Progressive Outer Retinal Necrosis
Necrotizing Herpetic Retinopathy is an umbrella term under which both Acute Retinal Necrosis (ARN) and Progressive Outer Retinal Necrosis (PORN) fall. While initially considered to be two distinct entities, recent literature suggests that these diseases are two ends of the necrotizing herpetic retinopathy spectrum. PORN is characterized by a rapid progression of necrosis of the outer retina in immunocompromised patients. The most common etiologic agent is Varicella Zoster Virus, followed by Herpes Simplex Virus. Primary treatment includes antiviral agents both intravitreally and intravenously. Additionally, attention is focused on management of disease sequelae including but not limited to retinal detachment repair. Visual prognosis is often guarded at best.
In 1971, Akira Urayama described acute retinal necrosis (ARN) as consisting of a clinical syndrome of an acute unilateral panuveitis associated with retinal periarteritis and necrotizing retinitis. This disease process was generally found to occur in otherwise healthy patients. In 1990, Forster and colleagues identified a syndrome affecting immunocompromised individuals and coined the term "progressive outer retinal necrosis," or PORN. They described an infectious retinitis associated with recent cutaneous zoster infection, marked by limited intraocular inflammation, predominant involvement of the outer retina, and involvement of the posterior pole. Since then, our understanding of the disease has evolved, but these remain the salient features. PORN has also been called as rapidly progressive herpetic retinal necrosis (RPHRN). Significantly less ocular inflammatory reaction is noted in PORN compared to ARN.
The overwhelming majority of cases of PORN are attributed to infection by Varicella Zoster Virus (VZV). One review (Wong, R.J. et. al) identified VZV as the etiologic agent in 71.5% of cases of PORN. Second were HSV strains, and in rare cases CMV has been cited as well. The role of CMV as an etiologic agent in PORN remains controversial, however, as often evidence of CMV-retinitis is an exclusion criteria in a number of studies. Additionally, some studies have only identified CMV in vitreous that is co-infected with HSV-1.
PORN occurs in patients who are severely immunocompromised. In patients with AIDS, the mean CD4 count at the time of PORN diagnosis was found to be 21, ranging from 1-130 (normal 500-1500). The median age was cited as 37 years (range 6 - 58 ). Approximately 22% of patients cited a history of cutaneous zoster. Of patients with history of cutaneous involvement, 41% involved the V1 distribution and 14% had concurrence of skin and intraocular manifestations. In a study, 73% patients had a history of cutaneous zoster and 73% patients had suspected viral involvement of the central nervous system (Ormerod et al.).
General Pathology and Pathophysiology
Retinal necrosis is inflicted predominantly through direct intraretinal spread of the replicating virus. Histology is significant for necrosis not only of the outer retina but all retinal layers. An acute reactive inflammatory granulomatous response within the retinal and choroidal vasculature also plays a role in retinal ischemia, however this occlusive vasculitis is a more prominent feature of ARN than PORN.
A hallmark feature of PORN is the lack of intraocular inflammation. Less than approximately 40% of patients have an anterior chamber reaction and less than 20% have vitreous cell. If present, it was found to be predominantly mild. This is likely a reflection of the severely immunocompromised state of affected patients.
Original descriptions of the disease emphasized posterior pole involvement, with initial multifocal lesions throughout the posterior pole that progressed later to confluence, and involved the peripheral retina at late stages. However, more recent reports show that deep necrosis can be present in any or multiple parts of the outer retina. These lesions can rapidly progress to full thickness as well as confluence without consistent directionality of spread.
Retinal detachments develop in at least 50% of patients by some accounts. Serous retinal detachments can occur secondary to fluid leakage from full thickness necrosis, often resolving with treatment leading to disease inactivity. Rhegmatogenous retinal detachments are also theorized to occur secondary to multi-level holes in the setting of full thickness necrosis.
Diagnosis is made based on history and clinical exam findings. Imaging studies may be helpful in identifying extent of retinal involvement but are not essential to the diagnosis.
Patients classically have vague clinical complaints that may initially be out of proportion to clinical findings. The median visual acuity at presentation has been found to be 20/30, however with a wide range from 20/20 - NLP. Approximately 30% of patients complain of constriction of visual fields. 2/3 of patients have a history of cutaneous zoster, and of these patients 14% have simultaneous skin and ocular complaints.
On exam, large patches of discrete yellow-white retinal opacification consistent with necrosis of the deep retinal layers are identified. These lesions can be found either in the peripheral retina, posterior pole, or both. Multifocal lesions can progress rapidly to confluence without consistent direction of disease spread. The majority of patients actually present with peripheral lesions, and approximately 1/3 of patients develop similar lesions in the macula as well. The majority of patients have a quiet anterior chamber and absence of vitreous cell; if present, reaction is classically minimal.
Other clinical features include a retinal vasculopathy with vascular sheathing and occlusion and optic nerve abnormalities including hyperemia or edema. A large number of patients, approximately 70% by some studies, develop retinal detachments.
While the diagnosis of Progressive Outer Retinal Necrosis is made primarily by clinical history and exam findings, certain testing modalities may aid in the diagnosis if necessary.
Fluorescein angiography (FA) findings can be variable. Active areas of necrosis demonstrate late staining, while inactive, atrophic regions display window defects. Focal vascular occlusions may be evident on FA as well.
Optical coherence tomography (OCT) is significant for not only outer retinal disorganization, consistent with necrosis of the outer layers, but also hyper-reflectivity of the inner layers as well. Cystoid spaces and foveal thickening can also be observed.
Fundus autofluorescence classically shows stippled areas of mixed hyper- and hypo- autofluorescence, indicative of adjacent "sick" RPE cells, accumulating lipofuscin (hyper-autofluorescent) and RPE and adjacent photoreceptor death (hypo-autofluorescent).
Blood work indicating immunocompromised state with decreased CD-4 count or otherwise low white blood cell count (in instances of hematologic disease or pharmacologic immunosuppression) may aid in the diagnosis.
Vitreous tap with viral PCR analysis is typically performed to isolate the pathogen. Common labs ordered are VZV-PCR, HSV-1, 2 PCR, CMV PCR. In cases of a younger patient or otherwise dry vitreous tap, an anterior chamber tap may yield positive results with greater facility.
Differential diagnosis can be broad, general categories which include infectious, inflammatory, neoplastic.
Infectious: CMV retinitis, ARN, Syphilitic retinitis, Toxoplasma retinochoroiditis, tuberculosis, toxocariasis, fungal or bacterial endophthalmitis
Inflammatory: Sarcoidosis, Behcet's, other retinal vasculitides
Neoplastic: intraocular lymphoma, leukemia, metastasis
PORN may appear similar to central retinal arterial occlusion, but fragmentation of blood column within retinal vessels is absent in PORN and there is typical paravascular clearing.
When the disease was first described, the predominant modality for treatment was intravenous antiviral therapy. Drugs were used alone or in combination. However, systemic treatment alone portends a poor prognosis (approximately 2/3 of patients progressed to NLP at 4 weeks by some studies). Acyclovir, which has a better relative safety profile, was found to have an increased rate of disease progression or recurrence. It also can be nephrotoxic. Ganciclovir, which has increased efficacy for CMV as well as VZV, HSV, can lead to bone marrow suppression. This may be an unacceptable side effect in patients who already suffer from severe immunosuppression. Foscarnet has recently been found to have increased resistance, and also can cause nephrotoxicity.
Intravitreal injections of antiviral therapy, most commonly ganciclovir (2 mg/0.1 cc) and foscarnet (2.4 mg /0.1 cc), have been shown to lead to improved outcomes. Compared to prior studies showing 2/3 progression to NLP at 4 weeks status post intravenous therapy alone, newer studies have found only 1/3 progression to NLP by 7 months following intravitreal antiviral injections. Median final visual acuity was shown to be count fingers, and likely correlates to visual acuity at presentation.
In the event of retinal detachment, a frequent occurrence following necrosis of the outer retina, surgical repair with silicone oil has been found to be effective. Retention of ambulatory vision has been demonstrated in some studies in up to 70% of patients. Silicone oil is the repair modality of choice given its permanence as well as the fewer post-operative activity limitations (including body positioning), improving compliance in patients who likely have other significant medical comorbidities. Prophylactic laser barricade of areas of retinal necrosis has not been shown to be effective in preventing retinal detachment in PORN, though it has shown success in ARN. Its failure is likely due to a combination of the rapid progression of necrosis, preventing the laser from creating areas of adequate adhesion, as well as the possibility that the necrotic retina may already be detached by the time of laser. Another consideration is the inability to laser lesions that are located in close proximity to the fovea.
Clinically inactive disease after antiviral therapy can lead to plaque-like scarring and sclerotic vessels often described as a "cracked mud" appearance. Atrophy of the RPE and all layers of the neurosensory retina in areas of prior necrosis may also be evident.
Visual prognosis is grim and may correlate to visual acuity at presentation. Approximately 66% of patients treated with only systemic antiviral therapy have been shown to progress to NLP, whereas those receiving prompt intravitreal antiviral therapy retain better vision-- median final VA is count fingers, and only 33% of patients progressed to NLP by 7 month follow-up.
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