mild
inflammation severe than VZV more severe than HSV
Iris
Iridoplegia May be present during acute phase, May be present during acute phase, Absent Absent Absent Absent
causing pupil flattening causing pupil flattening
Iris atrophy Sectoral or patchy atrophy with Sectoral atrophy with Mostly absent; Rarely diffuse Rarely sectoral Diffuse stromal atrophy; rarely Diffuse atrophy;  fine iris
transillumination defects;  transillumination defects; stromal atrophy may transilluminate transillumination
spiral atrophy Massive iris atrophy with gross
sphincter damage (rare)
Other features — —
 focal iris stromal haemorrhage  focal iris stromal haemorrhage  Amsler's sign  Amsler's sign;  Koeppe
nodules
Heterochromia Absent Absent Absent Absent Rare Present (especially in
light-coloured irides)
Posterior synechiae May be present May be present Absent Absent Absent Absent
Cataract Develops late in disease Develops late in disease Develops late in disease Develops late in disease Develops in 81.3% Develops early; Present at
presentation in 47%; Develops
in 45%
Posterior segment features
Vitritis Less common Common Absent Absent Rare Almost always present
Chorioretinal scars — — None None Absent May be present
Miscellaneous — — — — Disc hyperemia/swelling Disc hyperemia/swelling (9%);
(10.3%); Fluorescein angiography;
Fluorescein angiography; Disc hyperfluorescence or leakage
Prolonged arm-to-retina time (97.7%);
(73%); Vascular leakage (13.6%)
Disc hyperfluorescence or
leakage (27%);
Vascular leakage (9%)
CHAN AND CHEE
CHAN AND CHEE 325

FIGURE 2 Varicella-zoster virus and herpes simplex virus anterior uveitis. (Top left) small to medium-sized keratic precipitates (KPs) are seen over the
inferior corneal endothelium in varicella-zoster virus anterior uveitis. Note the overlying faint stromal scar. (Top right) corneal scars and medium-sized KPs in
Arlt's triangle are seen in herpes simplex virus (HSV) anterior uveitis. (Bottom left) the pupil has a flattened border at the 7 to 8 o'clock position due to
sectorial iris involvement by HSV. The eye is injected and the cornea is hazy secondary to raised intraocular pressure. (Bottom right) following resolution of
the acute episode, the same eye (bottom left) develops sectoral iris atrophy involving the pigmented epithelial layer, without the formation of posterior
synechiae

fellow eye. Other aetiologies of PSS have no gender predi-
lection nor specific pattern of KPs or iris atrophy.
Glaucoma develops in about 26%, of which 17% of
patients require filtration surgery.35 The risk of glaucoma
progression is 2.8 times higher in patients with PSS for more
than 10 years duration compared to those with PSS for less
than 10 years duration,35 and CMV-positive eyes are more
likely to require filtration surgery (13.24% vs 1.72%).44
Interestingly, despite transient hemodynamic changes that
occur at the optic nerve head during acute attacks, the num-
ber of episodes is not predictive of glaucoma progression45
and no evidence exists as to whether prolonged inflamma-
tion lead to glaucomatous field loss.
2.2 | Herpes simplex virus
HSV ocular disease is commonly caused by HSV type 1,46
and typically affects individuals of both genders in their
fourth and fifth decades of life.47 HSV AU occurs more fre-
quently during reactivation than in primary disease. When
the HSV viral genome lying latent within the trigeminal sen-
sory ganglion reactivates, it is transported down the axon,
manifesting in the periocular skin, cornea or as intraocular
inflammation. The patient may have a history of recurrent
fever or blisters.48 Several studies have also suggested that
HSV maintains latency in the cornea, although this is has
not been established definitively.49
2.2.1 | Clinical signs
The KPs are usually medium-sized (Figure 2) but may be
small. There is generally moderate anterior chamber activity
with cells and flare, and a prominent ciliary flush and small
hypopyon50 may be seen. Posterior synechiae may develop
(38%) and vitritis is present in 43%.14 The IOP is acutely ele-
vated likely due to trabeculitis.48,51,52
During acute inflammation, there may be sectoral irido-
plegia and localized flattening of the pupil border in the
affected area (Figure 2), associated with poor reaction to
light. After the acute attack resolves, destruction of the pig-
ment epithelium results in patchy or sectoral iris atrophy
(Figure 2) that transilluminates (in up to 50%).52,53
Corneal scars (33%) and hypoaesthesia may be present
from previous epithelial or stromal keratitis.14 HSV AU
commonly occurs in eyes with active or prior keratitis54 and
the severity of the uveitis generally correlates with the sever-
ity of the keratitis; chronic stromal or endothelial disease are
usually associated with more profound uveitis.55 However,
HSV AU may occur in the absence of keratitis55 as dendrites
are transient and present less frequently during recurrence.
326
2.3 | Varicella-zoster virus
Following primary infection, VZV lies dormant in the neural
sensory ganglia and reactivates when VZV-specific immu-
nity wanes, typically during the sixth or seventh decade
of life.
2.3.1 | Clinical signs
Herpes zoster ophthalmicus (HZO) often presents with pain,
followed by a vesicular eruption in the dermatome of the
ipsilateral ophthalmic division of the trigeminal nerve. The
presence of skin lesions at the tip, side or root of the nose
(Hutchinson's sign) is a strong predictor of ocular inflamma-
tion. VZV AU occurs in 40% to 60% of HZO in immuno-
competent patients56,57 and may present months after the
rash resolves.56–58 It can also occur in the absence of dermo-
pathy (herpes zoster sine herpete) or neuralgia.57–59
VZV AU presents as an acute mild to severe hyperten-
sive AU57 and is more frequently associated with conjuncti-
val redness, corneal oedema, posterior synechiae, vitritis and
higher IOP compared to HSV AU.15 There is often a high
aqueous flare count and moderate anterior chamber cellular
activity; anterior and posterior synechiae are common.14 The
KPs which may be small or medium-sized (Figure 2), or
mutton-fat, and trabecular meshwork tend to become pig-
mented even without treatment. Vitritis develops in 83% of
eyes.14
Segmental iris atrophy (triangular sectoral loss of iris
pigment epithelium with the base lying at the iris root)57
may develop after the acute episode resolves and cause a
transillumination defect. A minority may have massive iris
atrophy with gross sphincter damage.
Secondary glaucoma (15%-43%)56 may develop through
a variety of mechanisms including posterior synechiae, tra-
beculitis and peripheral anterior synechiae (PAS).57,58 Poste-
rior subcapsular cataract may be a result of chronic
inflammation or topical steroid use.57,58
Corneal manifestations including interstitial keratitis,
nummular keratitis and ring infiltrate,56,60 strongly support
the diagnosis of VZV AU. Coarse pseudodendrites with an
elevated appearance that lack terminal bulbs may be seen on
fluorescein staining61 and corneal sensation may be reduced.
Corneal scars may be seen (25%),14 and there may be con-
comitant episcleritis or scleritis.56,57
2.4 | Cytomegalovirus
Ocular tissues may be a site of CMV latency as suggested
by murine studies demonstrating CMV persistence in the
eye even after resolution of the systemic infection.62 CMV is
an important cause of hypertensive AU in immunocompetent
individuals,16,34,37,42,63–65 and there is likely a prominent
immunological component involved in CMV AU as it is not
seen in immunocompromised individuals.16
CHAN AND CHEE
The manifestations of CMV AU vary.16,34,37,42,64 Youn-
ger patients in their third to fifth decade usually present with
PSS, while older patients in their fifth to seventh decade
(mean 65 years old2) present with chronic unilateral hyper-
tensive AU which may resemble FUS.2 In a study of
105 eyes with hypertensive AU in immunocompetent
patients,34 22.8% were positive for CMV, of which 75% and
20.8% presented as PSS and FUS, respectively. A similar
study of 16 CMV-positive eyes reported 43.8% and 18.8%
of eyes presenting as PSS and FUS, respectively.36
CMV AU is predominantly seen in males (60%-
86%).2,16,34,36,42,43,64–69 Most cases have been reported from
Asian countries, particularly from Chinese and Japanese
populations,3,16,34,36,37,40,42,64–66,70,71 which may be related
to the higher seroprevalence in Asia.72
2.4.1 | Clinical patterns
Acute CMV anterior uveitis
CMV is thought to be the cause of PSS2,3,34,36,37,39–42 in
both Asian and Western populations, although other rarer
causes are possible.38 There is classically minimal inflamma-
tion, with minimal or no circumciliary injection, a single or
a few small- and medium-sized central KPs, few cells and
minimal flare.
Chronic CMV anterior uveitis
Ocular discomfort and blurring of vision are the usual pre-
senting symptoms in chronic CMV AU. Interestingly, there
are geographic differences in the manifestations of chronic
CMV AU.17 In Asian patients, CMV commonly presents as
FUS with mild ocular injection, mild-to-moderate anterior
chamber activity and fine stellate uniformly-distributed KPs.
In European patients, there are fewer pigmented KPs
(Figure 3) located inferiorly and minimal flare. Posterior
subcapsular cataract also develops in 75% of eyes.
Recurrent or chronic iridocyclitis
Unlike Asian patients who present similarly to FUS or PSS,
patients in the West often present with less distinct syn-
dromes, or an overlap of features from both syndromes,17
manifesting as a mild unilateral recurrent or chronic
iridocyclitis.16,34,36
Corneal endotheliitis
In corneal endotheliitis, KPs develop together with stromal
oedema and Descemet folds, and may be isolated or associ-
ated with AU.34,63,64,73 It can involve a focal area64 or pre-
sent similarly to diffuse bullous keratopathy with severe
corneal stromal oedema, and the IOP may be elevated. CMV
endotheliitis can also be associated with an immune ring for-
mation (Figure 3) similar to that seen in HSV-related
keratitis.74
CHAN AND CHEE 327

FIGURE 3 Spectrum of cytomegalovirus anterior uveitis. (top row, left) a few small to medium-sized keratic precipitates (KPs) are seen on the central
endothelium in acute cytomegalovirus (CMV) infection presenting as Posner-Schlossman syndrome. (Top row, right) chronic CMV infection with fine stellate
KPs diffusely distributed across the endothelium resembles Fuchs uveitis syndrome. (Middle row, left) a partial immune ring is seen here, surrounding an area
with small to medium-sized pigmented KPs in the central cornea. (Middle row, right) CMV endotheliitis involving the superior half of the cornea has
underlying KPs with Descemet folds and overlying stromal oedema. (Bottom row, left) multiple clusters of coin-shaped lesions in the central cornea are
pathognomonic of CMV. (Bottom row, right) nodular endothelial lesions in the paracentral cornea and diffuse iris stromal atrophy are seen in this eye with
chronic CMV infection

2.4.2 | Clinical signs (Figure 3) surrounded by a translucent halo possibly repre-

Features that favour the diagnosis of CMV AU include mild
ocular symptoms,75 low-grade anterior chamber inflamma-
tion with no or minimal flare or fibrin,34,64,75 a round pupil
with no posterior synechiae34,67,75 and the absence of vitritis
or retinitis.2,34 The corneal ECC is also significantly reduced
in CMV-positive eyes.40,68,76
Coin-shaped lesions (Figure 3), in which small-sized
KPs are distributed in a ring pattern, may be seen in acute
and chronic CMV infection and are pathognomonic of CMV
infection (positive predictive value 90.9%).71 KPs may also
be seen in a linear pattern just above the limbus.34 Centrally
positioned white medium-sized nodular endothelial lesions
sent swollen endothelial cells and are also characteristic find-
ings. They are seen more commonly in the chronic form and
become pigmented over time.2
Chronic CMV AU is associated with iris stromal atro-
phy2,34 that mostly involves the pupillary zone and may be
diffuse or patchy.34 Diffuse stromal atrophy creates a moth
eaten appearance of the iris. The posterior pigment epithe-
lium is often relatively intact, although transillumination
defects can be seen if it is atrophied. Heterochromia may
occasionally be seen.36,64
The IOP is often severely elevated in both acute and
chronic CMV AU.16,34,64,66 The magnitude of elevation is
328
greater in acute AU (exceeding 50 mmHg) compared to
chronic AU (mean 43.5 mmHg)34 and may be associated
with subtle subepithelial oedema.2 Trabeculitis is usually the
cause of acute ocular hypertension, while chronically ele-
vated IOP may be due to reduced aqueous outflow after pos-
sibly irreversible modifications of the trabecular meshwork
after chronic inflammation.16 Of steroid-recalcitrant AU
cases, those with elevated IOP are more likely to have CMV
infection (75%),43 with 19 of 20 eyes with non-HSV/VZV
corticosteroid-recalcitrant hypertensive AU being positive
for CMV in one study.71 Glaucomatous optic neuropathy
can develop in both acute (23%) and chronic (36%) CMV
infection2 and patients should therefore be monitored for
visual field defects.
Associated posterior segment abnormalities are uncom-
mon and include vasculitis or periphlebitis, disc and macular
oedema, and epiretinal membrane.20,77,78 Prolonged arm-to-
retina time on fluorescein angiography has been hypothe-
sised to reflect subclinical vasculitis.77
2.5 | Rubella virus
RV is a common cause of FUS, as proven by the presence of
RV-specific antibodies and RV DNA in the aqueous humour of
affected eyes.8,10,79 There are typically fine stellate diffusely dis-
tributed KPs, diffuse iris atrophy79 and mild anterior chamber
inflammation. Koeppe nodules may be present. Pain, redness,
posterior synechiae, skin and corneal involvement are absent.
RV AU is frequently chronic and is often unilateral but
may be bilateral (14%).14 It typically presents as a posterior
subcapsular cataract causing blurring of vision in a relatively
young patient. Unlike other viral AU in which cataracts
develop after chronic inflammation or multiple recurrent epi-
sodes, cataract is often found at the time of presentation
(47%).14 Patients may also present with floaters due to vitritis
and may be mistaken for intermediate uveitis. However,
unlike in intermediate uveitis, the visual acuity is relatively
good in RV AU as there is no cystoid macular oedema. Some
patients may have noticed heterochromia prior to the floaters
and visual impairment. RV AU may be complicated by ocu-
lar hypertension (25%)14 leading to secondary glaucoma.
2.6 | Less common viral aetiologies
Less common aetiologies of viral AU include human T-cell
lymphotropic virus Type 1, HIV, chikungunya virus, Zika
virus, Ebola virus and parvovirus B19 virus. The role of
Epstein-Barr virus in viral AU is uncertain.
3 | DI F F E RE NT IA L D IA G NO S E S F OR
H YP E RT E N S IV E A NT E RI O R U VE IT IS
Besides viral aetiologies, differential diagnoses of hyperten-
sive AU include other infections such as syphilis,
CHAN AND CHEE
toxoplasmosis, toxocariasis and chikungunya AU, as well as
immune-mediated causes such as sarcoidosis. This may
account for the focal “toxoplasmosis-like” chorioretinal scars
seen in eyes with FUS.14
4 | D I FFE RE NTIA TING TY PES O F V IR AL
AN TE RIOR UV EITIS
Although each virus has its own distinctive features, clinical
manifestations vary depending on the interplay between
active viral replication and the host inflammatory and
immune reaction to viral antigens.34,80 Different viruses can
present similarly, making it a challenge to identify the likely
causative virus.61,81–83 This section highlights certain clues
that favour the diagnosis of HSV, VZV, CMV or RV AU
(summarized in Table 1).
4.1 | Epidemiological factors
Age is a useful clue. HSV is more common in adults under
50 years old, while VZV predominantly affects those above
60 years old and the immunocompromised.48 RV AU usu-
ally presents in relatively younger patients (mean age
35  12 years).14
HSV, VZV and RV account for the large proportion of
viral AU in Western populations.3,7,34,65,79,84 CMV AU usu-
ally affects individuals from the third decade onwards, par-
ticularly Asians and males34; those in their third to fifth
decade usually present with PSS, while those in their fifth to
seventh decade present with chronic CMV AU resembling
FUS.2 The other viruses have no gender or population
predilection.14,85
There are epidemiological variations in the prevalence of
each virus. In Singapore, majority of hypertensive AU were
caused by CMV (88.5%) or HSV.34 A South Indian study
reported VZV to account for two-thirds of viral AU, while
19.4% and 8.3% were caused by HSV and CMV, respec-
tively.86 Of the 42 patients with AU in an Italian population,
HSV (83.3%) was the most common cause, followed by
VZV (11.9%) and CMV.87
4.2 | Laterality
Viral AU is almost always unilateral except for HSV and RV,
which may be bilateral in 18% and 14%, respectively.34,85
4.3 | Symptoms
Acute severe eye pain, redness, tearing and photophobia
with blurring of vision, is more likely to occur in HSV or
VZV AU, especially if there is a history of vesicular rashes.
An acute onset of haloes, unilateral headache and mild blur-
ring of vision with minimal eye redness, in a patient who
may have had prior similar episodes, is typical of PSS, of
which CMV is the likely cause.
CHAN AND CHEE
Chronic blurring of vision and/or floaters with minimal
eye redness and pain is suggestive of FUS. RV AU is the
more likely aetiology in a younger patient, especially if het-
erochromia is present, as CMV-associated FUS is seen in
older patients.
4.4 | Course
Herpes viruses have a lifelong latency and may reactivate
and manifest as recurrent disease.88 HSV and VZV typically
have an acute and/or recurrent course,14 while RV has a
chronic course.79 CMV infection may be acute and recurrent
in patients younger than 40 years of age, or chronic in those
above 40 years of age.
4.5 | Skin involvement
A history of dermal manifestations, if present, are helpful in
clinching the diagnosis. Vesicular rash involving the derma-
tome of the ophthalmic branch of trigeminal nerve is patho-
gnomonic of HZO, making VZV the most likely aetiology,
although HSV can also been reported to cause a dermatomal
rash (zosteriform herpes simplex).89 Grouped vesicles occur-
ring at the eyelid border with diffuse oedema are typical of
HSV. CMV and RV do not have any skin manifestations.
4.6 | Corneal involvement
As epithelial and stromal keratitis are mostly associated with
HSV and VZV, the presence of corneal scars is suggestive
of HSV or VZV rather than CMV infection. The typical
morphology and staining patterns of dendritic keratitis, when
present, can help to differentiate HSV from VZV.90 HSV
dendritic ulcers are usually branching, with well-developed
terminal bulbs. The ulcer base and borders are stained by
fluorescein and rose-bengal, respectively. In contrast, the
pseudodendritic ulcers in VZV infection are coarser, slightly
elevated, broader and polymorphous with less regular
branching and few terminal dilatations. Rose-bengal stains
centrally and fluorescein pools along the borders. HSV may
also cause disciform keratitis and interstitial keratitis,85,91
and VZV can manifest as nummular keratitis and limbal ker-
atitis. Immune ring keratitis is more common in HSV and
VZV infection, although it has been reported in association
with CMV as well.74,85,91
Endotheliitis is frequently associated with CMV infec-
tion.40,42,43,63,66,68,74,76 but has also been reported in HSV
and VZV infection.92,93 Although, endotheliitis may be mis-
taken for bullous keratopathy in cases of diffuse stromal
oedema, the presence of KPs underlying the affected areas
provide the clue that this may be of a viral aetiology.
Reduced corneal sensitivity48 or neurotrophic ulcers are
likely to develop from HSV and VZV infection; profound
and diffuse corneal anaesthesia is more common in VZV
infection.
329
RV does not affect the cornea. However, in the absence
of corneal involvement, a low ECC compared to the unaf-
fected eye points to a possible CMV infection.
4.7 | Keratic precipitates
The size and distribution of KPs are important clues. Most
cases of HSV and VZV AU have small to medium KPs
which are more numerous than in CMV-associated PSS;
some of these fresh KPs may be pigmented. Although the
KPs may be central, paracentral or diffuse, distribution in
Arlt's triangle is seen more commonly in HSV or VZV than
CMV AU. In keratouveitis, the KPs are usually located in
the same distribution as the inflamed cornea.
In CMV-associated PSS, there are medium-to-large
(39%) white or grey-coloured KPs,75 usually single or a few
in number in the central cornea, or located peripherally.
Chronic CMV inflammation in Asian populations presents
as fine stellate (44%) white or grey-coloured KPs are dif-
fusely distributed over the entire endothelium as in FUS.
Although CMV and RV present with similar KPs, the KPs
in RV AU do not become pigmented and persist despite
treatment. KPs tend to be brown in the chronic CMV AU
seen in Western populations.16 Medium-sized KPs are dis-
tributed in a ring pattern in coin-shaped lesions and nodular
endothelial lesions surrounded by a translucent halo are
characteristic of CMV AU.2
4.8 | Anterior chamber inflammation
Although the degree of anterior chamber inflammation in
variable in all herpetic AU, CMV and RV AU have mild
inflammation and minimal flare, while HSV and VZV tend
to have greater intraocular inflammation and flare which
may have associated hypopyon and streaks of hyphema. The
inflammation in VZV is generally more severe than in HSV
AU,75 possibly because VZV is believed to invade into the
root of the iris epithelium and cause occlusive vasculitis57,94
while HSV AU causes iris pigment epitheliitis.
4.9 | Koeppe nodules
Koeppe nodules may be seen in RV AU but not in HSV,
VZV or CMV AU.
4.10 | Iris stromal haemorrhage
Focal iris stromal haemorrhage may be seen in acute HSV or
VZV AU, which in severe cases may present with hyphema.
Amsler's sign may be seen in FUS from CMV or RV infec-
tion, where diffuse iris atrophy results in fragile iris vascula-
ture that bleed easily.
330
4.11 | Iris atrophy
Iris atrophy occurs in HSV (41%-51%), VZV (25%-88%)
and acute (43%) and chronic (60%) CMV AU,2,71,85,91 but
have different patterns.
During acute HSV or VZV AU, there may be an area of
iridoplegia in the sector of iris that is infected and inflamed.
The pupil is typically flattened in the affected area and is
poorly reactive to light. When the acute episode is over, the
affected area develops pigment epithelial atrophy, resulting
in a transillumination defect. The presence of sectoral iris
atrophy with unilateral recurrent iridocyclitis is therefore
highly suggestive of herpetic disease48 and is most com-
monly seen in HSV AU (83%48), although it has also been
reported in VZV.82,95 Spiral atrophy is typically associated
with HSV.
Diffuse atrophy is more common in CMV or RV infec-
tion but has rarely been reported in association with HSV.
CMV, unlike HSV and VZV, predominantly causes iris stro-
mal atrophy. It may cause transillumination defects in light-
coloured irides, although this is uncommon in dark-coloured
irides in Asian populations. Heterochromia may be seen in
severe cases.
4.12 | Pupil abnormalities
Posterior synechiae are more likely to be seen in HSV (38%)
and VZV (40%) AU.14 If posterior synechiae is absent, the
affected sector of iris becomes atrophic, resulting in an
eccentric dilated pupil. In contrast, posterior synechiae are
classically absent in CMV and RV AU and the pupil typi-
cally remains round.
4.13 | Gonioscopy findings
On gonioscopy, fragile vasculature in the iris and trabecular
meshwork or iridocorneal angle may be visualized in FUS.25
PAS may be seen in VZV AU.
4.14 | High IOP
Ocular hypertension is frequently observed during active
herpetic AU; the degree of IOP elevation correlates with the
viral load, which may be attributable to the degree of out-
flow obstruction from the severity of trabeculitis. The IOP in
CMV-associated PSS is often elevated out of proportion to
the mild anterior chamber inflammation, as compared to
HSV or VZV AU, in which the degree of IOP elevation is
greater in more severe intraocular inflammation. The maxi-
mum IOP is generally higher in CMV AU compared to that
in HSV AU.75
The IOP is typically persistently elevated in chronic
CMV AU, while episodic bouts of ocular hypertension are
more commonly seen in HSV, VZV and CMV-associated
PSS. These may cause secondary glaucomatous optic
CHAN AND CHEE
neuropathy. RV AU may be complicated by raised IOP and
glaucoma.
4.15 | Cataract
Unlike in HSV, VZV and CMV where cataract develops
later in the disease course, cataract (47%)14 is frequently
found at the time of presentation in RV AU.
4.16 | Posterior segment findings
Vitritis is more common in VZV (83%) than in HSV (43%)
AU.14 As vitritis is almost always present in RV but is rare
in CMV infection, this helps to distinguish RV from CMV
infection in a patient with FUS.8
5 | V A RI AB L E M A NI F E S T A T I ON S O F
VIR AL A NT ER IOR U VE IT IS
While viral AU is caused by active viral replication, the clin-
ical manifestations also depend on the host's inflammatory
and immune reaction to viral antigens.80 The viral load and
the innate immunity of the eye, and thus the clinical presen-
tation, may also be altered by medications such as topical
steroids. A single virus can therefore present with a spectrum
of clinical manifestations and the different viruses likewise
may present similarly.
The manifestations of a single virus may also evolve in
the same eye over time. A patient may initially present with
recurrent IOP spikes in acute CMV AU. However, progres-
sion of the infection may result in chronic inflammation with
a persistently elevated IOP.
6 | I N V E S T I GA T I O N S
6.1 | Anterior chamber tap
Aqueous humour analysis is a useful method to determine
the aetiology and disease severity15,96 as clinical features
may not always be sufficient to differentiate between the
various viral AU. An anterior chamber tap is performed
under aseptic technique, and aqueous humour is sent for
polymerase chain reaction (PCR) or Goldmann-Witmer
coefficient (GWC) analysis.
6.1.1 | Polymerase chain reaction
The PCR involves enzymatic amplification of nucleic acid
sequences in repeated cycles of denaturation, oligonucleo-
tide annealing, and DNA polymerase extension. PCR-based
analyses of aqueous humour samples can detect minimal
amounts of viral DNA and enable rapid confirmation of the
diagnosis. The aqueous tap should be done during the IOP
spike, preferably prior to initiating therapy especially when
suspecting CMV.34
CHAN AND CHEE
A negative PCR result does not exclude a viral aetiology;
this may be due to low intraocular viral load, the limited vol-
ume of aqueous humour sample, the short-lived phase of
DNA release that may have been missed during the time of
aqueous sampling due to delayed presentation or testing, the
presence of inhibitory compounds in the sample or microor-
ganism polymorphism.34,96 In some cases, a positive result
may only be obtained after repeated aqueous taps.64 Con-
versely, PCR may give a false positive result by detecting
DNA from latent viruses in leukocytes present in the anterior
chamber during inflammation.
A qualitative multiplex PCR can be done to screen for
viruses and subsequent real-time PCR can help to identify
the causative virus and quantify the viral load as a marker of
severity of the infection. A high CMV viral load in the aque-
ous humour is a significant risk factor for elevated IOP, the
need for more IOP-lowering eyedrops,40 recurrent inflamma-
tion40 and reduced ECC.76 Similarly, the VZV viral load
correlates with the severity of iris atrophy and pupil distor-
tion.97 Real-time PCR can also be used monitor the response
to therapy.
6.1.2 | Goldmann-Witmer coefficient analysis
The GWC calculation helps to determine pathogen-specific
intraocular antibody production and therefore, whether infec-
tion has occurred.48,96
6.1.3 | Choice of investigation
PCR tends to be positive at the outset and/or during early
reactivation but viral DNA levels may fall below the detec-
tion limit in later stages of the disease. GWC analysis may
take up to 2 weeks to become positive in the acute phase but
remains positive for longer periods of time.96 HSV and VZV
commonly present during the acute phase when the viral
load is higher and are frequently detected by PCR. In con-
trast, RV AU usually presents late due to chronic low-grade
inflammation and is commonly detected via positive GWC
results but only sporadically by PCR.8,10,14,79
Although GWC analysis is less specific than PCR due to
possible cross-reactivity of antibodies, it is more useful espe-
cially when patients present later during the acute episode
when DNA levels are low. However, PCR is more useful
than GWC analysis in immunocompromised individuals
with aberrant antibody synthesis.15,96,98 As the diagnostic
utility depends on the patient's immune status, the chronicity
of infection and the time of aqueous sampling, performing
both the PCR and GWC analysis in parallel is preferred as it
increases the diagnostic yield.3,14,15,67,96 Unfortunately, as
GWC analysis is not widely available in most countries,
most countries rely solely on PCR at present.
Viral cultures of aqueous humour samples, although can
be used to diagnose herpetic AU more securely, are difficult,
time-consuming and are therefore not commonly done.
331
6.2 | Other investigations
When CMV AU is suspected, a reduced ECC compared to
the fellow eye supports the diagnosis as this is not seen in
other viral AU. The extent of endothelial cell loss also corre-
lates with the viral disease burden.40,68,76 Anterior segment
optical coherence tomography can demonstrate the nodular
endothelial lesions and coin-shaped lesions,99 which are seen
as an irregularly thickened, highly reflective endothelial cell
layer. Confocal microscopy demonstrates the presence of
“owl eye cells” (large endothelial cells containing nuclei
with a high reflection area surrounded by a halo of low
reflection within the cornea),100 is non-invasive and allows
the monitoring of response to treatment.
Isolated serologic tests have limited value; most adults
have had prior exposure to these viruses and a negative
result does not exclude the diagnosis either. Even if IgM is
positive, this indicates active systemic infection but does not
prove ocular infection.
Newer investigations such as metagenomic deep
sequencing can detect fungi, parasites, and DNA and RNA
viruses in as little as 20 μL of intraocular fluid samples in a
single assay101 and are promising in their potential to
improve the diagnosis of infectious uveitis.
7 | C O NC L U S IO N
In conclusion, there should be a high index of suspicion for
a viral aetiology in any case of hypertensive AU or iris atro-
phy. Viral phenotypes include AU with granulomatous KPs
with or without corneal scars; PSS-like uveitis and FUS-like
uveitis. However, as each virus has variable clinical presen-
tations and different viruses may also have overlapping man-
ifestations, the preferred methods of confirming the
aetiology are quantitative PCR or GWC assay of aqueous
humour samples. It is important to have a specific etiological
diagnosis as the treatment of each virus may differ. Newer
diagnostic techniques offer opportunities to identify more
viruses and may shed light on AU that were previously
idiopathic.
CONFLICTS OF INTEREST
None declared.
OR CID
Soon-Phaik Chee https://orcid.org/0000-0002-6308-5721
REFERENCES
1. Jabs DA, Nussenblatt RB, Rosenbaum JT, Group SoUNSW. Standardiza-
tion of uveitis nomenclature (SUN) working group. Standardization of uve-
itis nomenclature for reporting clinical data. Results of the first
international workshop. Am J Ophthalmol. 2005;140:509-516.
332
2. Chee SP, Jap A. Presumed fuchs heterochromic iridocyclitis and Posner-
Schlossman syndrome: comparison of cytomegalovirus-positive and nega-
tive eyes. Am J Ophthalmol. 2008;146:883-889.
3. Kongyai N, Sirirungsi W, Pathanapitoon K, et al. Viral causes of unex-
plained anterior uveitis in Thailand. Eye. 2012;26:529-534.
4. Monteiro LG, Orefice F. Ciclite Heterocromica de Fuchs: Ciclite Hetero-
cromica de Fuchs. Rio de Janeiro: Cultura Médica; 2000.
5. Fuchs E. Lehrbuch fu¨r Augenheilkunde. 15th ed. Leipzig & Vienna: Franz
Deuticke; 1926.
6. Kimura SJ, Hogan MJ, Thygeson P. Fuchs' syndrome of heterochromic
cyclitis. AMA Arch Ophthalmol. 1955;54:179-186.
7. Anwar Z, Galor A, Albini TA, Miller D, Perez V, Davis JL. The diagnostic
utility of anterior chamber paracentesis with polymerase chain reaction in
anterior uveitis. Am J Ophthalmol. 2013;155:781-786.
8. Quentin CD, Reiber H. Fuchs heterochromic cyclitis: rubella virus anti-
bodies and genome in aqueous humor. Am J Ophthalmol. 2004;138:46-54.
9. Rothova A. The riddle of fuchs heterochromic uveitis. Am J Ophthalmol.
2007;144:447-448.
10. Suzuki J, Goto H, Komase K, et al. Rubella virus as a possible etiological
agent of Fuchs heterochromic iridocyclitis. Graefes Arch Clin Exp
Ophthalmol. 2010;248:1487-1491.
11. Barequet IS, Li Q, Wang Y, O'Brien TP, Hooks JJ, Stark WJ. Herpes sim-
plex virus DNA identification from aqueous fluid in Fuchs heterochromic
iridocyclitis. Am J Ophthalmol. 2000;129:672-673.
12. Teyssot N, Cassoux N, Lehoang P, Bodaghi B. Fuchs heterochromic cycli-
tis and ocular toxocariasis. Am J Ophthalmol. 2005;139:915-916.
13. Schwab IR. The epidemiologic association of Fuchs' heterochromie irido-
cyclitis and ocular toxoplasmosis. Am J Ophthalmol. 1991;111:356-362.
14. Wensing B, Relvas LM, Caspers LE, et al. Comparison of rubella virus-
and herpes virus-associated anterior uveitis: clinical manifestations and
visual prognosis. Ophthalmology. 2011;118:1905-1910.
15. Pleyer U, Chee SP. Current aspects on the management of viral uveitis in
immunocompetent individuals. Clin Ophthalmol. 2015;9:1017-1028.
16. de Schryver I, Rozenberg F, Cassoux N, et al. Diagnosis and treatment of
cytomegalovirus iridocyclitis without retinal necrosis. Br J Ophthalmol.
2006;90:852-855.
17. Chan NS, Chee SP, Caspers LB. Clinical features of CMV-associated ante-
rior uveitis. Ocul Immunol Inflamm. 2018;26:107-115.
18. La Hey E, Baarsma GS, De Vries J, Kijlstra A. Clinical analysis of Fuchs'
heterochromic cyclitis. 1991;78:3-4.
19. Jones NP. Fuchs' heterochromic uveitis: a reappraisal of the clinical spec-
trum. Eye. 1991;5:649-661.
20. Yang P, Fang W, Jin H, Li B, Chen X, Kijlstra A. Clinical features of Chi-
nese patients with Fuchs' syndrome. Ophthalmology. 2006;113:473-480.
21. Norrsell K, Sjodell L. Fuchs' heterochromic uveitis: a longitudinal clinical
study. Acta Ophthalmol. 2008;86:58-64.
22. Liesegang TJ. Clinical features and prognosis in Fuchs' uveitis syndrome.
Arch Ophthalmol. 1982;100:1622-1626.
23. Fearnley IR, Rosenthal AR. Fuchs' heterochromic iridocyclitis revisited.
Acta Ophthalmol Scand. 1995;73:166-170.
24. Basirir B, Altan C, Pinarci EY, Celik U, Satana B, Demirok A. Analysis of
iris structure and iridocorneal angle parameters with anterior segment opti-
cal coherence tomography in Fuchs' uveitis syndrome. 2013;33:3.
25. Loewenfeld IE, Thompson HS. Fuchs's heterochromic cyclitis: a critical
review of the literature. I. Clinical characteristics of the syndrome. Surv
Ophthalmol. 1973;17:394-457.
26. Amsler M, Verrey F. Hétérochromie de Fuchs et fragilité vasculaire.
Ophthalmologica. 1946;111:177-181.
27. Bloch-Michel E, Frau E, Chhor S, Tounsi Y. Amsler's sign associated sig-
nificantly with Fuch's heterochromic cyclitis (FHC). Int Ophthalmol. 1995-
1996;19:169-171.
28. Zamir E, Margalit E, Chowers I. Iris crystals in Fuchs' heterochromic irido-
cyclitis. Arch Ophthalmol. 1998;116:1394.
29. Bouchenaki N, Herbort CP. Fuchs' uveitis: failure to associate vitritis and
disc hyperfluorescence with the disease is the major factor for misdiagnosis
and diagnostic delay. Middle East Afr J Ophthalmol. 2009;16:239-244.
30. de Abreu MT, Belfort RJ, Hirata PS. Fuchs' heterochromic cyclitis and ocu-
lar toxoplasmosis. Am J Ophthalmol. 1982;93:739-744.
31. Jones NP. Glaucoma in Fuchs' heterochromic uveitis: aetiology, manage-
ment and outcome. Eye. 1991;5:662-667.
CHAN AND CHEE
32. Posner A, Schlossman A. Syndrome of unilateral recurrent attacks of glau-
coma with cyclitis symptoms. Arch Ophthalmol. 1948;39:517-535.
33. Päivönsalo-Hietanen T, Tuominen J, Vaahtoranta-Lehtonen H, Saari KM.
Incidence and prevalence of different uveitis entities in Finland. Acta
Ophthalmol Scand. 1997;75:76-81.
34. Chee SP, Bacsal K, Jap A, Se-Thoe SY, Cheng CL, Tan BH. Clinical fea-
tures of cytomegalovirus anterior uveitis in immunocompetent patients.
Am J Ophthalmol. 2008;145:834-840.
35. Jap A, Sivakumar M, Chee SP. Is Posner Schlossman syndrome benign?
Ophthalmology. 2001;108:913-918.
36. Woo JH, Lim WK, Ho SL, Teoh SC. Characteristics of cytomegalovirus
uveitis in immunocompetent patients. Ocul Immunol Inflamm. 2015;23:
378-383.
37. Bloch-Michel E, Dussaix E, Cerqueti P, Patarin D. Possible role of cyto-
megalovirus infection in the etiology of the Posner-Schlossmann syndrome.
Int Ophthalmol. 1987;11:95-96.
38. Yamamoto S, Pavan-Langston D, Tada R, et al. Possible role of herpes
simplex virus in the origin of Posner-Schlossman syndrome.
Am J Ophthalmol. 1995;119:796-798.
39. Hedayatfar A, Chee SP. Posner-Schlossman syndrome associated with
cytomegalovirus infection: a case series from a non-endemic area. Int
Ophthalmol. 2014;34:1123-1129.
40. Kandori M, Miyazaki D, Yakura K, et al. Relationship between the number
of cytomegalovirus in anterior chamber and severity of anterior segment
inflammation. Jpn J Ophthalmol. 2013;57:497-502.
41. Rodier-Bonifas C, Cornut PL, Billaud G, Lina B, Burillon C, Denis P.
Cytomegalovirus research using polymerase chain reaction in Posner-
Schlossman syndrome. J Fr Ophtalmol. 2011;34:24-29.
42. Teoh SB, Thean L, Koay E. Cytomegalovirus in aetiology of Posner-
Schlossman syndrome: evidence from quantitative polymerase chain reac-
tion. Eye. 2005;19:1338-1340.
43. Koizumi N, Inatomi T, Suzuki T, et al. Clinical features and management
of cytomegalovirus corneal endotheliitis: analysis of 106 cases from the
Japan corneal endotheliitis study. Br J Ophthalmol. 2015;99:54-58.
44. Su CC, Hu FR, Wang TH, et al. Clinical outcomes in cytomegalovirus-
positive Posner-Schlossman syndrome patients treated with topical ganci-
clovir therapy. Am J Ophthalmol. 2014;158:1024-1031. e2.
45. Darchuk V, Sampaolesi J, Mato L, Nicoli C, Sampaolesi R. Optic nerve
head behavior in Posner-Schlossman syndrome. Int Ophthalmol. 2001;23:
373-379.
46. Sugita S, Shimizu N, Watanabe K, et al. Use of multiplex PCR and real-
time PCR to detect human herpes virus genome in ocular fluids of patients
with uveitis. Br J Ophthalmol. 2008;92:928-932.
47. Young RC, Hodge DO, Liesegang TJ, Baratz KH. Incidence, recurrence,
and outcomes of herpes simplex virus eye disease in Olmsted County, Min-
nesota, 1976–2007. Arch Ophthalmol. 2010;128:1178-1183.
48. Van der Lelij A, Ooijman FM, Kijlstra A, Rothova A. Anterior uveitis with
sectoral iris atrophy in the absence of keratitis: a distinct clinical entity
among herpetic eye diseases. Ophthalmology. 2000;107:1164-1170.
49. Kennedy DP, Clement C, Arceneaux RL, Bhattacharjee PS, Hug TS,
Hill JM. Ocular herpes simplex virus type 1: is the cornea a reservoir for
viral latency or a fast pit stop? Cornea. 2011;30:251-259.
50. Dawnson CR, Togni B. Herpes simplex eye infections: clinical manifesta-
tions, pathogenesis and management. Surv Ophthalmol. 1976;21:121-135.
51. Falcon MG, Williams HP. Herpes simplex kerato-uveitis and glaucoma.
Trans Ophthalmol Soc UK. 1978;98:101-104.
52. Tabbara KF, Chavis PS. Herpes simplex anterior uveitis. Int Ophthalmol
Clin. 1998;38:137-147.
53. Marsh RJ, Easty DL, Jones BR. Iritis and iris atrophy in herpes zoster
ophthalmicus. Am J Ophthalmol. 1974;78:255-261.
54. Liesegang TJ. Epidemiology of ocular herpes simplex. Natural history in
Rochester, Minn, 1950 through 1982. Arch Ophthalmol. 1989;107:1160-
1165.
55. Thygeson P, Hogan MJ, Kimura SJ. Observations on uveitis associated
with viral disease. Trans Am Ophthalmol Soc. 1957-1958;55:333-349.
56. Womack LW, Liesegang TJ. Complications of herpes zoster ophthalmicus.
Arch Ophthalmol. 1983;101:42-45.
57. Marsh RJ, Cooper M. Ophthalmic herpes zoster. Eye. 1993;7:350-370.
58. Karbassi M, Raizman MB, Schuman JS. Herpes zoster ophthalmicus. Surv
Ophthalmol. 1992;36:395-410.
CHAN AND CHEE
59. Ross JV. Herpes zoster ophthalmicus sine eruption. Arch Ophthalmol.
1949;42:808-812.
60. Khan AO, Al-Assiri A, Wagoner MD. Ring corneal infiltrate and progres-
sive ring thinning following primary varicella infection. J Pediatr Ophthal-
mol Strabismus. 2008;45:116-117.
61. Jap A, Chee SP. Emerging forms of viral uveitis in the developing world.
Int Ophthalmol Clin. 2010;50:155-171.
62. Bale JF Jr, O'Neil ME, Hogan RN, Kern ER. Experimental murine cyto-
megalovirus infection of ocular structures. Arch Ophthalmol. 1984;102:
1214-1219.
63. Chee SP, Bacsal K, Jap A, Se-Thoe SY, Cheng CL, Tan BH. Corneal
endotheliitis associated with evidence of cytomegalovirus infection. Oph-
thalmology. 2007;114:798-803.
64. van Boxtel LA, van der Lelij A, van der Meer J, Los LI. Cytomegalovirus
as a cause of anterior uveitis in immunocompetent patients. Ophthalmol-
ogy. 2007;114:1358-1362.
65. Park SW, YU HG. Association of cytomegalovirus with idiopathic chronic
anterior uveitis with ocular hypertension in Korean patients. Ocul Immunol
Inflamm. 2013;21:192-196.
66. Yamauchi Y, Suzuki J, Sakai J, Sakamoto S, Iwasaki T, Usui M. A case of
hypertensive keratouveitis with endotheliitis associated with cytomegalovi-
rus. Ocul Immunol Inflamm. 2007;15:399-401.
67. Jap A, Chee SP. Viral anterior uveitis. Curr Opin Ophthalmol. 2011;22:
483-488.
68. Choi JA, Kim KS, Jung Y, Park HY, Park CK. Cytomegalovirus as a cause
of hypertensive anterior uveitis in immunocompetent patients. J Ophthal
Inflamm Infect. 2016;6:32.
69. Chee SP, Jap A. Cytomegalovirus anterior uveitis: outcome of treatment.
Br J Ophthalmol. 2010;94:1648-1652.
70. Tan WJ, Poh EW, Wong PY, Ho SL, Lim WK, Teoh SC. Trends in pat-
terns of anterior uveitis in a tertiary institution in Singapore. Ocul Immunol
Inflamm. 2013;21:270-275.
71. Hwang YS, Shen CR, Chang SH, et al. The validity of clinical feature pro-
files for cytomegaloviral anterior segment infection. Graefes Arch Clin Exp
Ophthalmol. 2011;249:103-110.
72. Shigemi D, Yamaguchi S, Otsuka T, Kamoi S, Takeshita T. Seroprevalence
of cytomegalovirus IgG antibodies among pregnant women in Japan from
2009-2014. Am J Infect Control. 2015;43:1218-1221.
73. Alfawaz A. Cytomegalovirus-related corneal endotheliitis: a review article.
Saudi J Ophthalmol. 2013;27:47-49.
74. Chee SP, Jap A. Immune ring formation associated with cytomegalovirus
endotheliitis. Am J Ophthalmol. 2011;152:449e1-53e1.
75. Takase H, Kubono R, Terada Y, et al. Comparison of the ocular
characteristics of anterior uveitis caused by herpes simplex virus,
varicella-zoster virus, and cytomegalovirus. Jpn J Ophthalmol. 2014;58:
473-482.
76. Miyanaga M, Sugita S, Shimizu N, et al. A significant association of viral
loads with corneal endothelial cell damage in cytomegalovirus anterior uve-
itis. Br J Ophthalmol. 2010;94:336-340.
77. Wong MH, Cheung GC, Chee SP. Posterior segment findings of ocular
cytomegalovirus infection in immunocompetent patients. Graefes Arch
Clin Exp Ophthalmol. 2014;252:1811-1816.
78. Bouchenaki N, Herbort CP. Fluorescein angiographic findings and clinical
features in Fuchs' uveitis. Int Ophthalmol. 2010;30:511-519.
79. de Visser L, Braakenburg A, Rothova A, de Boer JH. Rubella virus-
associated uveitis: clinical manifestations and visual prognosis.
Am J Ophthalmol. 2008;146:292-297.
80. Pepose JS. Herpes simplex keratitis: role of viral infection versus immune
response. Surv Ophthalmol. 1991;35:345-352.
81. Cunningham ET. Cytomegalovirus: ophthalmic perspectives on a pervasive
pathogen. Expert Rev Ophthalmol. 2014;6:489-491.
82. Liesegang TJ. Varicella-zoster virus eye disease. Cornea. 1999;18:
511-531.
333
83. Liesegang TJ. Classification of herpes simplex virus keratitis and anterior
uveitis. Cornea. 1999;18:127-143.
84. de Groot-Mijnes JD, de Visser L, Zuurveen S, et al. Identification of new
pathogens in the intraocular fluid of patients with uveitis. Am J Ophthal-
mol. 2010;150:628-636.
85. Miserocchi E, Waheed NK, Dios E, et al. Visual outcome in herpes sim-
plex virus and varicella zoster virus uveitis: a clinical evaluation and com-
parison. Ophthalmology. 2002;109:1532-1537.
86. Babu K, Kini R, Philips M, Subbakrishna DK. Clinical profile of isolated
viral anterior uveitis in a south Indian patient population. Ocul Immunol
Inflamm. 2014;22:356-359.
87. Meserocchi E, Fogliato G, Bianchi I, Bandello F, Modorati G. Clinical fea-
tures of ocular herpetic infection in an Italian referral center. Cornea. 2014;
33:565-570.
88. Predictors of recurrent herpes simplex virus keratitis. Herpetic eye disease
study group. Cornea. 2001;20:123-128.
89. Yamamoto S, Shimomura Y, Kinoshita S, Tano Y. Differentiating zosteri-
form herpes simplex from ophthalmic zoster. Arch Ophthalmol. 1994;112:
1515-1516.
90. Piebanga LW, Laibson PR. Dendritic lesions in herpes zoster ophthalmi-
cus. Arch Ophthalmol. 1973;90:268-270.
91. Tugal-Tutkun I, Otük-Yasar B, Altinkurt E. Clinical features and prognosis
of herpetic anterior uveitis: a retrospective study of 111 cases. Int Ophthal-
mol. 2010;30:559-565.
92. Amano S, Oshika T, Kaji Y, Numaga J, Matsubara M, Araie M. Herpes
simplex virus in the trabeculum of an eye with corneal endotheliitis.
Am J Ophthalmol. 1999;127:721-726.
93. Maudgal PC, Missotten L, De Clercq E, Descamps J. Varicella-zoster virus
in the human corneal endothelium: a case report. Bull Soc Belge Ophtal-
mol. 1980;190:71-86.
94. Naumann G, Gass JD, Font RL. Histopathology of herpes zoster ophthal-
micus. Am J Ophthalmol. 1968;65:533-541.
95. Schwab IR. Herpes zoster sine herpete. A potential cause of iridoplegic
granulomatous iridocyclitis. Ophthalmology. 1997;104:1421-1425.
96. De Groot-Mijnes JD, Rothova A, Van Loon AM, et al. Polymerase chain
reaction and Goldmann-Witmer coefficient analysis are complimentary for
the diagnosis of infectious uveitis. Am J Ophthalmol. 2006;141:313-318.
97. Kido S, Sugita S, Horie S, et al. Association of varicella zoster virus load
in the aqueous humor with clinical manifestations of anterior uveitis in her-
pes zoster ophthalmicus and zoster sine herpete. Br J Ophthalmol. 2008;
92:505-508.
98. Westeneng AC, Rothova A, de Boer JH, de Groot-Mijnes JD. Infectious
uveitis in immunocompromised patients and the diagnostic value of poly-
merase chain reaction and Goldmann-Witmer coefficient in aqueous analy-
sis. Am J Ophthalmol. 2007;144:781-785.
99. Yokogawa S, Kobayashi T, Sugiyama K. Mapping owl's eye cells of
patients with cytomegalovirus corneal endotheliitis using in vivo laser con-
focal microscopy. Jpn J Ophthalmol. 2013;57:80-24.
100. Shiraishi A, Hara Y, Takahashi M, et al. Demonstration of "owl's eye" mor-
phology by confocal microscopy in a patient with presumed cytomegalovi-
rus corneal endotheliitis. Am J Ophthalmol. 2007;143:715-717.
101. Doan T, Wilson MR, Crawford ED, et al. Illuminating uveitis: metage-
nomic deep sequencing identifies common and rare pathogens. Genome
Med. 2016;8:90.
How to cite this article: Chan NS-W, Chee S-P.
Demystifying viral anterior uveitis: A review. Clin.
Experiment. Ophthalmol. 2019;47:320–333. https://
doi.org/10.1111/ceo.13417