Acute Retinal Necrosis

Etiology

Acute retinal necrosis is a syndrome usually caused by the herpes virus family [VZV, HSV, rarely cytomegalovirus (CMV), or Epstein-Barr virus (EBV)]. The most common agent is VZV.[2]

Epidemiology

It is often found in immunocompetent individuals. It affects men and women equally. Acute retinal necrosis tends to occur in older patient populations as VZV immunity wanes. HSV-induced retinitis typically affects younger patients, who have a history of herpetic encephalitis. Acute retinal necrosis can also occur in immunocompetent patients, who become suppressed via corticosteroids, noncorticosteroid immunosuppressants, and chemotherapeutics. It is also seen in AIDS (acquired immune deficiency syndrome) and other immunocompromised patients. HLA-Aw33, HLA-B44, and HLA-DRw6 have been associated with acute retinal necrosis in the Japanese population. It has also been seen with the American Caucasian populations that have HLA-DQw7, HLA-Bw62, and HLA-DR4.[3]

Pathophysiology

The virus infects retinal cells and causes necrosis to occur. As necrosis occurs from virally induced cytolysis and arteriolar and choriocapillaris occlusion, the necrotic cells slough into the vitreous chamber exposing large areas devoid of retinal cells. 

In the acute phase, virus particles induce an inflammatory event, and this creates a response that damages the retinal cells. Inflammation of the arterioles leads to vaso-occlusive events furthering rapid necrosis of the retinal tissue. In the late phase, contractile membranes may form in the vitreous and on the surface of the damaged retina. Retinal necrosis causes multiple breaks in a pattern of the sieve and breaks at the margin of the normal and necrotic/inflamed retina. This may lead to retinal detachment. Retinal detachment may occur in up to 75% of eyes with ARN within 3 months of the onset of symptoms.[4] Vitreous traction and proliferative vitreoretinopathy often complicate the retinal detachment in ARN reducing the rates for surgical success.[5] The breaks may be located posteriorly as well as peripherally.[5]

Histopathology

Histology demonstrates eosinophilic intranuclear inclusions in retinal cells, retinal necrosis, and retinal arteritis.[6] Herpes group of viruses were noted in all the layers of the involved retina using electron microscopy.[6]

History and Physical

Patients will often present with rapid onset of ocular pain or periocular pain, pain on eye movement, redness, photophobia or light sensitivity, floaters, decreased vision, or blurred vision, and constriction of the visual field.

History of the following should be taken- risk factors for AIDS, immune status, any systemic or ocular therapy/ surgery, systemic diseases, and any previous herpetic infection including encephalitis. A thorough review of previous medical documents should be done.

An ocular examination that evaluates the anterior chamber and vitreous cells, intraocular pressure, as well as a dilated retinal examination with indirect ophthalmoscopy and scleral depression, need to be completed. A physical exam often reveals focal, well-demarcated areas of peripheral retinal whitening suggesting retinitis or retinal necrosis. A physical exam can also reveal occlusive arteritis and prominent inflammatory reaction in the vitreous and anterior chamber. The posterior pole is usually spared in the early course of the disease. Additional findings can include conjunctival injection, scleritis, increased intraocular pressure, sheathed retinal arterioles, retinal hemorrhage, optic disc edema, and retinal detachment.

A typical patient has severe anterior segment inflammation with fibrin with or without posterior synechia. The media is usually hazy due to haze in the anterior segment, vitritis with or without cataracts. The fundus examination may reveal disc edema and peripheral yellowish areas of retinitis which subsequently become confluent. Retinal hemorrhage, if present is usually not very prominent. 

Kyrieleis' periarteriolar plaque may be seen in ARN.[7]

Evaluation

Acute retinal necrosis is a clinical diagnosis and treatment should not be delayed in a typical case. The classical triad of ARN[8] consists of ' (1) arteritis and phlebitis of the retinal and choroidal vasculature, (2) a confluent, necrotizing retinitis that preferentially affects the peripheral retina, and (3) a moderate to severe vitritis.'[1]

American Uveitis Society criteria[2] for the diagnosis of ARN requires 'the following clinical characteristics be seen: focal, well-demarcated areas of retinal necrosis located in the peripheral retina (outside of the major temporal vascular arcades); rapid, circumferential progression of necrosis (if antiviral therapy has not been administered); evidence of occlusive vasculopathy; and a prominent inflammatory reaction in the vitreous, and anterior chamber. Supporting clinical criteria include optic neuropathy or optic atrophy, scleritis, and pain.

For the description of the involved area of retinitis 3 zones have been described (originally for CMV retinitis).[9] Retinitis at zone 1 (3000 microns around the center of the fovea and 1500 microns from the margin of the optic disc) is thought to be immediately sight-threatening. Zone 2 is the zone between zone 1 and the clinical equator denoted by the anterior margin of the vortex ampulla. Zone 3 is anterior to zone 2 till the ora serrata.

In a patient who presents with clinical findings of acute retinal necrosis, the physician should consider a complete blood count with differential, baseline liver and renal function test, HIV (human immunodeficiency virus) testing, FTA-ABS (fluorescent treponemal antibody absorption), and RPR (rapid plasma reagin), erythrocyte sedimentation rate, toxoplasmosis titers, purified protein derivative skin test (PPD), and chest radiograph to rule out other etiologies.

• An anterior chamber paracentesis or vitreous tap for polymerase chain reaction (PCR) for herpesviruses (VZV, HSV, CMV, EBV) and toxoplasmosis PCR can be performed in atypical cases. Though PCR of ocular fluids can support the clinical diagnosis of ARN, treatment should not be delayed for the results. PCR for VZV or HSV in the aqueous or vitreous humor of suspected ARN is positive in 79-100% of cases.[10]
• Viral titers (VZV, HSV, CMV)
• Intravenous fluorescein angiography can also be considered and may demonstrate the occlusive nature of arthritis.
• Optical coherence tomography of the macula and optic nerve head may be considered and may show cystoid macular edema/ epiretinal membrane or disc edema. 
• Ultrawide field fundus photography (Optos) may document and help in monitoring the progression of the disease.[11][12]
• Ultrasonograms may be helpful to rule out retinal detachment in hazy media.
• If intraocular lymphoma, tertiary syphilis, or encephalitis is suspected, then a CT scan or MRI of the brain and lumbar puncture should be performed.

Treatment / Management

Immediate treatment of the patient is required and can be done in either the inpatient or outpatient setting. The goal is to decrease the incidence in the fellow eye. One study showed that 75% of the patients treated with acyclovir remained disease-free in the fellow eye at 2 years versus 35% of patients not treated with acyclovir.[13] It is important to note, however, that treatment does not reduce the rate of retinal detachment in the first eye.

Acyclovir should be started at 10-13 mg/kg every 8 hours or 1500mg/m2/day intravenously (IV) for 5-10 days.[14] This should be followed by acyclovir 800 mg five times daily orally for 6 weeks to 3 months. In a study, 12 patients with ARN were treated with intravenous[15] acyclovir 1500mg/m2/day, oral aspirin or coumadin, and oral steroids (in 9 patients) after the initiation of acyclovir. The regression of retinitis lesions started at 3.9 days (on average) after starting the IV acyclovir and lesions regressed completely in 32.5 days on average.[15] Though progression was occasionally seen within 48 hours of initiation of therapy, after 48 hours no fresh retinitis lesions or progressive optic nerve involvement was seen.[15] The study also noted that the therapy did not reduce retinal detachment (occurring in 11 of 13 eyes after an average of 59 days of initiation of therapy) or vitritis.[15]

Other options include:

• Valacyclovir can be given 1000-2000 mg orally every 8 hours. This has good bioavailability and avoids the need for intravenous access. 
• Famciclovir should be given at 500 mg orally every 8 hours.
• Valganciclovir started at 900 mg twice daily orally for 3 weeks induction, followed by 900mg once daily orally for maintenance. Valganciclovir has been successfully used for CMV retinitis. It has activity against HSV, VZV, and CMV.

Initial intravenous antiviral or oral antiviral is effective in the treatment of ARN in terms of time taken for regression of retinitis and involvement of the fellow eye.[10]

If there is sight-threatening retinitis or there is the involvement of the optic disc or macula (zone 1), intravitreal injections should be performed. Ganciclovir can be given at 2 mg per 0.1 mL, and foscarnet can be given 1.2 mg to 2.4 mg per 0.1 mL.

Prednisone 0.5-2.0 mg/kg/day orally for up to 6 to 8 weeks should be started 24-48 hours after the start of antiviral therapy or once regression of necrosis is demonstrated on physical exam. Oral steroids should be considered particularly when the optic nerve is involved. A sub-tenon injection of triamcinolone 40 mg/1 mL can be considered after antiviral therapy has been loaded. Periocular or oral steroids should not be started in active retinitis before the initiation of antiviral therapy, as it may worsen the retinitis. 

In the presence of an anterior chamber reaction, topical cycloplegic agents and steroids should be considered. 

The physician may consider antiplatelet therapy (aspirin 81 mg to 650 mg daily) or coumadin to prevent ischemic damage to the optic nerve and retina, though the exact role in ARN is unknown.

Lastly, prophylactic barrier laser photocoagulation posterior to active retinitis may be considered to wall off or prevent subsequent retinal detachment. The laser, if applied should be placed behind the area of active retinitis in the apparently normal retina, as laser directly over the area of retinitis may cause an iatrogenic break. The prophylactic laser may be difficult because of the inflamed painful eye, poor dilation of the pupil, and media haze. The prophylactic laser is controversial and is not always practiced, as it might not prevent the development of retinal detachment in up to 58% of lasered eyes.[10]

Early pars plana vitrectomy before a retinal detachment has been tried in ARN. In a large series of 104 patients,[16] at the final visit, the retina was attached in 28 of 48 eyes (58.3 %) in the (early) vitrectomy group and 42 of 56 eyes (75.0 %) in the observation group at the final visit'. The role of early pars plans vitrectomy before retinal detachment needs further evaluation, and there is no strong evidence that it is helpful in preventing retinal detachment.(B2)

For retinal detachment, early vitreoretinal surgery should be planned. The surgery is difficult due to media haze due to aggressive anterior segment inflammation, cataract, posterior synechia causing a poorly dilating pupil, and extensive vitreous membrane. The breaks are multiple and may be posterior. The proliferative vitreoretinopathy may be severe. Aggressive postoperative inflammation including fibrinous reaction may be noted. Despite retinal reattachment visual gain may be limited by optic atrophy and epiretinal membrane. Proliferative vitreoretinopathy may lead to retinal redetachment after vitreoretinal surgery. In a series of 12 eyes of 10 patients with ARN with retinal detachment that underwent vitrectomy, at final follow up of mean 4.4 years, all cases had successful retinal reattachment.[17] A final visual acuity of better than 20/100 was achieved in only 3 eyes and lack of optic nerve involvement was associated with good visual outcomes.[17] 

Differential Diagnosis

The differential diagnosis includes:

• CMV retinitis- Salient differentiating features include
  • Immunocompromised patient
  • Clear media (minimal or no vitritis)
  • Prominence of hemorrhage
  • Early involvement of posterior pole/arcades though in granular CMV retinitis periphery may be involved early

• Progressive outer retinal necrosis (PORN)- PORN has specific characteristics including
  • Immunocompromised patient
  • No vitritis
  • Outer retinal involvement
  • Posterior pole involved early
  • Minimal retinal hemorrhage
  • Paravascular clear area

• Syphilis
  • Granulomatous inflammation
  • Posterior placoid chorioretinitis
  • Retinal arterial involvement
  • Round vitreous opacities
  • Systemic features of syphilis including skin changes at the palms and feet

• Toxoplasmosis- It is characterized by
  • Intense vitritis
  • Area of focal retinitis visible through vitritis as 'headlight in the fog'
  • Pigmented scar of old retinochoroiditis near the active area of retinitis, however, some cases may not have an adjacent scar
  • In immunocompromised/AIDS, the features may be atypical with multiple lesions, less vitritis, and cerebral involvement. 

• Behcet Disease
  • Most cases will have oral aphthous ulcers
  • Skin and genital lesion
  • Panuveitis
  • Hypopyon
  • Severe media haze/vitritis
  • Vasculitis with few retinal hemorrhages
  • Patches of retinitis
  • HLA-B51
  • Pathergy test may be positive

• Fungal or bacterial Endophthalmitis
  • Pain, redness, lid edema, photophobia may be severe
  • Hypopyon, corneal edema, corneal infection
  • History of previous ocular surgery, or intravenous infusion of drugs, sepsis
  • Discharge from eye
  • Severe visual decline, media haze, with echoes in vitreous with or without choroidal thickening on ultrasound
  • Vitreous tap positive for bacteria or fungus in stain and/or culture

• Panuveitis due to other causes
• Large Cell Lymphoma/Intraocular lymphoma
  • Old age
  • Vitreous opacity with no cystoid macular edema
  • Sheet-like vitreous on slit-lamp examination
  • Subretinal ill-defined orange lesions
  • History of behavioral change
  • The vitreous biopsy may show lymphoma cells, though the yield is typically not great and needs excellent collaboration with the pathologist
  • MRI brain may reveal central nervous system lymphoma

Prognosis

The visual prognosis of ARN is poor and 64% of affected eyes achieve a final acuity of worse than 20/200 due to multiple complications including retinal detachment, optic neuropathy, macular abnormality, and retinal ischemia.[18] Visual outcomes may improve (up to 92% of eyes may achieve at least 20/400, and 46% of eyes may achieve a final vision of at least 20/40) and involvement of fellow eye may reduce with prompt diagnosis and early treatment.[19] A large series noted that zone 1 disease and involvement of the optic disc were associated with a final vision of 20/200 or worse.[16]

Complications

The complications of ARN include:

• Rhegmatogenous retinal detachment, retinal necrotic breaks, proliferative vitreoretinopathy, vitreous traction
• Exudative retinal detachment
• Optic neuropathy
• Retinal ischemia
• Epiretinal membrane
• Cystoid macular edema
• Pigmentary retinopathy after healing of ARN
• Cataract with posterior synechia
• Glaucoma
• Vitreous haze
• Vitreous hemorrhage secondary to retinal and optic disc neovascularization[1]