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Woman presents with bilateral rapidly progressive blurry vision and eye pain
Both eyes had multifocal areas of retinal whitening, arterial attenuation with sheathing and scattered hemorrhages.
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A 59-year-old woman presented to an outside ophthalmologist with 1 week of blurry vision, headache, eye pain and tearing in both eyes. She was found to have anterior chamber inflammation with elevated IOP in the low 30s bilaterally. The ophthalmologist also noted peripheral multifocal white spots in both eyes on posterior examination. She was started on prednisolone acetate and timolol eye drops.
Over the next 3 days, her symptoms and examination worsened significantly, and the patient was referred to the New England Eye Center for evaluation. The patient had recently undergone resection of an intracranial meningioma with subsequent radiation, the last dose given 3 weeks before the onset of symptoms. She also recently completed an oral dexamethasone taper (prescribed in conjunction with radiation) 1 week before symptom onset. She had no other medical or ocular history.
Examination
Upon evaluation at NEEC, the patient’s visual acuities were 20/150 and 20/200 in the right and left eyes, respectively. She was pharmacologically dilated upon arrival, with IOP in the mid-teens. She had trace diffuse conjunctival injection, 2+ diffuse corneal edema with Descemet’s folds and 2+ fine anterior chamber cell in both eyes. She had mild nuclear sclerotic cataracts. Fundus examination was notable for mild bilateral optic nerve edema with small optic nerve hemorrhages in the left eye. Both eyes had 2+ vitreous cell and 1+ vitreous haze.
Source: Andre J. Witkin, MD, and Astrid C. Werner, MD
Retinal examination revealed multifocal areas of retinal whitening with coalescent patches of retinal whitening inferiorly in both eyes. The retinitis was associated with arterial attenuation with sheathing, and there were a few scattered hemorrhages in both eyes. The left eye also had a cotton wool spot in the nasal macula (Figure 1). OCT of the macula revealed some areas of inner retinal hyperreflectivity and other areas of inner retinal thinning, indicating various stages of macular ischemia. The right eye also had cystoid macular edema (Figure 2).
What is your diagnosis?
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Rapid bilateral progression
The differential diagnosis for multifocal retinitis with panuveitis and vasculitis includes infectious, inflammatory and neoplastic causes.
Toxoplasmosis is the most common cause of infectious posterior uveitis worldwide and classically causes a unilateral focal retinitis (yellow/white retinal lesion) with overlying vitritis. Ocular toxoplasmosis may occur simultaneously with a primary systemic infection or later, as a result of reactivation of dormant intraretinal cysts often adjacent to an old retinal scar. Other findings may include optic disc edema, vasculitis and anterior uveitis. Our patient had quickly progressive bilateral multifocal retinitis, which differs from these typical presentations of ocular toxoplasmosis.
Syphilis and tuberculosis are two other important bacterial considerations in any uveitic process because they can affect any ocular tissue and can present with a variety of posterior manifestations. In syphilis, posterior manifestations include vitreous inflammation, chorioretinitis, retinal vasculitis, serous retinal detachment and, rarely, necrotizing retinitis. Ocular tuberculosis can also have a variety of appearances, but the typical presentation is focal or multifocal choroiditis. Other posterior presentations of ocular tuberculosis include serpiginous-like choroiditis, intermediate uveitis, and retinal vasculitis and/or vascular occlusion (Eales disease). Because of the variety of presentations of syphilis and tuberculosis, testing for these infections should be considered for most cases of posterior uveitis.
Cytomegalovirus (CMV) causes a slowly progressive, necrotizing retinitis with perivascular retinal whitening and hemorrhages, usually in severely immunocompromised patients. Often it is associated with only mild vitritis (secondary to immune suppression); however, the presentation can be variable. CMV retinitis often starts as a solitary patch of retinitis. Advancement of infection into normal retina is characterized by a dry granular border with multiple dot-like satellite lesions. In contrast to CMV, acute retinal necrosis (ARN) secondary to varicella zoster virus (VZV), herpes simplex virus (HSV) or Epstein-Barr virus (EBV) has an explosive and multifocal presentation with marked vitritis, full-thickness retinal necrosis and arteritis. Initially, ARN lesions are discrete areas of whitening in the peripheral retina that become confluent and march centrally over the ensuing week to 10 days. This is in contrast to a related entity that occurs in immunosuppressed patients, progressive outer retinal necrosis (PORN), which starts in the posterior pole and is associated with much less vitreous inflammation.
Noninfectious inflammatory conditions that may cause retinitis include Behçet’s disease and sarcoidosis. Ocular involvement from Behçet’s disease typically presents after the classic systemic symptoms (aphthous ulcers and erythema nodosum); however, a small but significant portion of people will present with eye involvement as the first manifestation of the disease. Findings of ocular Behçet’s include marked anterior chamber inflammation often with hypopyon, vitritis, white retinal lesions with hemorrhages, perivascular sheathing and occlusion. There is often optic disc hyperemia. Like tuberculosis (TB) and syphilis, ocular sarcoidosis is included in the differential for all uveitic processes because of its characteristically variable presentation. Lastly, patients with primary intraocular lymphoma can present with creamy white retinal lesions, variable degrees of vitritis and, less commonly, anterior chamber inflammation.
Among the etiologies outlined above, bilateral ARN (BARN) was of particular concern because of the multifocal and quickly progressive nature of the disease, and the patient underwent bilateral anterior chamber paracenteses followed by intravitreal injections of foscarnet. Aqueous samples were sent for VZV, HSV-1, HSV-2, CMV and toxoplasmosis polymerase chain reaction (PCR). The decision was made to admit the patient for IV acyclovir, expedited workup, and access for daily ophthalmology examination and treatment. Testing was ordered for HIV, TB and syphilis. She was also started on prednisolone acetate drops every 2 hours and atropine twice daily.
Discussion
ARN is a rare, devastating viral syndrome first described in 1971 as a rapidly progressive, full-thickness, necrotizing retinitis with occlusive arteritis and vitritis. Presenting symptoms include pain, redness, floaters, flashes and decreased vision. Classically, ARN begins peripherally with multifocal discrete white lesions that subsequently become confluent and then spread circumferentially and centrally over 7 to 10 days if untreated. Involved areas of the retina are sharply demarcated from uninvolved areas. Severe vitreous inflammation is also characteristic. There may be associated anterior segment findings, such as anterior chamber inflammation, keratic precipitates, corneal edema and scleritis, but it is the posterior segment findings that are diagnostic. In 1994, the American Uveitis Society published the following diagnostic criteria for ARN: one or more discrete foci of peripheral retinal necrosis outside the vascular arcades; circumferential spread; occlusive arterial vasculopathy; prominent vitreous or anterior chamber inflammation; and rapid disease progression in the absence of antiviral therapy.
Herpetic infection (with members of the herpesviridae family) was first implicated in ARN due to an observed temporal relationship between a known herpetic infection and the development of ARN in several cases. Indeed, past or concurrent herpetic infection is common. In particular, a history of HSV-1 encephalitis or HSV-2 meningitis is an especially strong risk factor, with up to 8% of these patients developing ARN within 12 months. The first histologic evidence linking herpetic infection and ARN was published by Culbertson and colleagues in 1984. Since then, reports in the literature have found up to 80% to 100% of aqueous and/or vitreous samples in ARN patients are positive for VZV or HSV by PCR.
Among herpetic entities, VZV is the most common cause, followed by HSV-1 and then HSV-2. EBV has also been linked to ARN; however, this association remains controversial. EBV is a ubiquitous virus shown to be present in up to 20% of all cadaver eyes, and many PCR-positive EBV cases of ARN are also positive for VZV. PCR-positive CMV-associated ARN has also been reported; however, this is also a controversial association given the ubiquity of serologic evidence of CMV in the general population (60% to 90%). Further, advanced cases of CMV retinitis can look similar to ARN. A 2017 report by the American Academy of Ophthalmology found no PCR-positive cases of CMV in ARN. Despite this controversy, CMV retinitis does remain an important consideration in the differential diagnosis of ARN.
Usually, ARN presents unilaterally, although if untreated, up to 70% of patients will go on to have contralateral involvement within weeks. Recurrences have also been reported to occur up to decades later. Simultaneous bilateral presentation is much less common than sequential ARN; however, the exact rates are unknown. While clear risk factors for BARN have not been identified, there have been case reports of BARN after herpetic encephalitis and meningitis, disseminated VZV, and in patients on immune modulatory therapies.
ARN classically affects immunocompetent patients at any age without any sex predilection. This is in contrast to PORN, a related entity caused by herpetic infection that affects the posterior pole first in severely immune compromised people. In contrast to ARN, there is much less vitreous inflammation in PORN due to immune compromise, and there may not be much vasculitis. In practice, however, ARN can also affect immunocompromised patients; most likely ARN and PORN represent a spectrum of the same disease rather than discrete entities. There is some mounting evidence that certain individuals may have a genetic predisposition to develop ARN, as several studies have found a higher incidence of certain human leukocyte antigen types (DQw7, Bw62, DR4) among ARN patients. There have been several reports in the literature of neurosurgical intervention or radiation precipitating ARN. In the case of the patient presented in this report, antecedent meningioma resection and local radiation may have been factors in the development of ARN.
While primarily a clinical diagnosis, aqueous and vitreous PCR can reliably confirm the diagnosis of herpetic infection. Both aqueous and vitreous PCR have high sensitivity and specificity, and require only a small volume of fluid for analysis. Because data have not conclusively demonstrated the superiority of vitreous testing, many physicians will collect aqueous only due to the theoretical risks associated with a vitreous tap. Aqueous fluid can also reliably test for other similar-appearing infectious syndromes, particularly CMV retinitis and toxoplasmosis, for which treatment is different.
There is no level 1 evidence to guide therapy due to the rarity of ARN; however, generally agreed upon therapy consists of high-dose systemic and intravitreal antiviral therapy. Until recently, standard therapy consisted of intravenous acyclovir dosed at 10 mg/kg every 8 hours for 7 to 10 days followed by months of oral therapy. More recently, there has been a shift to treat ARN with oral valacyclovir initially. The appropriate dosing of oral valacyclovir is still up for debate. Studies have shown equivalent plasma drug levels with 2,000 mg of oral valacyclovir three times a day and 10 mg/kg of IV acyclovir every 8 hours; therefore, this is often the dosage employed, but the risk for renal toxicity is higher at doses greater than 1,000 mg three times a day. There are no prospective studies directly comparing outcomes of intravenous and oral therapy in ARN; however, a recent retrospective review of outcomes in 68 cases of ARN at Moorfields Eye Hospital found no difference in final visual acuity, rates of severe vision loss, eyes retaining good vision or rates of retinal detachment between patients treated with intravenous vs. oral therapy. Despite this, many clinicians will still use IV therapy in severe cases for 7 to 10 days before converting to oral therapy as there is some evidence that there is slightly higher maximal serum concentrations and faster time to maximal concentration with IV acyclovir.
In addition to systemic antiviral therapy, there is level 2 and level 3 evidence supporting the adjunctive use of intravitreal foscarnet and ganciclovir in ARN. Typical dosages are 1.2 mg/0.1 mL to 2.4 mg/0.1 mL of foscarnet and 200 µg/0.1 mL to 2,000 µg/0.1 mL of ganciclovir. Many physicians will repeat intravitreal injections every 2 to 3 days until the patient’s condition stabilizes. Aspirin is sometimes prescribed in hopes of mitigating the occlusive vasculitis as well as systemic steroids to manage the severe inflammation that accompanies ARN; however, neither has been shown to affect the final outcome.
Appropriate antiviral therapy should arrest the progression of ARN lesions and ultimately induce their regression. Failure to do so despite appropriate antiviral therapy should lead the physician to question the diagnosis. Yet, even in cases in which antivirals have successfully arrested disease progression, the visual prognosis is guarded. Approximately 50% of patients will go on to develop retinal detachments within an average of 2 months of presentation regardless of initial treatment strategy. Optic atrophy and proliferative vitreoretinopathy are also common.
Because ARN-related retinal detachments are difficult to treat, with recurrence rates as high as 50%, there has been significant interest in strategies to prevent detachments. Laser retinopexy (LRP) of the retina surrounding ARN lesions is a strategy that some physicians employ as prophylaxis against retinal detachment. Some studies have reported data to support this practice, such as decreased retinal detachment rates and better visual acuity outcomes; however, more recent studies have not. Positive results in the initial studies were likely due to selection bias as eyes selected for LRP had milder disease in terms of less vitritis and better initial visual acuity. Similarly, some have advocated the use of early vitrectomy to clear inflammatory mediators, relieve vitreous traction on the retina and provide a clear view for prophylactic laser, and prophylactic scleral buckling surgery. Once again, clear data in support of these practices do not exist. To date, the best practice in management of ARN hinges on early recognition and implementation of antivirals to halt lesions in the affected eye and to prevent contralateral involvement.
Clinical course continued
Over the next 2 days, the patient’s examination worsened with increasing confluent areas of retinal whitening, now involving the optic nerve in the right eye and encroaching the optic nerve and macula in the left eye (Figure 3). The dose of IV acyclovir was increased from 700 mg three times a day to 1 g three times a day, oral aspirin 325 mg was initiated, and intravitreal injections of foscarnet and ganciclovir were repeated in both eyes. On day 4 of admission, the aqueous PCR returned positive for VZV, and all other infectious tests of the aqueous fluid and serum were negative. An MRI of the brain did not reveal any inflammation or signs of infection. She underwent a total of five bilateral intravitreal foscarnet injections every other day until her retinal examination stabilized and the retinitis began to regress. She completed a 2-week course of IV acyclovir and then was transitioned to high-dose oral valacyclovir at 2,000 mg per day. By day 21 of treatment, the patient’s vision was hand motions in the right eye and 20/200 in the left eye. Fundus examination showed areas of retinal whitening beginning to regress (Figure 4). The risk of retinal detachment and overall poor prognosis were discussed at length with the patient and the family. Due to the proximity of the retinitis to the macula and optic nerve, the decision was made not to perform prophylactic LRP. She will continue oral antiviral therapy for several months and will continue to be followed closely in the ophthalmology clinic.
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- For more information:
- Andre J. Witkin, MD, and Astrid C. Werner, MD, can be reached at New England Eye Center, Tufts University School of Medicine. 800 Washington Street, Box 450, Boston, MA 02111; website: www.neec.com.
- Edited by Aubrey R. Tirpack, MD, and Astrid C. Werner, MD. They can be reached at the New England Eye Center, Tufts University School of Medicine, 800 Washington St., Box 450, Boston, MA 02111; website: www.neec.com.