Published in Infectious Diseases in Children March 2009

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A 15-year-old girl presented with progressive pain, erythema and diminished vision in her left eye. The history of her chief complaint began 12 days earlier. There was no associated injury, illness, sick contacts or recent travel. When initially seen, she was treated for conjunctivitis with a topical antibiotic; however her symptoms worsened with increasing pain and visual deterioration to 20/200 in her left eye.

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Her past medical history is that of a normal, previously healthy adolescent, and her family and social history are unremarkable, with a normal birth history. Immunizations are up to date. She says she was sexually active on one occasion a year earlier, but denies any sexually transmitted infections. Her review of systems was positive only for the chief complaint.

James H. Brien, DO	Gayatri Mirani, MD

She was referred to a vitrioretinal ophthalmologist who found on examination that she had ocular pain with marked conjuctival injection. Under magnification, sectoral mutton-fat corneal endothelial keratic precipitates were found (Figure 1), the anterior chamber was found to have marked inflammation, dense vitritis, papillitis (Figures 2a and 2b), retinal arterial occlusive vasculitis in several quadrants (Figures 2a, 3a and 3b), and diffuse peripheral retinal yellow-white exudation with associated intraretinal hemorrhages and inferior exudative retinal detachment (Figures 2a and 4). An atrophic, pigmented chorioretinal scar was visible along the inferotemporal vascular arcade (Figure 5).

Figure 1: Sectoral mutton-fat corneal endothelial keratic precipitates

Source: All photos courtesy of Daniel E. Goldberg

Figure 2a: Composite photograph showing papillitis	Figure 2b: Fluorescein angiogram with optic nerve head leakage

Figure 3a: Retinal arterial occlusive vasculitis	Figure 3b: Fluorescein angiogram showing leakage from arterial vasculitis

Figure 4: Inferior exudative retinal detachment	Figure 5: Pigmented, atrophic scar

These findings are consistent with the diagnosis of acute retinal necrosis.

What’s Your Diagnosis (Most Common Cause)?

1. Herpes simplex virus
2. Toxoplasma gondii
3. Varicella zoster virus
4. Cytomegalovirus

Case Discussion

Ophthalmology literature suggests that herpes simplex virus (HSV), answer A, is the most common cause of this relatively uncommon condition in adolescents.

Because of this, treatment with oral valacyclovir, 1 gram TID and prednisone, 40 mg per day was initiated immediately pending results of the blood tests. Blood was analyzed for HSV IgM, HSV1 IgG, HSV2 IgG, toxoplasmosis IgM & IgG, serum ACE and lysozyme, RPR, FTA-Abs and HIV antibody. Additionally, 0.2 ml of aqueous humor was aspirated from the anterior chamber and sent for PCR analysis for HSV, VZV, CMV and Toxoplasmosis. All testing was negative except for elevated serum HSV2 IgG and PCR positive for 54,500 copies/ml HSV DNA.

She was admitted to the hospital for a two-week course of intravenous acyclovir and oral steroids (60 mg/day for 2 weeks then tapered over a month). During this time, gradual retinal healing was observed with pigmentary atrophic areas in the retinal periphery and reduction in exudation and vasculitis and resolution of exudative retinal detachment. Visual acuity improved to 20/50 on discharge. This patient was discharged with instructions to complete a six-week course of oral Valacyclovir, 1 gm tid, which is the currently recommended standard therapy. On follow up, the patient had a good recovery, with resolution of the infection (Figure 6).

Figure 6: Composite follow up showing healing

Figure 7: Active CMV retinitis	Figure 8: Healed CMV retinitis

Figure 9: Toxoplasmosis, regressed

Acute retinal necrosis (ARN) is a necrotizing retinitis characterized by the clinical triad of vitritis, peripheral yellow-white necrotizing retinitis and occlusive arteriolitis. It is usually caused by retinal infection with HSV or VZV and is typically observed in immunocompetent patients. It is most often unilateral but bilateral cases have been reported. When the analogous herpetic retinitis occurs in immunocompromised patients with CD4 counts less than 50 cells/mm³, a syndrome of Progressive Outer Retinal Necrosis is described, characterized by a rapidly progressing necrosis which usually starts in the posterior pole of the retina and quickly advances into the macula. It is associated with severe, global retinal destruction and vision loss.

Progressive Outer Retinal Necrosis may be differentiated from ARN by the absence of vitritis and other inflammatory sequelae that are only observed in immunocompetent patients with preserved T-cells capable of mounting an immune response. While ARN is treated with acyclovir or valacyclovir, Progressive Outer Retinal Necrosis generally is rapidly fulminant and progressive and nonresponsive to therapy although the literature supports the combination of either intravitreal foscarnet or ganciclovir with IV Acyclovir. The diagnosis of ARN is generally made clinically. PCR has become a useful adjunct in establishing the diagnosis.

Current literature suggests that VZV and HSV1 are more likely to be causative agents in the population older than 25 and HSV2 is seen more commonly in younger age groups. Reactivation of congenital disease has been proposed as the mechanism of pathogenesis for HSV2 ARN. It has also been suggested that patients with HSV and VZV retinal necrosis have a decrease in CCR7+ plasmacytoid dendritic cells, which may play a role in NK cell innate activity.

The differential diagnosis for ARN includes Progressive Outer Retinal Necrosis, CMV-retinitis (Figure 7 active CMV and Figure 8, healing CMV), toxoplasmosis chorioretinitis (Figure 9), syphilitic chorioretinitis, sarcoidosis, Behcet’s disease, lymphoma and leukemia. In our case, the patient was empirically started on pyramethamine, sulfadiazine, and leukovorin to presumptively treat Toxoplasma retinitis given the presence of a characteristic chorioretinal scar. One large study found that chorioretinal scars were present in 79% of patients with congenital toxoplasmosis. Additionally, toxoplasmosis in immunocompromised patients may mimic ARN by producing an intense inflammatory retinochoroiditis. As the differential diagnosis for ARN is protean, the disease may be easily missed or misdiagnosed and thus requires a high index of clinical suspicion in the appropriate setting and a prompt referral to an ophthalmologist.

For more information:

• Aizman A, Johnson MW, Elner SG. Treatment of Acute Retinal Necrosis Syndrome with Oral Antiviral Medications. Ophthalmology 2007;114(2):307-312.
• Ganatra JB, Chandler D, Santos C; et al. Viral Causes of the Acute Retinal Necrosis Syndrome. Am J Ophthalmol 2000;129(2):166 – 172.
• Kittan NA, Bergua A, Haupt S; et al. Impaired Plasmacytoid Dendritic Cell Innate Immune Responses in Patients with Herpes Virus-Associated Acute Retinal Necrosis. J Immunol. 2007;179:4219-4230.
• Mets MP. Eye Manifestations of Intrauterine Infections. Ophthalmology Clinics of North America 2001;14(3):521-531.
• Van Gelder RN, Willig JL, Holland GN; et al. Herpes Simplex Virus Type 2 as a Cause of Acute Retinal Necrosis Syndrome in Young patients. Ophthalmology 2001;108:869-876.

Dr. Brien’s comments

Most of us never see what these retinal diseases look like to an ophthalmologist. So, I am particularly grateful to Dr. Mirani for sharing this case. Dr. Gayatri Mirani is a first-year pediatric infectious diseases fellow at The New York University Medical Center.

She completed her pediatric residency at UMDNJ-Robert Wood Johnson Medical School Program in New Brunswick, New Jersey. Prior to that, Dr. Mirani received her MD degree from SUNY Health Science Center in Brooklyn. Dr. Mirani received invaluable input from Dr. William Borkowsky (Professor, Saul Krugman Division of Pediatric Infectious Diseases and Immunology at NYU Medical Center), Dr. Alexander Aizman (Physician-in-Charge, Retina Service at Bellevue Hospital and Clinical Instructor in the Department of Ophthalmology at NYU Medical Center), and Dr. Daniel E. Goldberg, Vitrioretinal Specialist at New York Eye and Ear Infirmary). Dr. Goldberg provided all the photographs and editorial review.

As shown with this case and in last month’s column featuring a rare case of orbital pseudotumor, primary care providers need to be aware of these uncommon conditions in pediatric patients that may initially present similar to common eye conditions. Otherwise, a significant delay in diagnosis may result with potential permanent damage to the eye. Most of the time, you can tell when something just does not fit or seem right, especially when it does not respond to initial therapy. I’m sure many of you have heard that little voice in your head that told you “this is different.” Sometimes it’s barely whispering to you, and you don’t even mention it on rounds. Then again, it may be loud and clear, and cause you to initiate exploring a broader differential right away by consulting your ophthalmologist. Of course, this can apply to virtually any disease with which a child may present. I’ll have to admit, I hear voices every day. Sometimes they actually have something to do with medicine.

I would like to again thank Dr. Mirani for contributing this very interesting case and Dr. Goldberg for all the great pictures.

What’s Your Diagnosis? is a monthly case study featured in Infectious Diseases in Children, with treatment information and discussion to follow.