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Curr Ophthalmol Rep. Author manuscript; available in PMC 2016 September 01.
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Published in final edited form as:

Curr Ophthalmol Rep. 2015 September ; 3(3): 170–183. doi:10.1007/s40135-015-0076-6.

Infectious Uveitis
Phoebe Lin, MD, PhD
Assistant Professor of Ophthalmology, Casey Eye Institute, Oregon Health & Science University,
3375 SW Terwilliger Blvd, Portland, Oregon 97239, Phone: 503-494-0007, Fax: 503-494-7233
Phoebe Lin: [email protected]

Abstract
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Infectious uveitis is one of the most common and visually devastating causes of uveitis in the US
and worldwide. This review provides a summary of the identification, treatment, and
complications associated with certain forms of viral, bacterial, fungal, helminthic, and parasitic
uveitis. In particular, this article reviews the literature on identification and treatment of acute
retinal necrosis due to herpes simplex virus, varicella virus, and cytomegalovirus. While no
agreed-upon treatment has been identified, the characteristics of Ebola virus panuveitis is also
reviewed. In addition, forms of parasitic infection such as Toxoplasmosis and Toxocariasis are
summarized, as well as spirochetal uveitis. Syphilitic retinitis is reviewed given its increase in
prevalence over the last decade. The importance of early identification and treatment of infectious
uveitis is emphasized. Early identification can be achieved with a combination of maintaining a
high suspicion, recognizing certain clinical features, utilizing multi-modal imaging, and obtaining
specimens for molecular diagnostic testing.
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Keywords
infectious uveitis; molecular diagnostics; multi-modal ophthalmic imaging

1. Introduction
Uveitis due to infectious etiologies accounts for between 15–20% of all cases of uveitis in
certain parts of the United States, and likely accounts for a much more significant proportion
of uveitis worldwide. [1,2] At tertiary care referral centers, it represents an even higher
proportion of uveitis cases, approximately between 26–35%.[3,4] While infectious uveitis
can affect various anatomic locations of the eye ranging from anterior to posterior uveitis,
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the most devastating cases are represented by those that cause posterior involvement such as
acute retinal necrosis due to herpes family viruses, or toxoplasmosis retinochoroiditis.
Recognition of an infectious cause of uveitis, and early aggressive treatment with
antimicrobial agents are of paramount importance for visual recovery and preservation.

Correspondence to: Phoebe Lin, [email protected].

Conflict of Interest Statement
Dr. Phoebe Lin has no conflicts of interest to declare
Compliance with Ethics Guidelines
Human and Animal Rights and Informed Consent
This article contains no studies with human or animal subjects performed by the author.
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Because infectious uveitis can often mimic immune-mediated uveitis, intimate knowledge of
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the clinical presentation of various types of infectious uveitis and appropriate use of
molecular diagnostics to aid in identifying an infectious agent are crucial in the management
of these conditions.

2. Viral uveitis
a. Herpes Simplex Virus (HSV) and Varicella Zoster Virus (VZV)
i. Herpetic anterior uveitis—HSV-1/HSV-2 and VZV, in addition to causing a dendritic
and pseudodendritic epithelial keratitis, respectively, can cause acute recurrent or chronic
anterior uveitis. In the Pacific Ocular Inflammation Study, approximately 8% of uveitis was
due to HSV or VZV. [1] Clinical findings associated with herpetic uveitis include the
following: elevated intraocular pressure associated with acute iritis, stellate keratic
precipitates throughout the corneal endothelium rather than sequestered to the inferior third
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of the cornea (Arlt’s triangle), large granulomatous keratic precipitates, iris transillumination
defects in a sectoral or non-sectoral fashion, atrophy of the iris pigmented epithelium,
decreased corneal sensation, and a mydriatic or corectopic pupil in the absence of dilating
drops. Elucidating a history of herpetic lesions in the ipsilateral V1 dermatome in VZV or
the presence of HSV-type ulcerations on the skin or oral/genital mucosa is an important part
of distinguishing viral anterior uveitis from other causes. While usually unilateral, bilateral
herpetic anterior uveitis has been shown.[5] Confirmation of VZV or HSV-related anterior
uveitis can be obtained by procurement of an aqueous specimen for polymerase chain
reaction (PCR) testing, and does not rely on serological testing for antibodies against these
viruses given the widespread exposure to HSV and VZV (as well as vaccination against
VZV).
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In the absence of herpetic keratitis, topical anti-viral agents do not appear to be beneficial in
the treatment of HSV or VZV anterior uveitis. Rather, the hallmark of treatment for HSV or
VZV anterior uveitis includes the use of systemic antivirals such as oral acyclovir,
valacyclovir, or famciclovir (see Table 1 for dosage). The concomitant administration of
topical corticosteroids is also quite important, using either topical prednisolone acetate 1%
or difluprednate, with the use of a cycloplegic if anterior chamber inflammation exceeds a
grade of 1+ cell.

With the implementation of the varicella and zoster vaccination programs, the epidemiology
of VZV uveitis may change over time since less of the population will be exposed to and
develop natural immunity to chickenpox. In fact, reactivation of VZV keratitis has been
shown to occur after zoster vaccination, and also has been shown to occur despite varicella
vaccination. [6–8]
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ii. Acute retinal necrosis—Acute retinal necrosis (ARN) was first described by
Urayama as an acute unilateral diffuse necrotizing retinitis with panuveitis progressing to
retinal detachment. [9] Young and Bird were subsequently the first describe this syndrome in
two cases of bilateral disease and name the disease bilateral ARN or BARN. [10] Patients
with ARN present with acute redness, pain, photophobia, and vision loss. The clinical
examination reveals granulomatous or non-granulomatous anterior chamber cellular

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reaction, vitritis, and most typically, a multifocal or confluent full thickness necrotizing
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retinitis with an accompanying occlusive retinal arteritis and sometimes optic nerve edema
(Figure 1). The American Uveitis Society criteria for the diagnosis of ARN are shown in
Table 2.[11] The vast majority (over 50%) of ARN is due to VZV, followed by HSV-2
(5.1%), and HSV-1 (3.5%). [9] Interestingly, one study found concomitant Epstein-barr
virus (EBV) DNA by PCR with VZV in 3 patients with ARN, although most case series and
clinicians have not tested for EBV in ARN to confirm this result.[12] EBV-associated ARN
has also been shown histopathologically in one case, although clinically, this case appeared
to involve much more extensive hemorrhagic retinitis than in typical ARN. [13] VZV and
HSV-1 associated ARN are more commonly found in older and middle-aged patients
whereas HSV-2 associated ARN is more common in children and young adults. [14–16]

Without treatment of ARN, there is a much higher rate of poor visual outcomes, but with
prompt treatment, resolution of retinitis can be achieved within 4 weeks. Treatment of ARN
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requires aggressive anti-viral therapy, both with systemic anti-virals to prevent bilateral
disease, which can occur in up to one third of patients, and with intravitreal anti-viral agents
(Table 1). Second eye involvement usually occurs around 6 weeks after initial eye
involvement, but has also been reported to occur years after the first eye was involved. [17]
Resolution of active ARN is noted when there is consolidation of the borders of retinitis
with subsequent retinal pigment epithelial (RPE) pigmentary changes, retinal atrophy, and
often, a scalloped appearance at the junction of affected and unaffected retina. Up to 75% of
patients can develop a rhegmatogenous retinal detachment weeks to months after initial
presentation. [12,18] Poor visual outcomes are associated with optic nerve involvement,
extensive retinitis at the time of presentation, VZV and HSV-2 infection, and inappropriate
use of corticosteroids.[9,19] In our experience, optic nerve involvement, which occurs in
about 11%,[12] will usually result in poor visual outcomes even if treated early, and even in
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the absence of retinitis in the macula or retinal detachment. In one large series of ARN, half
of all patients had 20/200 or worse vision by 3 months. [20]

There is some, albeit moderate to low level, evidence for prophylactic confluent laser in
patients with ARN to prevent retinal detachment and improve outcomes.[21] When applying
laser either alone or during retinal detachment surgery in active ARN, it is important to
determine where the active border is, and to place 2–3 rows of laser spots posterior to this
border given that herpetic infection appears to spread contiguously and infect adjacent retina
which may not appear infected early on.[22] As is the case in up to 75% of patients, retinal
detachment surgery may be required, in which pars plana vitrectomy, endolaser, and long-
acting gas or silicone oil tamponade is the mainstay of surgery to maintain a successful
repair. The benefit of early vitrectomy has been proposed, although some find no final visual
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advantage. [23]

iii. Progressive outer retinal necrosis—Progressive outer retinal necrosis (PORN) is a

form of viral retinitis in human immunodeficiency virus/Acquired Immune Deficiency
Syndrome (HIV/AIDS) or immunosuppressed patients that is characterized by posterior
multifocal outer retinal to full thickness necrotizing retinitis with sparing of the perivascular
retina, usually due to VZV. Patients with PORN typically do not have associated vitreous or
anterior chamber inflammation. This entity is associated with CD4 cell counts below 50

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cells/mL and is treated with a combination of aggressive systemic and local anti-viral
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therapy (Table 1). In addition to anti-viral therapy, the key to resolution is also immune
reconstitution after highly active anti-retroviral therapy (HAART) for HIV patients with
PORN. While the prevalence of PORN has decreased in the HAART era, it often resulted in
NLP vision in affected eyes previously. [24]

b. Cytomegalovirus (CMV)
i. CMV anterior uveitis—While 80–85% of persons aged ≥ 40 years are seropositive for
CMV, few develop infection from CMV unless they are immunosuppressed. In contrast,
isolated anterior uveitis due to CMV in immunocompetent patients is an entity that has been
more recently been characterized. While clinical findings can be variable, it has been shown
to cause a unilateral (occasionally bilateral) anterior chamber inflammation associated with
iris sectoral defects, episodes of ocular hypertension, and diffuse fine to medium keratic
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precipitates, occasionally with focal endotheliitis.[25–27] It can be acute, recurrent, or

chronic, and some cases may have been previously characterized as Posner-Schlossman
syndrome. This diagnosis can be confirmed with PCR from an aqueous paracentesis. CMV
anterior uveitis can be treated successfully with oral valganciclovir (Table 1), intravenous
ganciclovir, intravitreal ganciclovir, or topical ganciclovir gel. [25–29] In fact, Chee and
colleagues have found that ganciclovir gel 0.15% had moderate response rates for anterior
uveitis due to CMV, but may have lower recurrence rates, though this conclusion was drawn
from retrospective data.[29]

ii. CMV retinitis—Retinitis due to CMV, unlike isolated anterior uveitis, usually occurs in
immunocompromised individuals such as those who have HIV/AIDS, or those who have
received chemotherapy for cancer. CMV retinitis usually presents bilaterally, with one of
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two presentations: a granular necrotizing retinitis or a hemorrhagic necrotizing retinitis,

usually associated with an occlusive retinal vasculitis. Typically, none or few vitreous cells
are present, and there is almost uniformly an absence of anterior chamber cell. Rarely, CMV
retinitis can present as a frosted branch angiitis or an isolated papillitis. While diagnosis is
based on the clinical findings and medical history, it can be confirmed by PCR of a vitreous
or aqueous paracentesis specimen. Like PORN, CMV retinitis increases when CD4 counts
drop below 50/mL. Occasionally, CMV retinitis can occur in patients with CD4 counts
above 100/mL, and is thought to be due to an incomplete restoration of immunity against
CMV, similar to what occurs in immunosuppressed individuals after bone marrow
transplantation or chemotherapy. In the latter scenarios, it is more common for CMV
retinitis to present with vitreous or anterior chamber cells (Figure 2).

Treatment of CMV retinitis requires aggressive systemic and intravitreal antiviral therapies
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that have increased efficacy against CMV compared to other herpes family viruses. These
treatments include ganciclovir, valganciclovir, and foscarnet. Resistance to these common
treatments occurs when CMV contains mutations in the UL97 and UL54 genes. UL54
mutations can also cause fosarnet resistance. Intravitreal therapy combined with systemic
therapy (foscarnet + ganciclovir/valganciclovir) can, to some extent, mitigate resistant
CMV, due to the high concentration of drug being delivered. Complications of CMV
retinitis can include rhegmatogenous retinal detachment (28% in one case series) [30],

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exudative retinal detachment, and immune recovery uveitis (IRU) after resolution of CMV
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retinitis. IRU is treated with topical or oral corticosteroids.

c. Other viruses
Rubella virus—Rubella virus is thought to be a causal factor in Fuchs’ heterochromic
iridocyclitis (FHI), a condition which presents with anterior chamber inflammation, fine
stellate keratic precipitates involving the entire corneal endothelium, cataract, glaucoma, and
iris heterochromia due to loss of anterior iris pigment. Abnormal bridging vessels in the
angle have also been described in FHI, resulting in hyphema during cataract surgery. In one
study, de Groot-Mijnes et al demonstrated intraocular antibody production with a
Goldmann-Witmer coefficient of > 3, against rubella virus in 13 of 14 cases, while
antibodies against HSV, VZV, and Toxoplasmosis were not discovered in these patients.
[31] In another study, Birnbaum demonstrated the decreasing prevalence of FHI after the
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institution of the rubella vaccination program, as well as the higher prevalence of FHI
among immigrants in the US who had not been vaccinated. [32] Treatment of FHI includes
control of glaucoma and removal of cataract. Topical corticosteroids are often not effective
in treating the cellular reaction, but inflammation in FHI seldomly causes sequelae such as
cystoid macular edema (CME) or posterior synechiae. Therefore, long-term corticosteroids
are not usually indicated although perioperative topical steroids are usually recommended.

Ebola virus—Ebola virus is of the virus family Filoviridae, containing three genera,
including Marburgvirus and Cuevavirus. As outlined recently at the keynote session of the
Association for Research in Vision and Ophthalmology meeting in May 2015, the current
outbreak of Ebola virus disease (EVD) has resulted in over 11,000 deaths among a total of
26,000 cases reported across 9 countries, including Sierra Leone, Liberia, Guinea, Mali,
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Nigeria, Senegal, the United States, the United Kingdom, and Spain. Ocular complications
during convalescence from Ebola virus infection were reported by Kibadi et al in 1999, in
which 4 patients who had survived Ebola virus infection developed eye pain, photophobia,
and vision loss between 42 and 72 days after diagnosis of EVD. All four of these patients
were diagnosed with anterior uveitis, vitritis, or a combination of the two. All patients
appeared to respond to topical cycloplegics and topical steroids. One patient in this series
had a positive PCR for Ebola virus from a conjunctival swab despite a negative enzyme-
linked immunosorbent assay (ELISA) from the blood.

In a very recent report by Varkey and colleagues from the most recent EVD outbreak, a 43
year-old male patient who acquired EVD while treating Ebola patients from Sierra Leone,
and who was transferred back to the US for care, developed low back pain, sacroiliitis,
bilateral enthesitis of the Achilles’ tendon and paresthesias, as well as photophobia, 10
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weeks after the onset of EVD after discharge from the hospital. Sparse pigmented
chorioretinal scars with hypopigmented halos were seen on fundus examination. One month
later, he presented with acute onset blurry vision, pain, and photophobia of the left eye, with
elevated intraocular pressure to 44 mmHg. Clinically, he had non-granulomatous keratic
precipitates and 1+ anterior chamber cell which worsened over 48 hours despite frequent
topical corticosteroids. Anterior chamber paracentesis was positive for Ebola virus by
reverse transcriptase (RT)-PCR and by viral cultures despite negative conjunctival swabs,

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RT-PCR of tears, and peripheral blood. The patient developed iris heterochromia and
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increasing vitritis. The patient received experimental systemic treatment for Ebola virus as
well as a posterior subtenon triamcinolone injection, and has since resolved to 20/15 visual
acuity in the affected eye. In summary, this patient represents the first to have developed
documented acute panuveitis due to viable Ebola virus after convalescence, which implies
that Ebola virus may persist in sites of immune privilege such as the eye and CNS. 33

West Nile Virus—West Nile virus is a single-stranded RNA mosquito-borne virus that
belongs to the Flaviviridae family. Clinical findings in uveitis due to West Nile Virus
include elevated intraocular pressure, typically bilateral anterior and intermediate uveitis,
and panuveitis, with chorioretinal lesions that have been described as linear, streak-like +/−
an occlusive retinal vasculitis. [34] Optic nerve edema has also been described. Chorioretinal
lesions have also been described to be nummular with central pigmentation and surrounding
haloes of atrophy, similar to the case of Ebola virus described above. [35] Treatment has
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been supportive, without any known antivirals that are active against West Nile Virus in
vivo.

Additional viruses—Other viruses that have also been shown to be associated with
uveitis include Dengue virus, another Flavivirus, which causes an often bilateral, retinal
vascultiis with retinal hemorrhages, retinal vascular sheathing, yellow subretinal dots, optic
neuritis, and an anterior chamber reaction. Chikungunya virus is a single-stranded RNA
virus of the Togaviridae family transmitted through Aedes aegypti mosquitoes. Chikungunya
causes retinal whitening, occlusive retinal vasculitis, optic neuritis, and can sometimes result
in central retinal artery occlusion and exudative retinal detachment. Rift valley fever virus is
an arthropod-borne virus of the Bunyaviridae family from sub-Saharan Africa and the
Arabian peninsula. The main symptoms include headache, arthralgias, and gastrointestinal
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symptoms. Ocular findings of Rift valley Fever virus include macular/paramacular retinitis
with optic disc edema, retinal vasculitis, and vitritis. These findings can resolve within 2–3
weeks, although with scarring, vision can become limited. Influenza A (H1N1) has also
been shown to cause ocular involvement rarely, including retinitis, choroiditis, frosted
branch angiitis, and optic disc edema. Severe manifestations can be treated with oral
prednisone. [36–38]

3. Spirochetal infections
a. Syphilis
Syphilis is caused by the spirochete Treponema pallidum. A number of factors, including
high risk behavior with improvements in pharmacotherapy of HIV and syphilis, have
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contributed to the increasing prevalence of this disease world-wide over the last 10–15 years
compared to the decade before that, especially in men having sex with men, and in patients
who are coinfected with HIV. The most common ocular manifestation of syphilis is uveitis,
which occurs in up to 5% of patients with tertiary syphilis. [39] Clinical findings range from
a granulomatous or non-granulomatous anterior chamber reaction, vitritis, retinal vasculitis,
and papillitis, to a retinitis. Retinitis can manifest in one of two main ways: either as a
punctate inner retinitis with dew-drop like collections along the surface of the retina,[40] or

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as a more diffuse yellowish or grayish outer retinitis which can form consolidated lesions
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termed acute syphilitic posterior placoid chorioretinitis;[41,42] syphilis patients can also
present with a combination of the above presentations. An outer retinal wipe-out syndrome
due to syphilis which is similar in presentation to acute zonal occult outer retinopathy (or
AZOOR) has also been described with an example shown in Figure 3, with recovery to near
normal after penicillin treatment. [43] Other ocular findings and manifestations in syphilis
include interstitial keratitis, chancre of the conjunctiva, episcleritis, and scleritis, as well as
the Argyll Robertson pupil which results in anisocoria with a light-near dissociation. Serous
and tractional retinal detachments can also result as a complication of inflammation.

Diagnosis of syphilis requires maintaining a high suspicion and low threshold for clinical
testing, which should include both treponemal tests such as fluorescent treponemal antibody
absorption (FTA-ABS) or microhemagglutinin assay for T. pallidum (MHA-TP) tests and
non-treponemal tests such as venereal disease research laboratory (VDRL) and rapid plasma
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reagin (RPR) tests. While the non-treponemal tests can be non-specific, they are useful, once
treponemal tests are used to confirm diagnosis, to guide treatment decisions given that the
titer can be followed upon treatment. While a positive VDRL test of the CSF is highly
specific, it is not sensitive, and a negative test does not rule out neurosyphilis.

Whereas ocular syphilis is always a sign of tertiary syphilis, optic neuritis and retinitis are
considered manifestations of neurosyphilis, and should be treated accordingly with a 14 day
course of intravenous aqueous penicillin G at 3–4 million units every 4 hours. In the absence
of neurologic involvement and just anterior syphilitic uveitis, it is unclear whether or not
treatment as tertiary syphilis without neurologic involvement (ie with Benzathine penicillin
at 2.3 million units intramuscularly weekly x 3 weeks) is sufficient. [44,45] Involvement of
an infectious disease specialist is usually helpful in the treatment of syphilitic uveitis.
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b. Lyme disease
Lyme disease is caused by Borrelia burgdorferi, a spirochete transmitted by the Ixodes tick
in certain geographical locations in the US, Europe, and Asia. Ocular manifestations of
Lyme disease vary, from conjunctivitis in early-stage Lyme disease, to optic neuritis and
intermediate uveitis with a retinal vasculitis, usually occurring in stage 2 and 3 disease
several years after inoculation. Diagnosis of Lyme disease should utilize a 2 step approach,
recommended by the Centers for Disease Control and Prevention, in which an ELISA is first
performed to detect IgG and IgM specific for B. burgdoferi, followed by Western blot to
determine if there is IgM or IgG against multiple Borrelia antigens.[46] Even with the latter
approach, false positives can be present due to the high proportion of patients in the general
population who have antibodies reactive against a flagellar antigen of the spirochete. Unless
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there is a clear history of tick exposure in an endemic location, we do not routinely perform
Lyme disease testing in uveitis patients due to this high rate of false positivity.

Treatment for the systemic manifestations of Lyme disease include the use of Doxycycline
100 mg PO BID x 14–21 days, but the treatment of the ocular manifestations is unclear, with
some suggesting the use of systemic corticosteroids, which have shown some benefit, while
others have reported that they may increase the rate of recurrence. [47]

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c. Leptospirosis
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Leptospirosis is a zoonotic spirochetal infection transmitted in tropical and subtropical

climates through rodents and other domestic livestock. Farmers, veterinarians, miners, sewer
workers, and patients exposed through ecotourism, are at higher risk for this infection,
which can invade through intact mucosa. A triad of fever, malaise, and uveitis, was first
described by Weil in 1886. Ocular manifestations are actually more variable, including
conjunctival chemosis, subconjunctival hemorrhage, retinal hemorrhages, retinal vasculitis,
and optic disc edema. [48] Diagnosis is by clinical findings in association with elucidation of
risk factors, but serological tests and dark field microscopy can also be used, as well as PCR.
Treatment of systemic leptospirosis typically utilizes penicillin G or an alternative antibiotic
such as doxycycline or azithromycin. Ocular manifestations are concurrently treated with
topical corticosteroids.
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4. Mycobacterial uveitis
a. Ocular tuberculosis
Mycobacterium tuberculosis (MTB) is a rod-shaped, non-spore-forming obligate
intracellular aerobic bacterium usually disseminated by the airborne droplet route. Ocular
manifestations of MTB can vary from phlyctenulosis, scleritis, and episcleritis, to multifocal
choroiditis, granulomatous papillitis, retinal vasculitis, panuveitis, and serpiginous-like
choroiditis mimicking classic serpiginous choroiditis.[49]

Diagnosis of MTB uveitis requires maintaining a high index of suspicion in individuals from
endemic areas or who live in high-risk environments such as nursing homes or prisons, but
is often presumptive given the difficulty of isolating these bacteria from ocular fluids or
tissues. PCR of aqueous or vitreous specimens can be performed to confirm diagnosis, but a
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negative result may not rule out disease given the slow-growing nature of this organism. A
quantiferon test, known commonly as interferon-gamma release assays (IGRAs) measures
the ability of the patient’s T cells to release interferon-gamma in response to specific MTB
antigens. While it is unclear whether or not this test is any more sensitive or specific for
active TB infection than a tuberculin skin test, it does have the advantage of not requiring a
return visit from the patient for the result, as well as avoiding a false positive result when
there is a history of Bacillus Calmette-Guerin (BCG) vaccination. However, like the skin
test, the quantiferon test also cannot distinguish between latent and active MTB infection.
Thus, a presumed diagnosis of MTB uveitis can be made with a combination of
characteristic clinical findings, a positive quantiferon or positive tuberculin skin test, with
concomitant chest X-ray or CT-chest findings. However, it must be noted that even in the
absence of pulmonary findings on chest imaging, MTB uveitis can occur. In fact, in one
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cohort, 57% of histopathologically-proven ocular TB patients had a normal chest X-ray. [50]

Treatment for MTB uveitis includes the use of four-drug therapy (Table 3) for 2 months
followed by isoniazid and rifampin for 4 additional months. Coritcosteroids are often
administered for enhanced efficacy against inflammatory consequence of MTB ocular
infection after antibiotics are initiated. Multiple-drug resistant (MDR) TB (resistant to
isoniazid and rifampin), and XDR-TB (resistant to isoniazid, rifampin, any fluoroquinolone,

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and any one of the injectable second-line drugs) is an emerging problem world-wide, and
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may require 8–10 drug combinations for 18–24 months. Molecular diagnostics to identify
MDR-TB by PCR is now available. [51]

Eales’ disease is an entity in which there is peripheral occlusive vasculitis with a history of a
positive Mantoux test for TB. It is thought to arise from an overactive inflammatory reaction
against mycobacterium antigens, and is treated (unlike MTB uveitis) with corticosteroids
either locally or systemically, and scatter laser to areas of non-perfused retina. However,
recent demonstration of MTB DNA in ocular samples from Eales’ disease patients argues
for the treatment of this disease as a primarily infectious rather than inflammatory disease.
[52,53]

b. Nontuberculous mycobacterial uveitis

Nontuberculous mycobacterium are organisms found ubiquitously in the environment that
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can occasionally be introduced via procedures or surgery into the ocular environment
causing an indolent infectious uveitis. [54,55] While nontubercular mycobacterium do not
respond to typical MTB drugs, they do respond to other antibiotics including amikacin and
certain fluoroquinolones.

5. Endogenous Bacterial Endophthalmitis

Endogenous bacterial endophthalmitis can be due to a variety of organisms though most
frequently, it is caused by gram positive bacteria such as Staphylcoccus aureus, and
streptococcal organisms. Other organisms include group B Streptococcus, Streptococcus
pneumonia, Propionibacterium acnes, Listeria monocytogenes, Bacillus spp, Serratia spp,
Nocardia spp, Klebsiella pneumonia, Pseudomonas aeruginosa, Escherichia coli,
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Enterococcus faecalis, Proteus spp, and others. Presenting symptoms can include pain,
photophobia, floaters, and vision loss. Clinical findings can include anterior chamber cell,
hypopyon with fibrin, vitritis, retinal or choroidal infiltrates, choroidal abscesses, septic
emboli, and intraretinal or white-centered hemorrhages. A work up for a systemic source, if
not already known, is imperative, given the severe consequences of unrecognized
septicemia. Systemic sources can be investigated by blood and urine cultures, cultures of
indwelling catheters or feeding tubes, and examination of chest imaging for possible
pneumonia.

Management of endogenous bacterial endophthalmitis includes vitreous paracentesis for

bacterial culture followed by intravitreal injection of antibiotics and systemic antibiotic
treatment directed against the causative organism. In early cases of endogenous bacterial
endophthalmitis perhaps sequestered to a small focal area of the choroid or retina, systemic
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antibiotic treatment alone may be effective. However, if retinal or vitreous involvement is

significant, intravitreal treatment is usually added. Early administration of intravitreal
antibiotics is likely associated with better visual and anatomical outcomes in endogenous
bacterial endophthalmitis. [56]

The role and timing of pars plana vitrectomy in endogenous bacterial endophthalmitis is
controversial, although most agree that it is sometimes necessary if there is a sequestered

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progressive infectious nidus in the eye despite systemic treatment, or if there is a pending or
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vision-threatening retinal detachment associated with the infectious nidus. In one study from
Vietnam, 108 consecutive patients with severe endogenous bacterial endophthalmitis were
randomized to either vitrectomy alone with intravitreal antibiotics or vitrectomy with
intravitreal antibiotics and silicone oil tamponade. They found that the overall success rate
defined as visual acuity ≥ counting fingers at 1 meter, attached retina, without silicone oil at
9 months follow up was higher in the silicone oil group than the vitrectomy alone group. 57

6. Endogenous Fungal Endophthalmitis

Candida albicans is the most common yeast isolated from patients with endogenous fungal
endophthalmitis, followed by Aspergillus spp, the most common mold isolate found in
fungal endophthalmitis. Other organisms found to cause fungal endophthalmitis include
Cryptococcus neoformans, Coccidioides immitis, Histoplasma capsulatum, Sporothrix
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schenckii, and others. Fungus can be introduced into the blood stream via indwelling
catheters, feeding tubes, and/or intravenous drug use. Occasionally, fungal infection can
occur without a specific source in immunosuppressed individuals. Diagnosis is determined
by vitreous paracentesis for fungal culture, or by inference from positive fungal blood
cultures in the setting of certain clinical features. Clinical features can include choroidal or
retinal infiltrates, vitritis, and an anterior chamber reaction with keratic precipitates. The
characteristic presentation of Candida endophthalmitis is a creamy white or fluffy choroidal
or retinal lesion in the posterior pole with overlying vitreous cells or haze in a “string of
pearls” configuration over the lesion. Up to 28% of candidemic patients can develop
candidal chorioretinitis. [58,59]

Treatment of fungal chorioretinitis includes systemic anti-fungal treatment with agents that
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have reasonable ocular penetration including voriconazole, fluconazole, flucytosine, and

liposomal amphotericin B. Systemic anti-fungals that have poor ocular penetration include
the echinocandin class of antifungals and non-liposomal amphotericin B. Intravitreal
antifungal therapy should be added if there are sight-threatening lesions, and include
amphotericin B 5–10 μg or voriconazole 100 μg. Pars plana vitrectomy is an important
adjunct treatment for fungal chorioretinitis, for microbiologic identification, to debulk
infectious organism, to prevent or treat retinal detachment, and to facilitate delivery of
antifungal drugs to potentially sequestered organism. [60]

7. Toxoplasmosis retinochoroiditis
Toxoplasma gondii is an obligate intracellular protozoan that utilize cats as their primary
host. They are inadvertently ingested in the bradyzoite, or tissue cyst, form, and then
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undergo transformation into the infectious, tachyzoite form. Bradyzoites can remain
dormant in the retina for years, and upon rupture, result in release of tachyzoites and
surrounding retinitis. While it only represents 25% of posterior uveitis in the US, it
represents up to 85% of posterior uveitis in other countries such as Brazil. Clinically, acutely
active toxoplasmic uveitis presents with blurry vision, photophobia, and floaters. The most
common clinical presentation is a partial or full thickness necrotizing retinitis adjacent to an
old hyperpigmented chorioretinal scar (Figure 4). This can be associated with a focal

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 Lin Page 11

arteritis, overlying vitritis, and anterior chamber cell. Occasionally, it can cause massive
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vitreous inflammation resulting in the “headlight in fog” appearance. It should be noted that
in HIV+ individuals, toxoplasmosis chorioretinitis can appear clinically disparate from that
in immunocompetent patients in that in immunocompromised patients, toxoplasmosis
retinochoroiditis is much more diffuse, hemorrhagic, and may not be associated with prior
chorioretinal scars.

While serologies for IgG and IgM against toxoplasmosis can be corroborative especially if
they are negative, high IgG can occur in the absence of active disease with prior exposure,
and IgM is often negative in active retinal disease. Toxoplasmosis PCR or a Goldmann
Whitmer coefficient from an aqueous or vitreous paracentesis specimen can be very useful
in these circumstances.

Treatment of toxoplasmosis retinochoroiditis using the common “classic” therapies (Table

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4) does not usually eliminate tissue cysts and therefore does not prevent chronic or recurrent
infection. Further, no randomized placebo-controlled trial has demonstrated definite benefit
of these treatments over no treatment. Nevertheless, most uveitis specialists agree that
vision-threatening or severe disease warrants treatment. However, atovaquone, which is
more commonly used for Pneumocystis Jiroveci infection in AIDS, has been shown in
animal models to be active against the bradyzoite form of Toxoplasmosis gondii, and
additionally, is tolerated well with very few side effects in both healthy and
immunocompromised patients, as well as in children. [61] It has been demonstrated to be
effective as a single agent. [61] Additionally, trimethoprim/sulfamethoxazole is also usually
well-tolerated, and has been tested in a small single-center randomized placebo-controlled
double-masked trial, which showed that it can prevent recurrent retinochoroiditis.[62]
However, hypersensitivity reactions and bone marrow suppression especially in
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immunocompromised patients, can sometimes limit its use. Local therapy with intravitreal
clindamycin with dexamethasone has also been found to be effective. [63,64] Adjunctive
treatment includes topical prednisolone acetate drops for the anterior uveitis component, and
oral prednisone after initiation of anti-infective agent(s).

8. Other parasites/helminths
a. Ocular Toxocariasis
Toxocariasis is caused by a roundworm, either Toxocara canis or Toxocara catis found in
dog or cat feces. It can present a granulomatous fibrous stalk either in the posterior pole or
in the retinal periphery. Histopathologically, the fibrous granuloma consists of roundworm
remnants surrounded by copious inflammatory cellular infiltrates, many of which are
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eosinophils. There is usually unilateral involvement, typically found in children, and is

therefore on the differential diagnosis for retinoblastoma and Coat’s disease. Chronic
endophthalmitis can also result from ocular toxocariasis, especially in younger patients, and
can present with a severe intraocular inflammation with hypopyon and granulomatous
keratic precipitates. Complications from ocular toxocariasis include tractional retinal
detachment, epiretinal membrane formation, rhegmategonous retinal detachment, cyclitic
membrane formation, hypotony, and phthisis bulbi. [65] Laboratory diagnosis involves
demonstration of positive serum antibody titers against Toxocara canis or catis using an

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ELISA. While a positive test does not prove causality of Toxocara for ocular involvement, a
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negative test can help to rule out toxocariasis.

Treatment of ocular toxocariasis involves the use of topical and systemic corticosteroids to
reduce the inflammation associated with infection. Because T. canis is not self-replicating,
systemic corticosteroids will not promote growth of the infectious agent. Anti-helminthic
drugs such as albendazole 400 mg PO BID x 30 days may also be effective in treating ocular
toxocariasis but should not be undertaken without concurrent corticosteroid administration
due to the severe inflammatory reaction that can occur with dying helminths. Retinal
detachment surgery is occasionally required either with vitrectomy or combination with
scleral buckle surgery to treat tractional or rhegmatogenous retinal detachments associated
with the organizing fibrous membranes over the area of inflammation.

b. Ophthalmomyiasis
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Ophthalmomyiasis interna is inflammation secondary to inoculation of the eye with

burrowing fly larvae such as the sheep bot fly, Oestris Ovis, which is found throughout
much of the world. Dermatobia hominis is another common bot fly found in Central and
South America that can cause ophthalmomyiasis. These organisms can invade the anterior
chamber, the vitreous, and the subretinal space. When found in the vitreous or anterior
chamber, it can induce a severe uveitis. When found in the subretinal space, it can cause
subretinal hemorrhage and an outer retinal inflammation that is best noted by criss-crossing
tracks throughout the retina. When it is located in the vitreous cavity, it can be removed via
vitrectomy with laser to the entry and exit sites if visible, although the importance of
keeping the organism whole during extraction should be emphasized to prevent a severe
inflammatory reaction. The organism can be identified morphologically by its width and
segmented appearance. Subretinal larvae can be removed in toto, by performing a pars plana
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vitrectomy with retinotomy. [66]Ivermectin 0.2 mg/kg PO once can be used in combination
with oral corticosteroids to treat subretinal larvae that cannot be isolated or removed.

c. Diffuse Unilateral Subacute Neuroretinitis (DUSN)

DUSN is caused by a nematode wandering the subretinal space and causing outer retinal
atrophy over a number of years. The organisms reported to cause DUSN include
Baylisascaris procyonis, Dirofilaria, and Ancylostoma caninum. While Baylisascaris larvae
are between 300–2000 μm long and infect raccoons and skunks, A. caninum is a hookworm
650 μm in size, found in dogs. In early DUSN, lesions made by the moving nematode appear
as outer retinal gray-white inflammatory lesions. On fluorescein angiography, lesions may
be wreath-like hyperfluorescent dots usually with early hypofluorescence. DUSN can also
present with perivenous infiltrates similar to sarcoidosis, and later develop multifocal
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chorioretinal scarring. DUSN can also present with crops of yellowish or whitish outer
retinal lesions[67,68] and vitritis, as well as rarely, hypopyon uveitis. [69] End-stage DUSN
can appear like unilateral retinitis pigmentosa, with outer retinal atrophy, optic nerve
atrophy, attenuated vessels, pigmented bony-spicule formation, and a posterior subcapsular
cataract. The nematode itself appears in the subretinal space as a thin S-shaped organism. In
addition to identifying the worm by slit lamp microscopy using a 78D or 90D lens, the
organism can sometimes be identified by its movement during the acquisition of an optical

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 Lin Page 13

coherence tomography scan (OCT), as the laser from this imaging modality will sometimes
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prompt movement.

Treatment of DUSN includes the use of laser to kill or sequester the subretinal nematode.
Laser photocoagulation using a 200–500 μm spot size at a duration of 0.2–0.5 seconds, is
required to destroy the worm. Oral anti-helminthic agents such as thiabendazole,
albendazole, or ivermectin have also been used to treat DUSN with varied success. [70]

d. Cysticercosis
Ocular cysticercosis is usually due to the human tapeworm, Taenia solium, which is
acquired via the ingestion of raw or undercooked pork. Anterior chamber cysticercosis can
present with a severe non-granulomatous anterior uveitis with keratic precipitates and fibrin,
and can be mistaken for an anteriorly dislocated crystalline lens. [71] While a live scolex in
the vesicular stage can incite an inflammatory response due to toxin and protein leakage into
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the eye, a dead scolex can cause an even more severe fibrinous reaction. A live scolex can
be distinguished from a dead scolex by movement upon shining a light on the vesicle.
Posterior segment cysticercosis is more common than anterior segment involvement and can
cause a severe vitritis, pupillary block glaucoma, and rarely, a subretinal cyst. If ocular
cysticercosis is suspected, imaging of the CNS should be obtained to rule out
neurocysticercosis. Because disruption of the vesicle or killing of the organism incites such
a severe inflammatory response, surgical intervention is preferred over anti-helminthic
treatment unless there is evidence of systemic disease; in the latter scenario, systemic
corticosteroids are required concomitantly with anti-helminthic treatment such as
albendazole. Surgical treatment includes viscoelastic-assisted expression of the entire
vesicle in total if in the anterior segment. When a cysticercus cyst is present under the retina,
pars plana vitrectomy with retinotomy, with engagement of the vesicle using a soft-tipped
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cannula, and extraction through an enlarged sclerotomy wound, can avoid rupture and the
subsequent inflammatory reaction. [72]

9. Molecular diagnostics for infectious uveitis

While microbial culture is the gold-standard for the diagnosis of infectious uveitis, the low
volume of ocular specimens and relative inaccessibility of ocular tissues and fluids have
limited the reliance on culture results due to low yield and difficulty in culturing indolent or
intracellular organisms. Instead, advancements in efficiency and decreases in cost for PCR
have resulted in more accurate microbiological classifications of uveitis, such as in the re-
identification of many cases of Posner-Schlossman syndrome as CMV anterior uveitis. The
sensitivity of PCR to diagnose HSV, VZV, and CMV is upward of 90% with specificities of
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95%, with the additional advantage of requiring less time to obtain the results than viral
culture. Furthermore, sub-typing of viral strains and molecular identification of resistant
strains can also be performed by PCR. 53 In ocular TB, PCR has increased the sensitivity of
ocular fluid testing, although this is still low, at only 37%, due to low bacterial load and the
thick cell wall of the bacterium. [53] Toxoplasmosis PCR in addition to Goldmann-Witmer
coefficient, has increased ocular fluid testing sensitivity and specificity to 80–93% for this
disease. [73,74]

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10. Summary
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A high suspicion for infectious causes of uveitis should always be maintained when
managing uveitis patients, given the importance of prompt initiation of antimicrobial therapy
to prevent devastating vision loss due to ocular infections from viruses, treponemes,
mycobacteria, parasites, or fungi. A full thickness necrotizing retinitis is almost never
associated with non-infectious uveitis, and a low threshold to perform molecular diagnostic
testing with PCR should be maintained in this setting to guide selection and response to
treatment.

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Papers of particular interest, published recently, have been highlighted as:

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neuroretinitis. Ocular immunology and inflammation. Jun; 2000 8(2):119–121. [PubMed:
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neuroretinitis. American journal of ophthalmology. Jan; 1998 125(1):109–111. [PubMed:

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intracameral cysticercosis masquerading as leukocoria. Canadian journal of ophthalmology.
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72. Wani VB, Kumar N, Uboweja AK, Kazem MA. A case of submacular cysticercosis treated by pars
plana vitrectomy in Kuwait. Oman journal of ophthalmology. Sep; 2014 7(3):144–146. [PubMed:
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73. Fekkar A, Bodaghi B, Touafek F, Le Hoang P, Mazier D, Paris L. Comparison of immunoblotting,

calculation of the Goldmann-Witmer coefficient, and real-time PCR using aqueous humor samples
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for diagnosis of ocular toxoplasmosis. Journal of clinical microbiology. Jun; 2008 46(6):1965–
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74. Talabani H, Asseraf M, Yera H, et al. Contributions of immunoblotting, real-time PCR, and the
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Figure 1.
A 39 year-old pregnant woman at 34 weeks presented with peripheral retinal whitening
suggestive of acute retinal necrosis with optic nerve involvement and visual acuity of 20/300
(A). Vitreous paracentesis revealed 800,000,000 copies/mL of VZV DNA by PCR. After 2
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weeks of intravitreal foscarnet every 3 days and 2 months of oral valacyclovir 2 g PO TID,
the retina remained attached, with resolution of retinitis, and improvement of vision to
20/200, limited by optic atrophy (B).
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Figure 2.
A 76 year-old man with a history of prostate cancer and follicular lymphoma s/p
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chemotherapy presented with a panuveitis and granular necrotoizing retinitis OU, left eye
shown in (A); visual acuity was 20/50 OS. Vitreous paracentesis revealed 640,000,000
copies/mL of CMV DNA by PCR. After two weeks of intravitreal foscarnet every 3 days
and 1 month of oral valganciclovir 900 mg PO BID, retinitis improved, and vision improved
to 20/25 OS, without any retinal detachment (B).
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Figure 3.
A 46 year-old previously healthy man presented with counting fingers vision OS, an outer
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retinitis in the macula and inferonasal retina, and panuveitis (A). Arrows delineate AZOOR-
like outer retinopathy in macula. RPR was 1:64 and FTA-ABS was positive. The patient was
treated with 21 days of IV penicillin G with resolution of outer retinitis and improvement of
visual acuity to 20/30 OS (B).
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Figure 4.
A 27 year-old healthy woman presented with a focal area of full-thickness retinitis adjacent
to the optic nerve and an old pigmented chorioretinal scar, with overlying vitreous cells (A).
Initial visual acuity was 20/30. She was treated with Atovaquone 750 mg PO QID for 3
months, as well as a tapering course of oral prednisone starting 3 days after initiating
Atovaquone. The retinal lesion consolidated and vitreous cell resolved (B), with return to
20/20 vision OS.
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Table 1

Pharmacologic Treatment of Viral Retinitis and Uveitis

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Drug Route Side effects Viral coverage

Acyclovir Intravenous: 1500 GI symptoms, hypersensitivity reactions, renal or HSV-1, HSV-2, VZV, EBV ≫
mg/m2/day divided Q8h x CNS dysfunction (requires renal dosing) CMV
14 days followed by
Oral: 800 mg five times a
day for 6 weeks (also dose
for viral anterior uveitis)
Prophylactic dose: 400 mg
PO BID-TID

Valacyclovir (prodrug) Oral: 1 g (viral anterior Similar to acyclovir HSV-1, HSV-2, VZV≫ CMV
uveitis)-2 g (viral retinitis)
Q8h x 6 weeks
Prophylactic dose: 1 g PO
BID
Ganciclovir Intravenous: 500 mg Q12h Anemia, thrombocytopenia, granulocytopenia HSV-1, CMV ≫VZV, HSV-2
x 14 days
Intravitreal: 2–5 mg/0.1
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mL, 3x/week
Topical gel: 0.15%
Applied 4x/day x 3 months
for CMV anterior uveitis
Intravitreal surgical
implant: lasts 8 months (no
longer available)

Valganciclovir Oral: 900 mg BID x 3–6 HA, GI symptoms, bone marrow suppression, HSV-1, CMV≫VZV, HSV-2
weeks anemia, renal dysfunction
Prophylactic dose: 450 mg
PO BID
Foscarnet Intravenous: 40–60 mg/kg HA, GI symptoms, renal or CNS toxicity HSV-1, HSV-2, VZV>CMV
Q8h x 3 weeks uncommonly
Intravitreal: 2.4 mg/0.1
mL every 3–4 days

Famciclovir (prodrug) Oral: 500 mg Q8h HA, GI symptoms, rash HSV-1>HSV-2>VZV

GI: gastrointestinal; HA: headache; CNS: central nervous system; PO: oral; BID: twice daily; TID: three times a day; HSV: herpes simplex virus;
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CMV: cytomegalovirus; EBV: Epstein-Barr virus

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Table 2

American Uveitis Society criteria for Acute Retinal Necrosis Syndrome

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Required Clinical Criteria Supporting Clinical Criteria

One or more foci of retinal necrosis with discrete borders, located in peripheral retina Scleritis

Evidence of occlusive vasculopathy and arteriolar involvement Pain

Prominent inflammatory reaction in vitreous and anterior chamber Optic neuropathy/atrophy

Rapid progression of disease without therapy

Circumferential spread of disease

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Table 3

Treatment of Ocular Tuberculosis

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Drug Dose (oral) Side effects

Rifampin*1 8–12 mg/kg Thrombocytopenia, hepatotoxicity

Isoniazid*1 4–6 mg/kg Peripheral neuropathy, transient elevation in LFTs

Pyrazinamide* 20–25 mg/kg Liver toxicity, pruritus

Ethambutol* 15–20 mg/kg Liver toxicity, possible retrobulbar optic neuritis

Fluoroquinolones** Ofloxacin 15 mg/kg GI symptoms, CNS side effects, elevated LFTs

Levofloxacin 15 mg/kg
Moxifloxacin 7.5–10 mg/kg

Injectable drugs# Capreomycin 15 mg/kg Nephrotoxicity, ototoxicity, neurotoxicity, hypersensitivity

Kanamycin 15 mg/kg
Amikacin 15 mg/kg
Streptomycin 15 mg/kg
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*
First-line therapy for first two months.
1
First line therapy for subsequent 4 months.
**
Second line therapy.
#
One must be used in the treatment of MDR or XDR TB.

GI: gastrointestinal; CNS: central nervous system; LFTs: liver function tests
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Table 4

Treatment of Ocular Toxoplasmosis

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Drug Dose Side effects

Pyrimethamine* 75–100 mg loading over 24 hours, then 25–50 mg daily x Hypersensitivity reaction, photosensitivity,
4–6 weeks abnormal skin pigmentation, bone marrow
suppression

Sulfadiazine* 2–4 g loading dose, then 1 g QID x 4–6 weeks Hypersensitivity reaction, bone marrow
suppression

Prednisone* 40–60 mg daily with taper, starting 3 days after starting Hyperglycemia, weight gain, mood lability
antibiotics including Atovaquone

Folinic acid* 5 mg 2–3 times/week with pyrimethamine

Atovaquone# 750 mg PO QID x 3 months Hypersensitivity reaction,

Trimethoprim/Sulfamethoxazole 160 mg/800 mg PO BID x 6 weeks Hypersensitivity reactions, bone marrow

suppression

Clindamycin1 Intravitreal: 1.5 mg/0.1 mL weekly for 4 weeks Risks of intravitreal injection
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Dexamethasone1 Intravitreal: 400 μg/0.1 mL given with intravitreal Elevated intraocular pressure, cataract
clindamycin

*
Used in combination as “classic” therapy.
#
May kill bradyzoite cysts based on animal data.
1
Used as intravitreal treatment of ocular toxoplasmosis.
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