REVIEW

CURRENT
OPINION Ocular manifestations of cytomegalovirus
in immunocompetent hosts
Ashlin Joye and John A. Gonzales

Purpose of review
This review highlights recent studies that have increasingly implicated cytomegalovirus (CMV) as a
significant cause of keratouveitis and retinitis in immunocompetent hosts.
Recent findings
Molecular testing has identified that CMV infection is frequently present in cases of Posner-Schlossman and
Fuchs, keratouveitis syndromes previously presumed to be idiopathic conditions. Ocular hypertension and
endothelial cell loss are important complications of CMV keratouveitis and are likely mediated by viral
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invasion of the trabecular meshwork and corneal endothelium. Topical ganciclovir is a well tolerated,
effective, and economical therapy. CMV retinitis is possible in the absence of HIV/AIDS.
Summary
CMV has long been considered an innocuous infection in the general population, though recent studies have
found otherwise. Intraocular reactivation, replication, and invasion of the trabecular meshwork and endothelium
lead to recurrent bouts of ocular hypertension and endothelial cell loss, the complications of which may be
tempered with initiation of antivirals. Topical ganciclovir is a promising therapy that needs investigation. CMV
retinitis, an entity previously believed isolated to the severely immunosuppressed population, has been reported
on numerous occasions in presumably immunocompetent individuals, particularly following local steroid
injections. Further studies may elucidate the pathogenesis of CMV in immunocompetent populations.
Keywords
anterior uveitis, cytomegalovirus, endotheliitis, immunocompetent, keratouveitis

INTRODUCTION iridocyclitis), frequently manifests as recurrent or

The Herpesviridae family, including herpes simplex
virus (HSV), varicella zoster virus (VZV), and cyto-
megalovirus (CMV), are considered ubiquitous
pathogens worldwide. HSV and VZV are known to
have ocular manifestations in healthy individuals,
including infection and inflammation of the cor-
nea, sclera, iris, and retina, whereas CMV gained
recognition during the HIV/AIDS epidemic for caus-
ing retinitis in acquired immunodeficiency. More
recently, however, CMV has emerged as a cause of
keratouveitis and retinitis in immunocompetent
patients, the complications of which are associated
with significant morbidity. Here we discuss the
ocular manifestations of CMV in immunocompe-
tent patients, including recent discoveries and
unanswered questions.
KERATOUVEITIS
Keratouveitis, an entity that encompasses corneal
endotheliitis and anterior uveitis (also known as
chronic, unilateral anterior segment inflammation
associated with ocular hypertension. Historically,
these findings have been attributed to either intra-
ocular infection (namely HSV and VZV) or idio-
pathic inflammatory syndromes. More recently,
however, CMV has gained recognition as a signifi-
cant cause of keratouveitis in immunocompetent
hosts.
Epidemiology
CMV seroprevalence has been correlated with eth-
nicity, age, and socioeconomic background, with
Francis I. Proctor Foundation, Department of Ophthalmology, University
of California, San Francisco, USA
Correspondence to John A. Gonzales, MD, Associate Professor, Francis I.
Proctor Foundation, Department of Ophthalmology, University of Califor-
nia, San Francisco, 95 Kirkham Street, San Francisco, CA 94122, USA.
E-mail: john.gonzales@ucsf.edu
Curr Opin Ophthalmol 2018, 29:535–542
DOI:10.1097/ICU.0000000000000521

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Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

Ocular manifestations of systemic disease
KEY POINTS
 Cytomegalovirus (CMV) is now recognized as a
significant pathogen (in immunocompetent hosts) that is
capable of causing keratouveitis and retinitis.
 Posner-Schlossman and Fuchs, keratouveitic syndromes
previously presumed idiopathic in nature, are frequently
due to CMV infection.
 Early recognition of CMV keratouveitis and initiation of
antiviral therapy may help prevent sequelae that result
from viral invasion and recurrent damage to the
trabecular meshwork and corneal endothelium.
 CMV retinitis is a potential complication of local
immunosuppression and should be considered in any
patient with signs of retinitis regardless of presumed
immune status.
 Investigation into host risk factors and viral genomics
may provide insight into the pathogenesis of CMV
keratouveitis and retinitis in otherwise
immunocompetent individuals.
overall estimates at 50% in the United States and as
high as 100% in developing countries [1,2].
Although generally considered innocuous in immu-
nocompetent hosts, recent studies have increasingly
implicated CMV as a significant cause of chronic
and recurrent ocular inflammation, including 22.8–
34.2% of hypertensive anterior uveitis cases [3–5].
Posner-Schlossman syndrome (PSS), an acute and
recurrent keratouveitic condition previously
thought idiopathic in nature, has demonstrated
anterior chamber CMV-PCR positivity ranging
between 37.5 and 56.2% [3,5,6]. Fuchs uveitis syn-
drome (FUS), another syndrome of previously pre-
sumed idiopathic cause, has shown CMV positivity
in as high as 31.3–41.7% of cases [3,7]. Of note, a
number of the positive results from these studies
were obtained in previously CMV-negative eyes.
This suggests that sampling and molecular techni-
ques, as well as fluctuations in viral replication, may
contribute to an underestimation of CMV’s impact.
For unknown reasons and despite high
worldwide seroprevalence, CMV keratouveitis seems
to occur more frequently in Asians [8]. Most
published studies come from Asia [3,4,6–
&& && && && & & &&
8,9 ,10 ,11,12 ,13 ,14,15 ,16 ,17–22,23 ,24–32],
and at our own tertiary referral center, we have found
that of 19 patients examined retrospectively over a 12-
year period, 14 were Asian (unpublished observation,
manuscript in preparation). Although atopy has been
described as a risk factor for herpetic eye disease
involving HSV and VZV, such a risk factor for CMV
anterior segment inflammation has not yet been
536 www.co-ophthalmology.com
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
discovered [33,34]. Most CMV keratouveitis studies
indicate a male preponderance as high 80.2%, and
risk appears to increase with age [3,22].
Pathogenesis
The pathogenesis of CMV keratouveitis has yet to be
fully elucidated. Herpesviridae are known to establish
latency after primary infection, and it is speculated
that intraocular latency allows for replication and
anterior segment recurrence of CMV. This is evi-
denced by reactivation and replication of CMV fol-
lowing local immune suppression, such as with
&
topical cyclosporine A [16 ], difluprednate, or fre-
quent use of topical corticosteroids. Additionally,
systemic immunosuppression has been associated
with recurrent CMV anterior segment inflammation
[22]. CMV has been visualized in the corneal endo-
thelium [21,24,35,36], as well as isolated from the
smooth muscle cells of the iris, ciliary body, and
trabecular meshwork [37]. Some postulate that
because of the immune-privileged nature of ocular
tissue, the eye may be a prime site for establishing a
reservoir of latent virus, leading to the accumulation
of antiviral CD8þ T cells and triggering chronic
inflammation that may occur with or without viral
&&
replication [38 ].
Few pathogenic mechanisms regarding the
sequelae of CMV keratouveitis, namely glaucoma
and endothelial cell loss, have been substantiated.
&&
Choi et al. [10 ] recently demonstrated that CMV-
infected human trabecular meshwork cells enhance
production of transforming growth factor (TGF)-b1,
a molecule that increases the resistance of the tra-
becular meshwork outflow pathway, supporting the
role of trabecular meshwork infection in the hyper-
tensive episodes of CMV keratouveitis. The same
study also described cytopathic changes of the tra-
becular meshwork, such as ballooned appearance,
disorganization, and decreased stress fiber density.
One case series found that CMV endotheliitis lesions
tend to progress from the peripheral to central cor-
nea, supporting theories that trabecular meshwork
and ciliary body harbor latent virus [22]. The same
authors theorized that CMV antigens may exhibit
anterior chamber-associated immune deviation
(much like has been shown in a rabbit model of
HSV-1 endotheliitis), which would allow for CMV
invasion of endothelial cells [22,35]. Despite acti-
vating canonical inflammatory pathways following
endothelial invasion, CMV is able to evade immune
targeting, which may be related, in part, to decreas-
ing function of CD8 T cells in older individuals
&&
[23 ]. Additionally, increased anterior chamber
viral load has been associated with greater severity
of inflammation [28], supporting the theory that
Volume 29  Number 6  November 2018
 Ocular manifestations of CMV Joye and Gonzales

viral invasion and lytic processes contribute to CMV
&&
keratouveitis pathogenesis [39 ].
Clinical findings
CMV keratouveitis constitutes a spectrum of endothe-
liitis (inflammation of the corneal and/or trabecular
endothelium) and anterior uveitis (inflammation of
the iris and/or ciliary body). The anatomic site of
inflammation dictates clinical findings, although
signs of anterior chamber inflammation and elevated
intraocular pressure (IOP) are almost always present.
Keratic precipitates are an important feature of
CMV keratouveitis and provide a unique indication
as to the etiology. Unlike noninfectious uveitis,
where keratic precipitates are classically located in
Arlt’s triangle by virtue of anterior chamber convec-
tion currents, the keratic precipitates in viral kera-
touveitis may also be located above the corneal
equator, signifying endotheliitis because of viral
invasion of the corneal endothelial cells. This has
been corroborated by the presence of CMV in the
endothelium and deep stroma on immunohis-
tochemistry [36], as well as classic ‘owl’s eye’ inclu-
sions demonstrated by in-vivo confocal microscopy
of endothelial cells [21,24,26]. Additionally, the
CMV viral load is high in patients exhibiting endo-
theliitis [7]. Keratic precipitate morphology may
also help differentiate infectious from noninfectious
keratouvetitis, as well as CMV from other viral
causes. The keratic precipitates of viral keratouveitis
are often small, nongranulomatous, and, may
be stellate in shape. Distinguishing morphology
in CMV keratouveitis include ‘coin-shaped’
(or circinate) keratic precipitates (Fig. 1), which have
been reported to have a positive predictive value of
90.9% [18,22,32]. This feature has recently and more
aptly been referred to as a ‘corral configuration,’
a term introduced by David Heiden (personal
communication) to describe the convening of the
individual keratic precipitates into a circular pattern
reminiscent of a corral.
Iris atrophy is also frequently present in viral
keratouveitis, particularly with long-standing disease.
This atrophy may be related to direct infiltration of
uveal smooth muscle and vasculature, or recurrent
ischemic damage from ocular hypertension. CMV
keratouveitis may exhibit a diffuse, anterior stromal
atrophy [3] versus the more sectoral and diffuse trans-
illumination defects of VZV and HSV, respectively,
though this is not always the case [40]. Iris nodules are
another feature more often associated with CMV
when compared with other herpetic causes.
CMV keratouveitis almost certainly involves
varying degrees of invasion and damage to the
corneal and trabecular endothelium [18]. Signs of
trabecular meshwork involvement include elevated
IOP and, if left untreated, potential for eventuation
to secondary glaucoma and glaucoma surgery [6,37].
Acutely, corneal endotheliitis presents with corneal
edema, whereas recurrent damage can lead to reduc-
tion in endothelial cell density and risk for decom-
pensation (Fig. 1).
Phenotypes
There are multiple phenotypes associated with CMV
keratouveitis. The two most frequently encountered

FIGURE 1. Keratic precipitate morphology in cytomegalovirus keratouveitis. Slit-lamp photos demonstrating the keratic
precipitates highly specific for CMV keratouveitis. These have been described as coin-shaped, cercinate, or ‘corral’
configuration. Reproduced by courtesy of Thanapong Somkijrungroj, MD (for photographs). CMV, cytomegalovirus.

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Ocular manifestations of systemic disease
phenotypes seem to exist on a spectrum, beginning
with an acute and relapsing hypertensive anterior
uveitis (consistent with Posner-Schlossman Syn-
drome) that may progress to a chronic hypertensive
anterior uveitis (consistent with Fuchs uveitis syn-
drome).
The acute and relapsing form typically presents
in the third to fifth decade, with acute unilateral
blurred vision (with or without associated head-
ache), corneal edema, keratic precipitates at the
central and peripheral cornea, and 1/2 to 1þ anterior
chamber cell with minimal flare. IOP is frequently
elevated above 50 mmHg during attacks and nor-
&&
malizes between flares [7,9 ]. This acute form tends
to resolve on its own, but recurs frequently, with
resulting inflammatory changes leading to progres-
sive anterior segment damage and secondary glau-
&&
coma [19,41 ].
The chronic hypertensive form usually presents
later during the fifth to seventh decade, and is
characterized by asymptomatic, low-grade inflam-
mation, and chronically elevated IOP [7]. Charac-
teristic findings include nodular endothelial
changes, stellate keratic precipitates, diffuse stromal
iris atrophy, iris nodules, and iris heterochromia (in
which naturally darker irides will appear lighter, and
lighter irides, particularly blue or light green, will
&&
appear darker) [9 ]; this constellation of features is
most commonly attributed to CMV, though other
viral causes, including rubella, have been described
[42]. Although chronic inflammation typically
FIGURE 2. Corneal endothelial cell loss in cytomegalovirus keratouveitis. In-vivo confocal microscopy comparison of corneal
endothelial cells in the same patient’s unaffected eye (left image) and CMV-affected eye (right image). The CMV-affected eye
demonstrates polymegathism and pleomorphic cells suggestive of endothelial cell loss. CMV, cytomegalovirus.
538 www.co-ophthalmology.com
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
continues until antivirals are used, we have
encountered some patients exhibiting inflam-
mation for months who have ultimately gone
into remission without antiviral treatment.
Anterior chamber inflammation in both pheno-
types is typically minimal, and posterior synechiae are
extremely rare. Ocular hypertension may be accom-
panied by new keratic precipitates or anterior chamber
cell (with as little as 1/2þ anterior chamber cell),
although it may be as high as 2þ as graded by the
Standardization of Uveitis Nomenclature system
[3,43]. Occasionally, the first or only sign of recurrent
inflammation is the recurrence of ocular hyperten-
sion. Interestingly, it has been postulated that in cases
of ocular hypertension while on concurrent topical
antiviral therapy (and presumed inhibition of viral
replication), the intraocular pressure elevations are
related to secondary inflammatory changes [6].
Complications
Early recognition of CMV keratouveitis is essential
to prevent (or minimize) the long-term sequelae of
recurrent and chronic anterior segment inflamma-
tion. The most pertinent of these sequelae are endo-
thelial cell loss and secondary glaucoma.
Recurrent bouts of viral invasion and cell lysis
&
leads to endothelial cell loss [44 ] (Fig. 2). Su et al.
compared endothelial cell density in patients
between CMV-positive and CMV-negative Posner-
Schlossman Syndrome. In both groups, affected eyes
Volume 29  Number 6  November 2018

demonstrated reduced endothelial cell density com-
pared with unaffected eyes and with normal con-
trols [45], and those positive for CMV demonstrated
significantly more reduced endothelial density com-
pared with CMV-negative eyes [6]. Furthermore,
increased viral load is associated with more severe
endothelial cell loss [4,14,28], increasing risk for
decompensation that may require corneal trans-
plant to restore vision [30]. Unfortunately, these
transplants are at risk for re-infection and failure
of the graft, the appearance of which may resemble
allograft rejection following penetrating kerato-
plasty or Descemet’s stripping automated endothe-
&
lial keratoplasty [15 ,17,30].
Secondary glaucoma may develop as a result of
presumed trabecular meshwork infection and asso-
ciated recurrent or chronic elevations in IOP. Anti-
glaucoma medications are necessary during acute
attacks and may be helpful in managing chronically
elevated IOP. Still, glaucomatous optic neuropathy
is common (36%)[7] and many eyes eventuate to
glaucoma surgery despite treatment (13.3–60%)
&
[6,8,46,47 ].
Microbiology
Historically, patients who exhibited clinical features
suggestive of viral keratouveitis would be trialed on
empiric oral acyclovir, valacyclovir, or famciclovir.
Patients who did not respond to empiric therapy
would then be switched to oral valganciclovir, with
a response providing indirect evidence that CMV
was mediating the keratouveitis. PCR is now widely
available and able to provide a definitive diagnosis
of CMV keratouveitis following anterior chamber
paracentesis, which can be performed safely in the
clinic [48]. In the setting of unilateral hypertensive
anterior uveitis, PCR Multiplex testing for CMV,
VZV, and HSV can be very helpful in guiding ther-
apy [5], and some even suggest addition of the
&&
Goldmann-Witmer coefficient [49 ], a test that is
not readily available in the United States. Repeat
PCR, or even metagenomic deep-sequencing if avail-
able, may uncover CMV following previously nega-
&
tive results and a high index of suspicion [50 ].
Routine use of aqueous PCR testing has allowed
for recognition of CMV’s role in keratouveitis. Still,
the relationship between viral burden and clinical
features, disease progression, and treatment options
are relatively unexplored. Mean viral loads sampled
during periods of active inflammation range
from 9.6  103 copies/ml (SD 1.8  104 copies/ml)
to 1.1  106 copies/ml (SD 1.2  106 copies/ml)
[27,28,30]. Very few studies have investigated the
effects of antiviral therapy on the reduction in viral
load, a task that is especially challenging, given the
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Ocular manifestations of CMV Joye and Gonzales
ability for the acute-recurrent phenotype to resolve
quickly regardless of therapy. Fittingly, most of
these studies have demonstrated undetectable post-
treatment loads [6,30], leaving us to speculate as to
whether the effect was because of the antiviral ther-
apy or the host immune response itself.
These results are consistent with the theory that
inflammation is influenced by active CMV replica-
tion. This was further supported by Kandori et al.
[28], who reported that viral load was significantly
correlated with intraocular pressure elevation, pres-
ence of coin-shaped lesions, recurrent inflamma-
tion, and reduction in endothelial cell density;
additionally, intraocular pressure elevation, reduc-
tion in endothelial cell density, and recurrent
inflammation, and not disease phenotype, were
significant predictors of the presence of more than
103 CMV viral copies/ml in the aqueous.
Treatment strategy
As discussed previously, the acute recurrent pheno-
type of CMV keratouveitis frequently exhibits qui-
escence without treatment [51]. Still, acute and even
prophylactic antiviral therapy should be strongly
considered and may prevent complications associ-
ated with recurrent and chronic inflammation. Var-
ious topical steroid regimens are also frequently
employed by clinicians. Optimal management,
however, is yet to be determined.
CMV does not utilize a viral thymidine kinase
and is, therefore, very poorly suppressed by acyclo-
vir and valacyclovir. Ganciclovir and valganciclovir,
however, inhibit CMV’s DNA polymerase after
being phosphorylated by CMV’s viral kinase
encoded by the UL97 gene [52]. There is question
as to whether oral versus topical therapy is the
appropriate choice for CMV keratouveitis. In the
United States, antiviral therapy typically consists
of oral valganciclovir [900 mg b.i.d. for treatment,
450 mg b.i.d. for maintenance – established by the
United States Food and Drug Administration
(USFDA) for CMV retinitis], although frequent test-
ing is required to monitor for signs of renal, hepatic,
and bone marrow toxicity. Many clinicians in Asia
have found that locally prepared topical ganciclovir
solutions (ranging from 0.5 to 2%, used six times
daily for treatment, three times daily for mainte-
nance) are effective, well tolerated, and economical,
and capable of preserving endothelium and
reducing recurrence of CMV keratouveitis
&& &&
[6,12 ,13 ,20,30]. Studies utilizing concentrations
as low as 0.15% have shown mixed effectiveness
&
[19,47 ], possibly related to failure to reach the 50%
inhibitory dose for CMV in the anterior chamber
&
[53 ]. Randomized controlled trials are needed to
www.co-ophthalmology.com 539
Ocular manifestations of systemic disease
confirm the optimal route and dosing for treatment
and maintenance therapy, though topical ganciclo-
vir seems to provide a very promising answer.
Treatment dosing and frequency is typically
maintained until features of inflammation (active
KP, stromal edema, elevated intraocular pressure,
anterior chamber cells) exhibit quiescence [25].
Recurrence rates associated with cessation of ther-
apy approach 85% [8,19,25], so transitioning to
maintenance therapy should be strongly considered
to minimize optic neuropathy and preserve endo-
thelial function and corneal clarity [8,20]. In severe
cases, where stromal edema or bullous keratopathy
significantly affects vision, endothelial or full kera-
toplasty may be appropriate. Treatment dosing of
antivirals should be used perioperatively to prevent
or limit CMV involvement of the grafted endothe-
lium, and grafts can do well when antiviral therapy
is instituted either orally, topically, or both
&& & &&
[13 ,15 ,30,54 ]. If graft failure occurs, determin-
ing whether graft failure is related to CMV recur-
rence or graft rejection alone can be challenging. In
these cases, sampling the aqueous for PCR testing of
CMV can be helpful [17,30]. Nevertheless, early
recognition and management of CMV keratouveitis
may prevent grafting in the first place.
CYTOMEGALOVIRUS RETINITIS/
POSTERIOR AND PANUVEITIS
CMV retinitis was a frequent and devastating con-
sequence of advanced AIDS, although the advent of
combination antiretroviral therapy dramatically
FIGURE 3. Retinal nonperfusion in cytomegalovirus retinitis. Fluorescein angiography demonstrating profound retinal nonperfusion
(left image) in the eye of a patient with CMV retinitis following high-dose systemic corticosteroids for treatment of giant-cell arteritis.
Follow-up OCT (right image) confirms inner retinal atrophy because of ischemic damage. CMV, cytomegalovirus; OCT, optical
coherence tomography.
540 www.co-ophthalmology.com
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reduced its incidence in the HIV-infected popula-
&&
tion [55 ]. It is, however, important to recognize
immunocompetency as a spectrum, and that there
are HIV-negative individuals at risk for developing
&& &&
CMV retinitis [55 ,56 ,57]. This includes patients
with oncologic issues [58], primary immunodefi-
&& &&
ciencies [55 ,56 ], and on systemic immunosup-
pression [59,60].
Although much less common than CMV kera-
touveitis, CMV retinitis has been reported numerous
times in presumably immunocompetent patients
who received intraocular or periocular steroid injec-
tion [61–68]. One article recognized CMV as the most
common cause of retinitis following local corticoster-
oid administration, identifying the virus in 23 of 30
cases during literature review [63]. Some presumably
healthy patients have even developed CMV retinitis
in the absence of local corticosteroids [57]. Irrespec-
tive of local immunosuppression, many of these
patients were elderly and had diabetes mellitus.
Advanced age, in particular, has been associated with
immunosenescence [69–71], posing a question as to
the extent that other systemic risk factors influence
CMV reactivation.
Clinical findings of CMV retinitis in immuno-
competent patients resemble those of AIDS-associ-
ated CMV retinitis, with hemorrhagic and granular
&&
retinitis [56 ]. Other findings included vitritis, ante-
rior chamber inflammatory reaction, a predomi-
nantly arterial retinal vasculitis with profound
retinal nonperfusion (Fig. 3), and even presenta-
tions that initially resembled acute retinal necrosis
&&
[56 ,57,63,65]. Treatment of CMV retinitis typically
Volume 29  Number 6  November 2018

requires hospitalization for intravenous ganciclovir
therapy with or without the addition of intravitreal
ganciclovir or foscarnet. Further studies are needed
to define appropriate management for various
patient populations.
CONCLUSION
Recent studies have investigated and partially illumi-
nated CMV’s role as a pathogen in immunocompetent
hosts. In particular, CMV has been identified as a
major cause of viral keratouveitis and retinitis, thanks
in part to the availability of molecular testing.
Improved recognition of CMV keratouveitis in previ-
ously presumed idiopathic uveitis syndromes (such as
Posner-Schlossman and Fuchs) allows clinicians to
initiate CMV-specific therapy and prevent sequelae
related to ocular hypertension and endotheliitis. Top-
ical ganciclovir seems to be a well tolerated, effective,
and economical therapy for CMV keratouveitis,
though further studies are needed to confirm optimal
management. It is still unclear why presumably
immunocompetent individuals develop CMV kera-
touveitis and retinitis. Exploration into host risk fac-
tors and viral genomics may provide more insight into
the pathogenesis of these recently discovered entities.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
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Volume 29  Number 6  November 2018