Acute retinal necrosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Luke Rusowicz-Orazem, B.S.

Acute retinal necrosis is an inflammatory eye condition usually caused by reactivation of latent viruses, including Herpes simplex virus 1 & 2, Varicella-zoster virus, cytomegalovirus, and Epstein-Barr virus. Symptoms include eye pain, vision loss, floaters, flashes, excessive sensitivity to light, flu symptoms, and redness of the affected eye. The pathogenesis of acute retinal necrosis is characterized by retinal inflammation due to ocular viral infection. Particles from Herpes simplex virus 1 (HSV-1), Herpes simplex virus 2 (HSV-2), and Varicella zoster virus (VZV) infiltrate the retina through various locations of epithelial penetration, including the skin, conjunctiva, cornea, and nasal cavity. Acute retinal necrosis may be classified both by staging—acute or late—or by severity: mild or fulminant. The natural progression of ARN depends on whether the case is mild or fulminant. Mild cases of ARN present with white-yellow necrotic lesions that do not coalesce or lead to retinal detachment; the disease is self-limited. Fulminant cases of ARN will lead to progressive necrosis of retinal tissue, leading to pigmentation scarring, vitreous debris, and retinal detachment. Without treatment, ARN will usually progress to bilateral acute retinal necrosis (BARN) within weeks to a few months. With treatment, the prognosis for ARN is good if the therapy is administered early and sustained until symptoms resolve. The mainstays of medical therapy for acute retinal necrosis are regimens of empiric and pathogen-directed antimicrobial therapy. The primary risk factors for acute retinal necrosis include immunocompromised status and immunosuppression from disease and prolonged corticosteroid use.

Acute retinal necrosis was first discovered in 1971 by Urayama A, Yamada N, Sasaki T. Acute retinal necrosis was first officially classified as bilateral acute retinal necrosis in 1978 by N.J. Young and A.C. Bird, applied to 4 cases of bilateral necrotizing retinitis that progressed to retinal detachment and phthisis despite corticosteroid and antibiotic therapy. In the 1980s, emergence of pathological and electron findings from analysis of vitrectomy and enucleation specimens led to the identification of members of the herpes virus family as the cause of acute retinal necrosis. The official diagnostic criteria for acute retinal necrosis was proposed by the American Uveitis Society in 1994.

Acute retinal necrosis may be classified both by staging—acute or late—or by severity: mild or fulminant.

• The pathogenesis of acute retinal necrosis is characterized by retinal inflammation due to ocular viral infection. Particles from Herpes simplex virus 1 (HSV-1), Herpes simplex virus 2 (HSV-2), and Varicella zoster virus (VZV) infiltrate the retina through various locations of epithelial penetration, including the skin, conjunctiva, cornea, and nasal cavity. Acute retinal necrosis develops from HSV-1, HSV-2, and VZV due to the viruses’ ability to transmit and replicate in the central nervous system (CNS), as well as their ability to transport anterograde through the optic nerve, establish latency, reactivate, and cause retinal inflammation.
• For Caucasian populations, possessing the HLA-DQw7, HLA-Bw62, and HLA-DR4 antigens is correlated to a genetic predisposition to ARN. For Japanese populations, possessing the HLA-Aw33, HLA-B44, and HLA-DRw6 antigens is correlated to a genetic predisposition to ARN.
• Acute retinal necrosis is associated with the following ocular conditions: progressive outer retinal necrosis, uveitis, cytomegalovirus retinitis, toxoplasmic chorioretinitis, and endophthalmitis.

Acute retinal necrosis is usually caused by reactivation of latent viruses: Herpes simplex virus 1 & 2, Varicella-zoster virus, cytomegalovirus, and Epstein-Barr virus.

Acute retinal necrosis must be differentiated from other diseases that cause eye pain, conjunctival infection, photophobia, and vision loss.

• The incidence of acute retinal necrosis (ARN) is approximately 6.3 per 100,000 individuals.
• ARN developed from Herpes simplex virus 1 and Varicella-zoster virus is most common among patients older than 50 years, while the incidence of HSV-2 caused ARN is highest in children and young adults between age 9 and 22 years.
• There is no racial or gender predisposition to acute retinal necrosis.

The primary risk factors for acute retinal necrosis include immunocompromised status and immunosuppression from disease and prolonged corticosteroid use. Genetic predisposition for certain Caucasian and Japanese populations heightens the possibility of developing ARN.

There is no established, diagnostic screening process for acute retinal necrosis.

• Symptoms of acute retinal necrosis (ARN) develop rapidly upon onset of pathogenic infection.
• The natural progression of ARN depends on whether the case is mild or fulminant.
  • Mild cases of ARN presents with white-yellow necrotic lesions that do not coalesce or lead to retinal detachment; the disease is self-limited.
  • Fulminant cases of ARN will lead to progressive necrosis of retinal tissue, leading to pigmentation scarring, vitreous debris, and retinal detachment.
• Without treatment, ARN will usually progress to bilateral acute retinal necrosis (BARN) within weeks to a few months. Complications resulting from acute retinal necrosis occur due to retinal tissue damage and subsequent infection from the causative pathogen.
• Without treatment, the prognosis for acute retinal necrosis (ARN) varies.
  • Mild ARN is usually self-limited and will resolve itself without treatment; risk of permanent vision loss is very low.
  • Fulminant ARN will usually progress to complications such as progressive outer retinal necrosis and has a worse prognosis.
• With treatment, the prognosis for ARN is good if the therapy is started early and sustained until symptoms resolve.

The American Uveitis Society determined five diagnostic criteria for acute retinal necrosis in 1994.

Patient history of prior or concurrent diseases, particularly those associated with acute retinal necrosis pathogens or sources of immunocompromised status, should be considered in the diagnosis of ARN.

Symptoms of acute retinal necrosis include:

• eye pain
• vision loss
• floaters
• flashes
• excessive sensitivity to light
• flu-like symptoms
• redness of the affected eye

Physical examination of patients with acute retinal necrosis may reveal erythema and hyperaemia of the retina, white-yellow necrotic lesions, purulent exudate, opaque vitreous, and other indications of inflammation in the eye.

Laboratory findings consistent with a diagnosis of acute retinal necrosis are those used to determine the presence of the viral pathogen, including PCR test results, viral cultures, immunoflourescence results, and detection of antibodies indicative of sources of ARN via the Goldmann-Witmer coefficient.

There are no diagnostic electrocardiogram findings associated with acute retinal necrosis.

There are no diagnostic chest x ray findings associated with acute retinal necrosis.

CT imaging may reveal indicators of inflammation and infection by the causative pathogen for acute retinal necrosis, including hypoattenuation along the optic tract—indicative of Varicella-zoster virus (VZV) infection—and hyperattenuation along the optic tract, retina, sclerae, and lateral geniculate body.

MRI imaging may reveal lesions indicative of infection from acute retinal necrosis pathogens.

There are no diagnostic echocardiography or ultrasound findings associated with acute retinal necrosis.

Other imaging findings that may be helpful in the diagonsis of acute retinal necrosis include fundus autofluorescence (FAF), fluorescein angiography, and optical coherence tomography.

There are no other diagnostic studies associated with acute retinal necrosis.

The mainstays of medical therapy for acute retinal necrosis are regimens of empiric and pathogen-directed antimicrobial therapy.

Surgery is not the first-line treatment option for patients with acute retinal necrosis; it is indicated primarily when there is a substantial risk of complications, including retinal detachment and tissue atrophy.

Preventing the onset of acute retinal necrosis is dependent upon preventing the causative infection from Herpes simplex virus (HSV), Varicella-zoster virus (VZV), Cytomegalovirus (CMV), and Epstein-Barr virus (EBV).

While recurrence of acute retinal necrosis is not completely preventable at present, the administration of topical and intravitreal antiviral therapy targeted to the specific cause of the disease can reduce the chance of recurrence.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Luke Rusowicz-Orazem, B.S.

Acute retinal necrosis was first discovered in 1971 by Urayama A, Yamada N, and Sasaki T. Acute retinal necrosis was first officially classified as bilateral acute retinal necrosis in 1978 by N.J. Young and A.C. Bird, applied to 4 cases of bilateral necrotizing retinitis that progressed to retinal detachment and phthisis despite corticosteroid and antibiotic therapy. In the 1980s, emergence of pathological and electron findings from analysis of vitrectomy and enucleation specimens led to the identification of members of the herpes virus family as the cause of acute retinal necrosis. The official diagnostic criteria for acute retinal necrosis was proposed by the American Uveitis Society in 1994.

• Acute retinal necrosis was first discovered in 1971 by Urayama A, Yamada N, and Sasaki T.^[1]
• Acute retinal necrosis was first officially classified as bilateral acute retinal necrosis in 1978 by N.J. Young and A.C. Bird.^[2]
  • The classification was applied to 4 cases of bilateral necrotizing retinitis, in which the patients developed bilateral confluent retinitis progressing to retinal detachment and phthisis despite corticosteroid and antibiotic therapy.^[1]
• The first extension of the classification of acute retinal necrosis to unilateral cases was given in 1983 by Hayasaka S. et al.^[3]
  • They showed that cases of bilateral acute retinal necrosis and cases of Kirisawa-type uveitis presented nearly identical characteristics:^[4][2]
    • Periarteritis
    • Opaque, dense vitreous
    • Peripheral retinal exudates
    • Retinal detachment
    • Vision loss
    • Resistance to antibiotic therapy
    • Negative test results for bacterial infection
• In the 1980s, emergence of pathological and electron findings from analysis of vitrectomy and enucleation specimens led to the identification of members of the herpes virus family as the cause of acute retinal necrosis.
• The official diagnostic criteria for acute retinal necrosis was proposed by the American Uveitis Society in 1994.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Luke Rusowicz-Orazem, B.S.

Acute retinal necrosis may be classified both by duration of symptoms into acute or late, or by severity: mild or fulminant.

• Acute retinal necrosis (ARN) may be classified by duration of symptoms as follows:^[1]
  • Acute stage: Occurs at onset of disease and usually progresses past acute classification after a few weeks
    • Presents with coalescence of white, necrotic tissue in the peripheral retina
    • Vaso-occlusive retinal vasculitis is usually present
    • Optic nerve head of the affected eye will appear swollen, but the posterior pole will usually not be affected
  • Late stage: Is the natural progression of the disease and will present differentiating characteristics after a few weeks up to a few months
    • Characterized by a regression of the coalesced necrosis in the peripheral retina, presenting starkly contrasted necrotic/non-necrotic tissue, mild pigmentation scarring, and increased vitreous debris
    • Retinal detachment, severe vision loss, and potentially blindness in the affected eye
    • If the infection is bilateral, the second eye will usually present signs of ARN in the weeks and months following the initial symptom manifestation in the first eye
• Acute retinal necrosis can also be classified by severity as follows:^[2]
  • Mild: Used to characterize ARN that is stable and non-progressive
    • There is usually no sign of retinal detachment.
  • Fulminant: ARN that is progressive and will usually lead to retinal detachment and further complications if left untreated

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Luke Rusowicz-Orazem, B.S.

The pathogenesis of acute retinal necrosis is characterized by retinal inflammation due to ocular viral infection. Particles from Herpes simplex virus 1 (HSV-1), Herpes simplex virus 2 (HSV-2), and Varicella zoster virus (VZV) infiltrate the retina through various locations of epithelial penetration, including the skin, conjunctiva, cornea, and nasal cavity. Acute retinal necrosis develops from HSV-1, HSV-2, and VZV due to the viruses’ ability to transmit and replicate in the central nervous system (CNS), as well as their ability to transport anterograde through the optic nerve, establish latency, reactivate, and cause retinal inflammation. For Caucasian populations, possessing the HLA-DQw7, HLA-Bw62, and HLA-DR4 antigens is correlated to genetic predisposition to ARN. For Japanese populations, possessing the HLA-Aw33, HLA-B44, and HLA-DRw6 antigens is correlated to genetic predisposition to ARN. Acute retinal necrosis is associated with the following ocular conditions: progressive outer retinal necrosis, uveitis, cytomegalovirus retinitis, toxoplasmic chorioretinitis, and endophthalmitis.

The pathogenesis of acute retinal necrosis is characterized by retinal inflammation due to ocular viral infection.^[1] Particles from Herpes simplex virus 1 (HSV-1), Herpes simplex virus 2 (HSV-2), and Varicella zoster virus (VZV) infiltrate the retina via various modes of transmission:^[2]

• Epithelial penetration of the skin: transmitted through the ophthalmic branch of the trigeminal nerve.
• Epithelial penetration of the conjunctiva: transmitted directly through the optic nerve.
• Epithelial penetration of the cornea: transmitted through the maxillary branch of the trigeminal nerve.
• Epithelial penetration of the nasal cavity: transmitted through the olfactory nerve in the subarachnoid space.
• Acute retinal necrosis develops from HSV-1 and HSV-2 due to the viruses’ ability to transmit and replicate in the central nervous system (CNS), as well as their ability to transport anterograde through the optic nerve, establish latency, reactivate, and cause retinal inflammation.^[3]
• Retinal inflammation is caused by the up-regulated production of cytokines.

There is evidence of genetic predisposition to acute retinal necrosis:

• For Caucasian populations: possessing the HLA-DQw7, HLA-Bw62, and HLA-DR4 antigens is correlated with genetic predisposition to ARN.^[4]
• For Japanese populations: possessing the HLA-Aw33, HLA-B44, and HLA-DRw6 antigens is correlated to genetic predisposition to ARN.^[5]

Possession of the above antigens in their respective demographics are correlated to impaired immunity and increased predisposition to infection.

Acute retinal necrosis is associated with the following ocular conditions:

• Progressive outer retinal necrosis^[6]
• Uveitis^[7]
• Cytomegalovirus retinitis^[8]
• Toxoplasmic chorioretinitis^[9]
• Endophthalmitis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Luke Rusowicz-Orazem, B.S.

Acute retinal necrosis is usually caused by reactivation of latent viruses, including Herpes simplex virus 1 & 2, Varicella-zoster virus, cytomegalovirus, and Epstein-Barr virus.

Acute retinal necrosis (ARN) is usually caused by the reactivation of the following pathogenic viruses in the Herpesviridae family:^{[1][2][3][4][5][6]}

• Herpes simplex virus 1 (HSV-1)
• Herpes simplex virus 2 (HSV-2)
• Varicella-zoster virus (VZV)
• Less commonly, ARN can be caused by Epstein-Barr virus and cytomegalovirus.^[5][7][8]
• VZV and HSV-1 are usually the causes of ARN in individuals older than 25 years.
• The majority of the ARN cases for individuals older than 50 years are caused by VZV and HSV-1.^[9]

HSV-2 is usually the cause of ARN in individuals younger than 25 years.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Luke Rusowicz-Orazem, B.S.

Acute retinal necrosis must be differentiated from other diseases that cause eye pain, conjunctival infection, photophobia, and vision loss.

Acute retinal necrosis must be differentiated from other diseases that cause eye pain, conjunctival infection, photophobia, and vision loss. Accurate and prompt diagnosis is critical to prevent blindness and other complications. Differentiating acute retinal necrosis from other diseases is crucial due to varying etiologies of ocular diseases, particularly to ensure the best prognosis by applying the proper therapy. Specific diseases from which ARN must be differentiated include:^{[1][2][3][4][5][6]}

• Progressive outer retinal necrosis^[7]
• Uveitis^[8]
• Endophthalmitis
• Toxoplasma chorioretinitis^[1]
• Cytomegalovirus retinitis^[9]
• Conjunctivitis
• Scleritis
• Corneal abrasion
• Glaucoma
• Corneal ulcer
• Retinal vasculitis^[10]
• Acute papillitis^[11]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Luke Rusowicz-Orazem, B.S.

The estimated incidence of acute retinal necrosis (ARN) is approximately 6.3 per 100,000 individuals. ARN that has developed from Herpes simplex virus 1 or Varicella-zoster virus is most common among patients older than 50 years, while the incidence of HSV-2 caused ARN is highest in children and young adults between age 9 and 22 years. There is no racial or gender predisposition to acute retinal necrosis.

• The estimated incidence of ARN is approximately 6.3 per 100,000 individuals.
• Worldwide, the increase in immunocompromised and aged populations in most countries has been correlated with an increase in the incidence of acute retinal necrosis.^[1]
• There is evidence that this incidence is underestimated due to biases in case adjudication and under-reporting of data.^{[2][3][4][5][6]}

• Acute retinal necrosis (ARN) developed from Herpes simplex virus 1 and Varicella-zoster virus is most common among patients older than 50 years.^[7]
• Herpes simplex virus (HSV) 2 infection is more common among children and adolescents; the incidence of HSV-2-caused ARN is highest in children and young adults between age 9 and 22 years.

There is no gender predisposition to acute retinal necrosis.

There is no racial predisposition to acute retinal necrosis.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Luke Rusowicz-Orazem, B.S.

The primary risk factors for acute retinal necrosis include immunocompromised status and immunosuppression from disease and prolonged corticosteroid use. Genetic predisposition for certain Caucasian and Japanese populations can increase one’s odds of developing acute retinal necrosis.

Risk factors for the development of acute retinal necrosis (ARN) include:^[1]

• For Caucasian populations: possessing the HLA-DQw7, HLA-Bw62, and HLA-DR4 antigens^[2]
• For Japanese populations: possessing the HLA-Aw33, HLA-B44, and HLA-DRw6 antigens^[3]
• Experiencing encephalitis from herpes simplex virus^[4]
• Immunocompromised status from prior or concurrent disease^[5]
• Immunosuppresion from extended corticosteroid therapy^[6]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Luke Rusowicz-Orazem, B.S.

There is no established, diagnostic screening process for acute retinal necrosis.

There is no established, diagnostic screening process for acute retinal necrosis.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Luke Rusowicz-Orazem, B.S.

Symptoms of acute retinal necrosis (ARN) develop rapidly upon the onset of pathogenic infection. The natural progression of ARN depends on whether a case is mild or fulminant. Mild cases of ARN presents with white-yellow necrotic lesions that do not coalesce or lead to retinal detachment; the disease is self-limited. Fulminant cases of ARN will lead to progressive necrosis of retinal tissue, causing pigmentation scarring, vitreous debris, and retinal detachment. Without treatment, ARN will usually progress to bilateral acute retinal necrosis (BARN) within weeks to a few months. Complications resulting from acute retinal necrosis occur due to retinal tissue damage and subsequent infection from the causative pathogen. Without treatment, the prognosis for acute retinal necrosis (ARN) varies. Mild ARN is usually self-limited and will resolve itself without treatment; risk of permanent vision loss is very low. Fulminant ARN will usually progress to complications such as progressive outer retinal necrosis, and therefore carries a worse prognosis. With treatment, the prognosis for ARN is good if the appropriate therapy is administered in the early stages and sustained until symptoms resolve.

Symptoms of acute retinal necrosis (ARN) develop rapidly from inflammatory response to the onset of pathogenic infection.^[1]

• Initial signs and symptoms include conjunctivitis, vision loss, photophobia, and eye pain and pressure.

The natural progression of ARN depends on whether the case is mild or fulminant.

• Mild cases of ARN presents with white-yellow necrotic lesions that do not coalesce or lead to retinal detachment; the disease is self-limited.^[2]
• Fulminant cases of ARN will lead to progressive necrosis of retinal tissue, causing pigmentation scarring, vitreous debris, and retinal detachment. Fulminant ARN has a much greater chance of blindness in the affected eye.

Without treatment, ARN will usually progress to bilateral acute retinal necrosis (BARN) within weeks to a few months.^[3]

• There have been exceptions in which the disease spread from the affected to the previously unaffected eye up to 17 years after the initial diagnosis of ARN, due to reactivation of latent viral infection.^[4]

Complications resulting from acute retinal necrosis occur due to retinal tissue damage and subsequent infection from the causative pathogen, including the following:^[1][5]

• Retinal detachment
• Neurological conditions (e.g., encephalitis, meningitis)^[6]
• Optic neuropathy
• Occlusive retinal vasculopathy
• Proliferative vitreoretinopathy^[7]
• Macular pucker^[8]
• Vitreous hemorrhage
• Neovascularization^[9]
• Phthisis bulbi^[9]

Without treatment, the prognosis for acute retinal necrosis (ARN) varies:^[1]

• Mild ARN: Usually self-limited and will resolve itself without treatment; risk of permanent vision loss is very low.
• Fulminant ARN: Will usually progress to complications such as progressive outer retinal necrosis and has a worse prognosis.
  • Retinal detachment will usually occur without treatment, leading to permanent vision loss.
  • Spread of infection through the anterior chamber to the brain has a particularly poor prognosis if encephalitis or meningitis develops.

With treatment, the prognosis for ARN is good if the therapy is administered in the early stages and sustained until symptoms resolve.

• Uncommonly, prognosis can worsen if the patient is immunocompromised and experiences a subsequent infection due to vulnerability from prolonged topical corticosteroid use.

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