Infectious Posterior Uveitis

VIRAL INFECTION

HERPETIC

Karina Julian, Bahram Bodaghi, and Phuc LeHoang

Herpes viruses infecting the retina manifest themselves differently depending upon the interaction between the virus and the host immune system. Necrotizing retinopathies are the more common clinical picture, but non-necrotizing forms should also be considered in atypical cases of chronic posterior uveitis.

• Necrotizing retinopathies are by far the most frequent clinical picture, with a spectrum of severity ranging from acute retinal necrosis (ARN; almost always seen in healthy individuals) to progressive outer retinal necrosis (PORN) and cytomegalovirus (CMV) retinitis, both of which mainly affect severely immunocompromised patients.

• Non-necrotizing herpetic retinopathies are less frequent and have a number of different presentations, including vitritis, occlusive vasculitis, papillitis, or macular edema.

ACUTE RETINAL NECROSIS SYNDROME

ARN syndrome is characterized by peripheral necrotizing retinitis, retinal vasculitis (mainly arteritis), a prominent inflammatory reaction in the vitreous, and a granulomatous anterior uveitis.

Epidemiology and Etiology

• ARN is a rare disease, occurring in 1 per 1.6 to 2.0 million people per year in Western countries.

• In most cases, ARN is caused by varicella zoster virus (VZV); however, herpes simplex virus 1 (HSV-1) and herpes simplex virus 2 (HSV-2) also cause ARN.

• HSV-2 is more prevalent in children and adolescents, whereas HSV-1 mainly occurs in young adults. VZV is usually found in the elderly patient.

Signs

• Anterior granulomatous uveitis that rarely can have a hypopyon or hyphema.

• Intense vitritis

• Patchy or confluent areas of white or cream-colored retinal necrosis initially affecting the peripheral retina and then extending centripetally (Figs. 9-1, 9-2, 9-3 and 9-4)

• Occlusive vasculopathy

• Papillitis of varied intensity

• Immunocompetent, otherwise healthy young or middle-aged patients, with or without a remote history of herpes virus infection or herpetic encephalitis (an established risk factor for ARN) • ARN is a medical emergency. It is rapidly progressive, and second eye involvement will naturally occur in almost 70% of patients in the absence of treatment. More than 50% of patients develop a rhegmatogenous retinal detachment (RRD) because of retinal atrophy secondary to necrosis and vitreous contraction.

Differential Diagnosis

• ARN needs to be differentiated from other necrotizing retinopathies, infectious or not (Table 9-1):

Extensive Toxoplasma retinochoroidopathy (Fig. 9-5)
Syphilitic retinitis
Fungal endogenous endophthalmitis
Primary intraocular lymphoma (Fig. 9-6)
Retinitis associated with Behçet disease
CMV retinitis (occurs only in severely immunocompromised patients)

Diagnostic Evaluation

• ARN is primarily a clinical diagnosis.

• Given the devastating natural disease course, ancillary tests confirming the etiology and/or eliminating nonviral causes should never cause a delay starting empirical treatment.

• Two different assays are performed in ocular samples (aqueous humor or vitreous):

Polymerase chain reaction (PCR) for direct detection of viral DNA is highly sensitive with 80% to 96% positivity in both immunocompetent and immunocompromised hosts.
Indirect detection of antibodies directed against virus proteins has 50% to 70% positivity in immunocompetent patients.

• In cases of suspected meningitis, a brain magnetic resonance imaging (MRI) and a lumbar puncture should be performed without delay because simultaneous herpetic meningitis or encephalitis is possible.

Diagnostic Criteria

• Diagnostic criteria were developed by the Japanese ARN Study Group, based on clinical features, clinical course, and results of virologic testing of intraocular fluids.

Clinical Features (Ocular Findings in the Early Stage)	Clinical Courses
Anterior chamber cells/mutton fat keratic precipitates Yellow-white lesions in the peripheral retina Retinal arteritis Optic disc hyperemia Vitritis Elevated intraocular pressure (IOP)	Rapid and circumferentially expansion of the retinal lesions Development of retinal breaks or RRD Retinal vascular occlusion Optic disc atrophy Response to antiviral agents

TABLE 9-1. Necrotizing Retinopathies

	Acute Retinal Necrosis	Extensive Toxoplasmosis	Syphilis	Fungal Endogenous Endophthalmitis	PIOL	Behçet Disease	CMV Retinitis
Predisposing conditions	None History of herpes encephalitis or other herpes virus infection	Elderly patients Immunocompromised	AIDS	Immunosuppression IV drug users Diabetes	Elderly patients	Young adults Silk road disease	Immunocompromised (e.g., HIV)
Clinical picture	Vitritis Midperipheral whitish necrosis with hemorrhage, extends rapidly	Pigmented scars Dense vitritis	Papillitis, vasculitis, retinal necrosis	Chorioretinitis Dense vitritis	Infiltrative retinal lesions	Vasculitis, retinitis, papillitis, vitritis	Yellow-white necrosis with hemorrhage, slowly progressive
Diagnosis	Clinical, PCR, detection of antibodies	PCR and Goldmann-Witmer coefficient are useful for the diagnosis	TPHA, VDRL, FTA-abs	Culture and PCR	Cytology High IL-10 to IL-6 ratio is highly suggestive	Diagnostic criteria defined by the International Study Group for Behçet disease	Clinical, PCR, HIV serology
CMV, cytomegalovirus; FTA-abs, fluorescent Treponema antibody-absorption; IL-10, interleukin 10; IL-6, interleukin 6; IV, intravenous; PCR, polymerase chain reaction; PIOL, primary intraocular lymphoma; TPHA, Treponema pallidum particle agglutination assay; VDRL, Venereal Disease Research Laboratory.

• Based on the results of intraocular fluid analysis, cases are further classified into virus-confirmed ARN and virus-unconfirmed ARN.

Virus-confirmed ARN	Virus-unconfirmed ARN
Presence of both 1 and 2 early-stage ocular findings	Presence of 4 of the 6 early-stage ocular findings including 1 and 2
Presence of 1 of the 5 clinical courses	Presence of any 2 of the 5 clinical courses
Virologic test (+)	Virologic test (−) or nonperformed

Treatment

• The primary treatment is systemic antiviral agents. Traditionally, these drugs have been administered in an inpatient setting during the acute phase; however, outpatient management has been reported as successful in multiple case reports.

The goal of systemic antiviral therapy is to control viral replication and to reduce the risk of bilateral involvement. Intravitreal antiviral injections can be used in cases that are imminently threatening the macula or optic nerve, as a combined approach.
The combination of systemic and intravitreal therapy increasingly has been reported as a treatment paradigm in cases of ARN; however, further studies are necessary to define the exact role of intravitreal therapy in the management of ARN.

TABLE 9-2. Medical Treatment of ARN

	Active Drug	Dosages
Antivirals	Acyclovir	10 mg/kg/8 h (1500 mg/m²) IV or 800 mg PO five times per day
	Foscarnet	90 mg/kg/12 h IV or/and intravitreal injections
	Ganciclovir	5 mg/kg/12 h IV or/and intravitreal injections
	Valganciclovir	900 mg/d b.i.d.
Anti-inflammatory drugs	Methylprednisolone	500 mg daily IV for 3 days
	Prednisone	0.5-1 mg/kg/d with a gradual taper
Antithrombotic drugs	Standard heparin
	Aspirin (acetylsalicylic acid)	100 mg/d
ARN, acute retinal necrosis; IV, intravenous.

Anti-inflammatory therapy is used to minimize the deleterious effects associated with inflammation. Viral replication must be under control with antiviral medications before administration of systemic corticosteroids.
Whenever an infectious viral uveitis is a diagnostic consideration, systemic and local corticosteroids should be used with extreme care (not only because of exacerbation of ARN but also because of the development of de novo ARN related to corticosteroid use).
Antithrombotic therapy should be considered in order to reduce vascular complications; however, strong evidence supporting its use does not currently exist.

• Laser retinopexy may reduce the occurrence of an RRD, but its efficacy remains controversial.

• Patients with vitreous hemorrhage secondary to retinal neovascularization or for RRD should undergo pars plana vitrectomy with silicone oil tamponade. Early vitrectomy with intravitreal injection of antiviral medications and laser retinopexy can be performed to prevent RRD, although no improvement in final visual acuity has been reported.

• Treatment medications are outlined in Table 9-2.

Prognosis

• Despite early recognition and institution of prompt therapy, the final visual outcome is generally poor.

• RRD and ischemic optic neuropathy (with subsequent optic nerve atrophy) preclude good final visual acuity.

REFERENCES

Aizman A, Johnson MW, Elner SG. Treatment of acute retinal necrosis syndrome with oral antiviral medications. Ophthalmology. 2007;114:307-312.

Balansard B, Bodaghi B, Cassoux N, et al. Necrotizing retinopathies simulating acute retinal necrosis syndrome. Br J Ophthalmol. 2005;89(1):96-101.

Ganatra JB, Chandler D, Santos C, Kuppermann B, Margolis TP. Viral causes of the acute retinal necrosis syndrome. Am J Ophthalmol. 2000;129(2):166-172.

Holland GN. Standard diagnostic criteria for the acute retinal necrosis syndrome. Executive Committee of the American Uveitis Society. Am J Ophthalmol. 1994;117(5):663-667.

Takase H, Okada AA, Goto H, et al. Development and validation of new diagnostic criteria for acute retinal necrosis. Jpn J Ophthalmol. 2015;59(1):14-20.

Tibbetts MD, Shah CP, Young LH, Duker JS, Maguire JI, Morley MG. Treatment of acute retinal necrosis. Ophthalmology. 2010;117(4):818-824.

Wong R, Pavesio CE, Laidlaw DA, Williamson TH, Graham EM, Stanford MR. Acute retinal necrosis: the effects of intravitreal foscarnet and virus type on outcome. Ophthalmology. 2010;117(3):556-560.

PROGRESSIVE OUTER RETINAL NECROSIS

PORN is the major form of necrotizing herpetic retinitis affecting immunocompromised patients. Early diagnosis and aggressive antiviral therapy is mandatory, but the visual prognosis generally remains poor.

Epidemiology and Etiology

• PORN is the most severe clinical form of herpetic retinitis. Although it appears to affect the outer retina, all retinal layers can become involved.

• VZV is the most common agent identified in patients with PORN, but a few cases of HSV-1-associated PORN have been also described.

• Patients are usually deeply immunocompromised. Most of them suffer from AIDS; however, it has also been described in patients who have had bone marrow transplantation and also those treated with high-dose systemic corticosteroids.

• PORN represents an ophthalmologic and medical emergency because it is usually bilateral and progresses rapidly, and central nervous system (CNS) involvement is possible.

• The visual outcome in PORN is usually very poor.

Signs

• Multifocal, poorly demarcated, deep retinal opacities of various sizes, without granular borders, scattered throughout the posterior pole and the midperipheral retina. The retinitis spreads outwardly and peripherally, becoming confluent within a few days (Figs. 9-7, 9-8 and 9-9).

• Retinal vasculitis and optic neuritis occur in less than 20% of cases.

• The aqueous humor and the vitreous have minimal to no inflammation.

• Extremely rapid progression to total retinal necrosis over the course of a few days

• The disease is bilateral at presentation in 70% of cases, and 80% will become bilateral within the first month.

• There is a history of recent or ongoing VZV infection in 75% of cases.

Differential Diagnosis

• CMV retinitis remains the most common opportunistic infection in patients with AIDS, but the clinical picture and course is very different so it usually does not represent a diagnostic dilemma.

• ARN syndrome occurs in otherwise healthy patients, affects the retinal vasculature, and is associated with vitritis (Table 9-3).

• Toxoplasma retinochoroiditis when affecting the elderly or immunosuppressed hosts may also produce a similar clinical picture.

Diagnostic Evaluation

• The classic clinical picture should suggest the diagnosis, and prompt empirical treatment should be administered before ancillary tests are performed.

• Aqueous humor PCR should be performed for viral DNA identification and antibody production in order to confirm the pathogenic agent and rule out other nonviral etiologies.

• Brain MRI and lumbar puncture should be performed in every case of PORN because extremely immunosuppressed patients have an increased risk of encephalitis.

TABLE 9-3. Clinical Characteristics of ARN and PORN Syndromes

	ARN	PORN
Host immune status	Immunocompetent or immunocompromised	Immunocompromised, mainly AIDS
Etiologic agent	VZV, HSV-1, HSV-2	Mainly VZV
Retinal vasculitis	Present	Rare
Intraocular inflammation (KPs, AC cells, vitritis)	Present and very important	Rare
Bilaterality	25% at presentation	70% at presentation
Progression	Centripetally from peripheral foci of retinal necrosis to posterior pole	Centrifugally with rapid confluence
Prognosis	Poor	Extremely poor
AC, anterior chamber; ARN, acute retinal necrosis; HSV, herpes simplex virus; KPs, keratic precipitates; PORN, progressive outer retinal necrosis; VZV, varicella zoster virus.

Treatment

• Patients with PORN must be treated in an inpatient setting (Table 9-4).

• Combined intravenous (IV) and intravitreal treatment with ganciclovir and foscarnet is the strategy of choice because IV acyclovir does not treat PORN effectively.

• IV corticosteroids must be avoided in nearly all cases.

• Acetylsalicylic acid (Aspirin 81 to 100 mg a day) can be used to decrease platelet hyperaggregation that occurs in herpetic retinitis.

• Prophylactic argon laser retinopexy delimitating necrotic retinal areas can be applied in an effort to reduce the high risk of RRD, although studies are inconclusive about its advantages.

• Once RRD has occurred, vitrectomy with silicone oil tamponade is usually required. Some authors advocate performing early vitrectomy with intravitreal acyclovir lavage and laser demarcation to prevent RRD, although this has not led to an improvement in final visual acuity.

TABLE 9-4. Medical Treatment of PORN

Active Drug	Dose and Route of Administration	Toxicity
Ganciclovir	5 mg/kg IV b.i.d. for 3 weeks, then 5 mg/kg daily IVT injections: 1-2 mg/0.05 mL	Blood cells and liver
Foscarnet	180 mg/kg/day IV divided into 2-3 infusions for 3 weeks, then 90-120 mg/kg/day IVT injections: 1.2-2.4 mg/0.05 mL	Renal failure
Valganciclovir	900 mg/day PO, after IV induction phase, as a maintenance regimen	Blood cells and liver
Valacyclovir	1 g PO t.i.d. as maintenance treatment	Renal failure
IV, intravenous; IVT, intravitreal; PORN, progressive outer retinal necrosis.

• Patients suffering from PORN should be tested for comorbid conditions, such as AIDS. If human immunodeficiency virus (HIV) is found, highly active antiretroviral therapy should be promptly instituted.

Prognosis

• Despite aggressive treatment, the prognosis is extremely poor. The final visual outcome is no light perception in almost 60% of eyes, mainly related to total retinal necrosis and RRD.

• Ischemic optic neuropathy with further optic atrophy also precludes good visual restoration.

REFERENCES

Benz MS, Glaser JS, Davis JL. Progressive outer retinal necrosis in immunocompetent patients treated initially for optic neuropathy with systemic corticosteroids. Am J Ophthalmol. 2003;135(4):551-553.

Chau Tran TH, Cassoux N, Bodaghi B, Lehoang P. Successful treatment with combination of systemic antiviral drugs and intravitreal ganciclovir injections in the management of severe necrotizing herpetic retinitis. Ocul Immunol Inflamm. 2003;11(2):141-144.

Engstrom RE Jr, Holland GN, Margolis TP, et al. The progressive outer retinal necrosis syndrome. A variant of necrotizing herpetic retinopathy in patients with AIDS. Ophthalmology. 1994;101(9):1488-1502.

Forster DJ, Dugel PU, Frangieh GT, Liggett PE, Rao NA. Rapidly progressive outer retinal necrosis in the acquired immunodeficiency syndrome. Am J Ophthalmol. 1990;110(4):341-348.

Gore DM, Gore SK, Visser L. Progressive outer retinal necrosis: outcomes in the intravitreal era. Arch Ophthalmol. 2012;130(6):700-706.

Moorthy RS, Weinberg DV, Teich SA, et al. Management of varicella zoster virus retinitis in AIDS. Br J Ophthalmol. 1997;81(3):189-194.

FIGURE 9-1. Acute retinal necrosis. Granulomatous anterior uveitis in a patient with acute retinal necrosis syndrome.

FIGURE 9-2. Acute retinal necrosis. There are multiple white to yellow-white foci of peripheral retinal necrosis in a case of acute retinal necrosis syndrome. These occur in a circumferential manner.

FIGURE 9-3. Acute retinal necrosis. This 48-year-old patient presented with sudden onset of blurred vision and floaters. A. There are numerous focal white areas of retinitis and vasculitis in the periphery along with optic disc edema.

FIGURE 9-3. (continued) B. Three days after the institution of therapy, the areas of retinitis appear slightly larger and better defined. Some scattered peripheral retinal hemorrhages are visible. C. In the late frames of the fluorescein angiogram, there is staining of the optic disc. D. The larger, superior patch of retinitis appears hypofluorescent centrally with a ring of late staining. (Courtesy of Paul Baker, MD.)

FIGURE 9-4. Acute retinal necrosis. This patient with extensive acute retinal necrosis developed a retinal detachment.

FIGURE 9-5. Toxoplasma retinochoroiditis. This person had extensive toxoplasma retinochoroiditis masquerading as acute retinal necrosis.

FIGURE 9-6. Primnary intraocular lymphoma. Pseudo-acute retinal necrosis syndrome with dense vitritis, retinal necrosis, and hemorrhages in a case of primary intraocular lymphoma.

FIGURE 9-7. Progressive outer retinal necrosis. Varicella zoster virus-associated progressive outer retinal necrosis with retinal necrosis and retinal hemorrhages in an AIDS patient.

FIGURE 9-8. Progressive outer retinal necrosis. Multifocal areas of outer retinal necrosis in a patient with progressive outer retinal necrosis.

FIGURE 9-9. Progressive outer retinal necrosis. Optical coherence tomography showing full-thickness retinal involvement, most prominent in the outer retina. (Courtesy of Sunir J. Garg, MD, and Heather Shelsta, MD.)

CONGENITAL RUBELLA SYNDROME

P. Vijayalakshmi

Introduction

Rubella is a mild systemic viral illness transmitted by respiratory droplets, and has an incubation period of 2 weeks. When a pregnant woman gets infected for the first time, the virus is transmitted transplacentally, and it can lead to miscarriage, stillbirth, or to an infant with multiple systemic abnormalities. The range of congenital defects differs according to the gestational age of the child and the earlier in gestation that the infection occurs, the worse the damage; infection during the first 12 weeks usually results in cardiac and ocular involvement, whereas infection during 12th to 28th weeks results in deafness and pulmonary artery stenosis. The consequences of rubella infection in utero are collectively termed congenital rubella syndrome (CRS).

Etiology and Epidemiology

Rubella is a single-stranded RNA virus, and humans are the only host. The World Health Organization (WHO) estimates that more than 100,000 children are born with CRS each year worldwide, most of them in developing countries. Vaccination tremendously reduces the occurrence of CRS.

Systemic Signs

• Cardiac

Patent ductus arteriosus
Pulmonary artery stenosis
Atrial and ventricular septal defects

• Deafness

The most common finding is progressive sensorineural deafness, which occurs in 44% of cases.
Vestibular function is rarely impaired.

• Brain damage

Moderate-to-severe mental retardation
Spastic diplegia
Microcephaly
Schizophrenia-like clinical picture
Intrauterine growth retardation
Failure to thrive
Hepatosplenomegaly
Insulin-dependent diabetes mellitus
Meningoencephalitis

• Ocular signs

Cataract (usually bilateral, occasionally unilateral) occurs in the majority of patients.
Salt and pepper retinopathy occurs in approximately 20% of patients. The appearance ranges from a fine stippling of the retinal pigment epithelium (RPE) to dark, patchy areas, and are most prominent in the posterior pole.
Congenital glaucoma (in 10% of cases)
Microphthalmos (occurs in 10% of cases)
Corneal edema in the absence of a raised IOP
Nystagmus
Strabismus
Optic atrophy
Dacryostenosis

Differential Diagnosis

• Other TORCH infections

Toxoplasma gondii

Others (syphilis, HIV, West Nile virus, VZV, Epstein-Barr virus)
Rubella
CMV
HSV

Testing

The serum of an infant is tested for rubella-specific immunoglobulin M (IgM). Older infants may need additional investigations such as IgG avidity test, reverse transcription (RT)-PCR for demonstration of virus in lens matter and other body fluids, such as serum, throat secretions, and urine.

Treatment

The treatment is directed to the affected organs and tissues. If a cataract is present, lens aspiration is performed in conjunction with primary posterior capsulorrhexis and anterior vitrectomy. Intraocular lenses are usually avoided in young children. A severe inflammatory response can follow cataract surgery and requires intensive therapy with topical steroids with or without systemic steroids. Glaucoma is initially managed medically followed by glaucoma surgery if needed.

FIGURE 9-10. Congenital rubella syndrome. This child has congenital rubella syndrome. Although full term, the baby is small for his gestational age. There is leukocoria due to a cataract in the left eye.

Prognosis

Poor when multiple systems are involved, and these children need a multidisciplinary team of a pediatrician, neurologist, ophthalmologist, otolaryngologist, and rehabilitation personnel (Figs 9-10, 9-11, 9-12, 9-13, 9-14, 9-15 and 9-16).

REFERENCES

Guidelines for surveillance of congenital rubella syndrome and rubella. Geneva: World Health Organization, Department of Vaccines and Biologicals. Filed test version, 1999.

Vijaylakshmi P, Muthukkaruppan VR, Rajasundari A, et al. Evaluation of a commercial rubella IgM assay for use on oral fluid samples for diagnosis and surveillance of congenital rubella syndrome and postnatal rubella. J Clin Virol. 2006;37(4):265-268.

Vijayalakshmi P, Rajasundari TA, Prasad NM, et al. Prevalence of eye signs in congenital rubella syndrome in South India: a role for population screening. Br J Ophthalmol. 2007;91(11):1467-1470.

Vijayalakshmi P, Srivastava KK, Poornima B, Nirmalan P. Visual outcome of cataract surgery in children with congenital rubella syndrome. J AAPOS. 2003;7(2):91-95.

FIGURE 9-11. Congenital rubella syndrome. A. This child had bilateral cornea clouding, and is small for gestational age. B. A higher magnification of another child with cloudy corneas.

FIGURE 9-12. Congenital rubella syndrome. This child has bilateral microphthalmos.

FIGURE 9-13. Congenital rubella syndrome. This child has corneal scarring and buphthalmos as a result of congenital glaucoma.

FIGURE 9-14. Congenital rubella syndrome. There is a mature cataract in the right eye and an early cataract in the left eye.

FIGURE 9-15. Congenital rubella syndrome. This child has a bilateral posterior capsular cataract.

FIGURE 9-16. Congenital rubella syndrome. There is diffuse mottling of the retinal pigment epithelium giving a salt and pepper fundus in rubella retinopathy.

WEST NILE VIRUS

Rim Kahloun, Moncef Khairallah, and Sunir J. Garg

West Nile virus is a single-stranded RNA flavivirus transmitted by mosquito vector of the genus Culex, with wild birds serving as its reservoir. It causes a bilateral uveitis, with multifocal chorioretinal lesions that have a target-shaped and/or linear appearance.

Etiology and Epidemiology

• West Nile virus was first identified in Uganda, and is endemic to many parts of the world.

• Although birds are the natural host of the virus, the virus is transmitted by mosquitoes. West Nile virus is in the same virus family as yellow fever, dengue fever, and Japanese encephalitis.

• The disease has been reported to occur in warm seasons, with a peak onset in late summer.

• Patients older than 50 years and those with diabetes may be more susceptible to ocular manifestations.

Signs

• Patients have bilateral ocular involvement.

• The most characteristic finding is multiple, discrete, circular cream-colored lesions scattered throughout the midperiphery, periphery, and posterior pole that become pigmented and “punched out” over time (Figs. 9-17, 9-18, 9-19, 9-20 and 9-21).

• In diabetic patients, these chorioretinal lesions are more prevalent in the posterior pole, and tend to be larger and more numerous.

• Linear clustering of chorioretinal lesions, following the course of the retinal nerve fiber layer, is a common finding.

• Retinal hemorrhages

• Bilateral mild vitritis

• Transient mild anterior chamber cells

• Retinal arteriolar sheathing, narrowing, and/or occlusion

• Optic disc edema, optic neuritis, neuroretinitis and retinitis, and optic atrophy

• Patients may develop choroidal neovascular membranes late in the course of the disease.

Differential Diagnosis

• Tuberculosis (TB)

• Syphilis

• Sarcoidosis

• Systemic lupus erythematosus

• Herpes virus

• Lyme disease

• Epstein-Barr virus

• Ocular histoplasmosis

• Idiopathic multifocal choroiditis

• Vogt-Koyanagi-Harada disease

• Other arboviruses: Rift Valley fever, dengue, chikungunya

• Rubella

Diagnostic Evaluation

• Clinical exam is the most helpful.

• Fluorescein angiography (FA) can demonstrate the chorioretinal lesions. In early stages of infection, the angiogram can show early blockage with late staining. Inactive lesions will show “target-shaped” focal areas of central hypofluorescence surrounded by hyperfluorescence.

• Indocyanine green angiography (ICGA) shows more lesions in the form of hypofluorescent spots that are appreciated clinically or by fluorescein angiography.

• Spectral-domain optical coherence tomography (SD-OCT) shows focal involvement of the outer retina and RPE corresponding to chorioretinitis. It may also shows granular hyperreflective specks located predominantly within the outer and inner nuclear layers.

• Fundus autofluorescence shows multiple well-delineated uniformly hypoautofluorescent or centrally hyperautofluorescent and peripherally hypoautofluorescent spots.

• OCT angiography may be useful for accurate detection and precise delineation of areas of retinal capillary hypoperfusion due to occlusive retinal vasculitis.

• Visual field testing can show nonspecific field defects.

• MRI can demonstrate myelitis (a nonspecific sign).

• IgM and IgG can be elevated, both in the serum and in cerebrospinal fluid (CSF).

• Real-time RT-PCR and RT loop-mediated isothermal gene amplification assays may be used to confirm the diagnosis.

Treatment

• Supportive because this is a self-limited disease.

• Topical steroids can be used to treat anterior segment inflammation.

• Other specific ophthalmic treatment may be required, including peripheral retinal photocoagulation for neovascularization because of occlusive vasculitis, pars plana vitrectomy for nonclearing vitreous hemorrhage or tractional retinal detachment, and intravitreal anti-vascular endothelial growth factor agent for choroidal neovascularization.

• Prevention of infection is the mainstay of West Nile virus control.

Prognosis

• Generally good, with most patients retaining good central acuity.

• Patients with significant vascular occlusion can experience significant vision loss.

REFERENCES

Chan CK, Limstrom SA, Tarasewicz DG, Lin SG. Ocular features of West Nile virus infection in North America: a study of 14 eyes. Ophthalmology. 2006;113:1539-1546.

Khairallah M, Ben Yahia S, Attia S, et al. Indocyanine green angiographic features in multifocal chorioretinitis associated with West Nile virus infection. Retina. 2006;26(3):358-359.

Khairallah M, Ben Yahia S, Attia S, Zaouali S, Ladjimi A, Messaoud R. Linear pattern of West Nile virus-associated chorioretinitis is related to retinal nerve fibres organization. Eye (Lond). 2007;21(7):952-955.

Khairallah M, Ben Yahia S, Ladjimi A, et al. Chorioretinal involvement in patients in patients with West Nile virus infections. Ophthalmology. 2004;111(11):2065-2070.

Khairallah M, Yahia SB, Letaief M, et al. A prospective evaluation of factors associated with chorioretinitis in patients with West Nile virus infection. Ocul Immunol Inflamm. 2007;15(6):435-439.

Learned D, Nudleman E, Robinson J, et al. Multimodal imaging of West Nile virus chorioretinitis. Retina. 2014;34(11):2269-2274.

Sivakumar RR, Prajna L, Arya LK, et al. Molecular diagnosis and ocular imaging of West Nile virus retinitis and neuroretinitis. Ophthalmology. 2013;120(9):1820-1826.

Wang R, Wykoff CC, Brown DM. Granular hyperreflective specks by spectral domain optical coherence tomography as signs of West Nile virus infection: the stardust sign. Retin Cases Brief Rep. 2016;10(4):349-353.

FIGURE 9-17. West Nile virus. Fundus photograph (A) and fluorescein angiogram (B) of the left eye of a 64-year-old diabetic woman with serologically proven West Nile virus infection showing numerous small and large atrophic chorioretinal lesions in the posterior pole and midperiphery. There is also nonproliferative diabetic retinopathy.

FIGURE 9-18. West Nile virus. A. Red-free fundus photograph of the left eye of a diabetic man with serologically proven West Nile virus infection showing chorioretinal lesions extending superotemporally in a linear pattern from the optic disc. Note the presence of multifocal retinal arterial sheathing. There is also nonproliferative diabetic retinopathy. B. Fluorescein angiogram (FA) of the same eye showing central hypofluorescence and peripheral hyperfluorescence of the chorioretinal lesions. C. Late-phase indocyanine green angiography of the same eye showing well-delineated hypocyanescent choroidal lesions, which are more numerous than those appreciated clinically or by FA.

FIGURE 9-19. West Nile virus. A. Fundus photograph of the left eye of a 58-year-old man with serologically proven West Nile virus infection showing multiple, inactive chorioretinal lesions of various sizes. Note the linear clustering of several chorioretinal lesions (curvilinear pattern in the vicinity of inferior major temporal vessels, and a radial pattern superiorly). There are also features of nonproliferative diabetic retinopathy. B. Fluorescein angiogram of the same eye showing more lesions than that observed clinically. Several lesions show the typical “target-like appearance” with central hypofluorescence and peripheral hyperfluorescence.

FIGURE 9-20. West Nile virus. A. Fundus photograph of the right eye of a 65-year-old man with serologically proven West Nile virus infection showing mild nonproliferative diabetic retinopathy with a few retinal hemorrhages and microaneurysms, multiple round atrophic chorioretinal lesions, with central pigmentation in some of them (arrowheads). Note the linear clustering of chorioretinal lesions (arrows). B. Fundus autofluorescence showing multiple well-delineated uniformly hypoautofluorescent (arrows) or centrally hyperautofluorescent and peripherally hypoautofluorescent spots (arrowheads). C. Spectral-domain optical coherence tomography showing focal involvement of the outer retina and retinal pigment epithelium corresponding to areas of chorioretinitis.

FIGURE 9-21. West Nile virus. A. Fundus photograph of 60-year-old woman with serologically proven West Nile virus infection showing superficial and deep hemorrhages in the posterior pole, perivascular sheathing with occlusive vasculitis, extensive retinal opacification, and optic disc pallor in the right eye. B. Late-phase fluorescein angiogram showing extensive areas of retinal capillary nonperfusion, and retinal and optic disc neovascularization in the right eye.

CHIKUNGUNYA

Lalitha Prajna and S. R. Rathinam

Introduction

Chikungunya is usually a self-limiting viral illness characterized by fever, severe arthralgia, and fatigue. However, more recent outbreaks have been associated with sight as well as life-threatening complications.

Etiology and Epidemiology

• It is an arthropod-borne Alphavirus, belonging to the family Togaviridae and is transmitted by the bite of the mosquitoes, Aedes aegypti.

• It is endemic in parts of Africa and of Asia. Major epidemic outbreaks occurred in 2005.

Ocular

• Ocular disease

Photophobia, red eye, blurred vision, floaters, and retro-orbital pain
Loss of vision, color vision defect, central or centrocecal scotoma, and peripheral field defects

Signs

• Mild granulomatous or nongranulomatous anterior uveitis

• Pigmented diffuse keratitic precipitates on the central or over the entire corneal endothelium and stromal edema. Stromal keratouveitis has been reported (Fig. 9-22).

• Compared to herpetic retinitis, chikungunya retinitis has markedly less vitreous reaction, and posterior pole retinitis is uncommon.

• Optic neuritis, neuroretinitis, macular choroiditis, and exudative retinal detachment (Fig. 9-23)

• Chikungunya virus has been detected in corneal grafts.

Differential Diagnosis

• Toxoplasmosis

• Herpetic viral retinitis

• Syphilis

• Cat-scratch disease (CSD)

Testing

• Virus isolation and RT-PCR are useful during the initial viremic phase, whereas serologic methods are useful after 10 days of infection.

Prognosis

• Visual prognosis is poor in posterior uveitis (Figs. 9-22, 9-23 and 9-24).

REFERENCES

Babu K, Adiga M, Govekar SR, Kumar BR, Murthy KR. Associations of Fuchs heterochromic iridocyclitis in a South Indian patient population. J Ophthalmic Inflamm Infect. 2013;3(1):14.

Calisher CH, Shope RE, Brandt W, et al. Proposed antigenic classification of registered arboviruses I. Togaviridae, Alphavirus. Intervirology. 1980;14:229-232.

Chanana B, Azad RV, Nair S. Bilateral macular choroiditis following Chikungunya virus infection. Eye (Lond). 2007;21(7):1020-1021.

Couderc T, Gangneux N, Chrétien F, et al. Chikungunya virus infection of corneal grafts. J Infect Dis. 2012;206(6):851-859.

Enserink M. Infectious diseases. Massive outbreak draws fresh attention to little-known virus. Science. 2006;311:1085.

Hayek S, Rousseau A, Bouthry E, Prat CM, Labetoulle M. Chikungunya virus infection and bilateral stromal keratouveitis. JAMA Ophthalmol. 2015;133(7):849-850.

Khairallah M, Kahloun R, Ben Yahia S, Jelliti B, Messaoud R. New infectious etiologies for posterior uveitis. Ophthalmic Res. 2013;49(2):66-72.

Lalitha P, Rathinam S, Banushree K, Maheshkumar S, Vijayakumar R, Sathe P. Ocular involvement associated with an epidemic outbreak of chikungunya virus infection. Am J Ophthalmol. 2007;144(4):552-556.

Leparc-Goffart I, Nougairede A, Cassadou S, Prat C, de Lamballerie X. Chikungunya in the Americas. Lancet. 2014;383(9916):514.

Mahendradas P, Ranganna SK, Shetty R, et al. Ocular manifestations associated with chikungunya. Ophthalmology. 2008;115(2):287-291.

Martínez-Pulgarín DF, Chowdhury FR, Villamil-Gomez WE, Rodriguez-Morales AJ, Blohm GM, Paniz-Mondolfi AE. Ophthalmologic aspects of chikungunya infection. Travel Med Infect Dis. 2016;14(5):451-457.

Pialoux G, Gaüzère BA, Jauréguiberry S, Strobel M. Chikungunya, an epidemic arbovirosis. Lancet Infect Dis. 2007;7(5):319-327.

Pleyer U, Chee S-P. Current aspects on the management of viral uveitis in immunocompetent individuals. Clin Ophthalmol. 2015;9:1017-1028.

Reddy V, Ravi V, Desai A, Parida M, Powers AM, Johnson BW. Utility of IgM ELISA, TaqMan real-time PCR, reverse transcription PCR, and RT-LAMP assay for the diagnosis of Chikungunya fever. J Med Virol. 2012;84(11):1771-1778.

Scripsema NK, Sharifi E, Samson CM, Kedhar S, Rosen RB. Chikungunya-associated uveitis and exudative retinal detachment: a case report. Retin Cases Brief Rep. 2015;9(4):352-356.

FIGURE 9-22. There are multiple, diffuse, pigmented keratic precipitates in chikungunya anterior uveitis.

FIGURE 9-23. Chikungunya. A. This person has macular retinitis with areas of outer retinal whitening with hard exudates in the outer plexiform layer. B. This frame of the late venous phase of the fluorescein angiogram showing irregular hypofluorescence in the inferior macula, with enlargement of foveal avascular zone. The hypofluorescence is caused by reduced perfusion as a result of capillary closure and also caused by blocked fluorescence secondary to the retinitis. C. Later frame of the angiogram demonstrating leakage from the vasculitis secondary to retinitis. D. Late phase showing diffuse leakage from an altered inner blood retinal barrier secondary to vasculitis and retinitis.

EBOLA VIRUS DISEASE

Bryn Burkholder

Ebola virus disease (EVD) is a highly transmissible, hemorrhagic fever associated with multisystem organ failure and high mortality. In the wake of the West African epidemic of 2013 to 2016, a “post-EVD syndrome,” with multiple systemic manifestations, including uveitis, has been recognized in survivors.

Epidemiology and Etiology

• EVD is most commonly caused by Zaire ebolavirus, an RNA virus in the genus Ebolavirus.

• Fruit bats are the natural reservoirs for the virus, and outbreaks typically occur in tropical regions of sub-Saharan Africa.

• Transmission of the virus occurs through bodily fluids.

• Ocular complications of EVD have been reported in 16% to 34% of survivors.

• Ebola virus has been identified in the aqueous of a survivor, 9 weeks after serologic clearance of viremia. It is thought that the eye may be an immune-privileged reservoir for the virus.

• The etiology of EVD-associated uveitis is currently unknown, but it may be the result of either the cytopathic effect of replicating virus in the eye or the immune reaction to the virus or both.

Symptoms

• Patients with acute EVD infection present with high fever, sore throat, and headache and quickly progress to vomiting, diarrhea, and disseminated hemorrhage.

• Eye symptoms during acute infection include burning, photophobia, and foreign body sensation.

• The post-EVD syndrome has been characterized by a variety of systemic complaints, including diffuse arthralgias and myalgias, fatigue, and neurocognitive symptoms, as well as ocular complaints of eye pain, floaters, and blurred vision.

Signs

• Hemorrhagic conjunctivitis has been commonly described in patients who are acutely ill with EVD.

• Eye findings in survivors include anterior chamber cell, keratic precipitates, posterior synechiae, corneal edema, vitritis, chorioretinal scars (Fig. 9-25), and optic nerve pallor.

• Several different types of uveitis (anterior, posterior, and panuveitis) have been described in EVD survivors, but there is currently no consensus on which type occurs most commonly.

• EVD-associated uveitis may be unilateral or bilateral and has been observed as soon as a few days, and as late as 13 months, after recovery from acute illness.

Differential Diagnosis

• The differential diagnosis for the febrile illness includes tropical diseases such as malaria, typhoid fever, dengue, and Marburg virus disease.

• The differential diagnosis for the uveitis associated with EVD is broad; however, in patients with the commonly described chorioretinal scars, one should consider multifocal choroiditis, sarcoidosis, TB, ocular histoplasmosis, toxoplasmosis, and syphilis.

Prognosis

• Acute EVD carries a high mortality rate (40% to 50%).

• EVD-associated uveitis can be recurrent and can result in blindness.

FIGURE 9-24. Ebola virus. Fundus photograph of a chorioretinal scar in an Ebola virus disease (EVD) survivor. Round, chorioretinal scars like the one shown here (arrow) have been described in EVD survivors with active uveitis and also in survivors with no other evidence of prior eye inflammation. (Photo credit: Allen Eghrari, MD.)

• The risks associated with intraocular surgery following EVD are still poorly understood.

• Long-term data on outcomes of EVD-associated uveitis are still limited.

REFERENCES

Hebert EH, Bah MO, Etard JF, et al. Ocular complications in survivors of the Ebola outbreak in Guinea. Am J Ophthalmol. 2017;175:114-121.

Shantha JG, Crozier I, Hayek BR, et al. Ophthalmic manifestations and causes of vision impairment in Ebola virus disease survivors in Monrovia, Liberia. Ophthalmology. 2017;124:170-177.

Van Gelder RN, Margolis TP. Ebola and the ophthalmologist. Ophthalmology. 2015;122:2152-2154.

Varkey JB, Shantha JG, Crozier I, et al. Persistence of Ebola virus in ocular fluid during convalescence. N Engl J Med. 2015;372:2423-2427.

ZIKA VIRUS

Shilpa Kodati and H. Nida Sen

Zika virus (ZIKV), a mosquito-borne flavivirus, was first discovered in Uganda in 1947 and was identified in humans in 1952. Since the start of the recent ZIKV epidemic, the virus has spread throughout the Americas and Caribbean. The WHO declared the epidemic a public health emergency of international concern from February to November 2016. Brazilian newborns born to mothers infected with ZIKV can have chorioretinal atrophy and optic nerve abnormalities that are now thought to be part of congenial Zika syndrome. In addition to these congenital findings, self-limiting cases of anterior and posterior uveitis have also been reported.

Etiology and Epidemiology

• Zika is an enveloped, single-stranded RNA virus, belonging to the Flaviviridae family (genus Flavivirus), which includes other arthropod transmitted viruses, such as dengue, West Nile, and yellow fever viruses.

• ZIKV is primarily transmitted through infected Aedes species mosquitoes. The virus can also be sexually transmitted.

• Prior to the recent ZIKV epidemic, the virus was thought to be endemic to parts of Africa and Asia. Since the start of the outbreak in 2015, the virus has spread throughout the Americas and Caribbean.

Signs

• Congenital Zika syndrome

Microcephaly
Intracranial calcifications (present between cortex and subcortical white matter)
Congenital brain abnormalities
Hypertonia
Arthrogryposis (joint contractures)
Ophthalmic (Fig. 9-25)
- Most common
  - Chorioretinal atrophy (excavated appearance is typical)
  - RPE pigment mottling
  - Optic nerve abnormalities (severe optic disc cupping and hypoplasia)
- Other congenital ophthalmic findings that have been described
  - Glaucoma
  - Iris coloboma
  - Lens subluxation

• Uveitis (in reported cases, uveitis has developed after the onset of systemic symptoms)

Increased IOP
Mild anterior uveitis
Mild vitreous inflammation
Chorioretinal lesions (Fig. 9-25)
Acute maculopathy

Differential Diagnosis

• Congenital

Other TORCH infections
- T. gondii
- Others (syphilis, HIV, West Nile virus, VZV, Epstein-Barr virus)
- Rubella
- CMV
- HSV
Maternal exposure to teratogens (alcohol, tobacco, teratogenic medications, and illicit drugs)

• Uveitis

West Nile virus
Dengue fever
Syphilis
Epstein-Barr virus
Coxsackie virus

Diagnostic Evaluation

• Congenital disease

Both mothers and neonates with suspected congenital Zika syndrome should be screened with ZIKV IgM.

• Acquired disease

Fundus autofluorescence, fluorescein angiography, and ICGA can help with the visualization of chorioretinal lesions.

Consider anterior chamber tap and submitting aqueous sample to the U.S. Centers for Disease Control (CDC) or similar organization for ZIKV RT-PCR testing.
RNA nucleic acid testing (NAT) on serum and urine within first 14 days following the onset of symptoms
If testing is performed after 14 days or RNA NAT testing is negative, obtain ZIKV serology (IgM is positive from day 4 to 12 weeks postinfection).

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