Progressive outer retinal necrosis
Synonyms and keywords: PORN syndrome

# Overview
Progressive outer retinal necrosis, also known as PORN syndrome, is a form of necrotizing retinitis that primarily affects severely immunocompromised individuals.  It is primarily caused by Varicella zoster virus infection, most commonly manifesting in patients who have AIDs or are undergoing chemotherapy.  Symptoms of PORN syndrome primarily include vision lossprogressing to blindness if untreatedas well as other visual symptoms such as floaters and flashes. The clinical presentation of progressive outer retinal necrosis includes white-yellow necrotic lesions that coalesce to form a single film, as well as opacification of the retina and abnormal pigmentation. Unlike the associated condition acute retinal necrosis, PORN syndrome does not usually manifest with anterior chamber or vitreous inflammation, nor do patients usually experience eye pain. It is important to differentiate PORN syndrome from other ocular conditions to prevent complications, including blindness, retinal detachment, and cataracts. If left untreated, the prognosis of PORN syndrome for visual acuity is poor: approximately 67% of cases will lead to blindness in the affected eye (and 61% cases of PORN syndrome will spread to the previously unaffected eye).  Medical therapy should be started as early as possible to stop the progression of symptoms.  The mainstay of therapy is intravenous antimicrobial therapy, usually a combination of Ganciclovir and Foscarnet.  Individual uses of the two therapies, in addition to Ancyclovir, may be indicated for less severe cases.

# Historical Perspective
- In 1987, a clinical presentation of necrotizing retinitis occurring specifically in immunocompromised individuals was first documented by Jabs DA et al.
- In 1990, progressive outer retinal necrosis (PORN) was first identified by Forster, DJ et al. 
It was identified and differentiated from acute retinal necrosis by its rapid progression, unresponsiveness to antiviral therapy (acyclovir), and resultant retinal detachment.
A study of two HIV-positive individuals led to the identification of Varicella-zoster infection as the cause of PORN
Immunocompromised status was recognized as an important means of differentiating PORN patients from acute retinal necrosis patients
- It was identified and differentiated from acute retinal necrosis by its rapid progression, unresponsiveness to antiviral therapy (acyclovir), and resultant retinal detachment.
- A study of two HIV-positive individuals led to the identification of Varicella-zoster infection as the cause of PORN
- Immunocompromised status was recognized as an important means of differentiating PORN patients from acute retinal necrosis patients

# Classification
There is no official classification schema for progressive outer retinal necrosis.

# Pathophysiology

## Pathogenesis
The pathogenesis of progressive outer retinal necrosis (PORN) is characterized by retinal necrosis due to ocular viral infection.
Viral particles infiltrate the retina via various modes of transmission:
- 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
Retinal inflammation is caused by the up-regulated production of cytokines.
- Retinal necrosis occurs due to the vascular occlusion resulting in white-yellow necrotic lesions that begin in the outer layers of the retina, coalesce, and spread inward without intervention.

## Associated Conditions
Progressive outer retinal necrosis is associated with the following ocular conditions:
- Acute retinal necrosis
Uveitis
- Uveitis
- Cytomegalovirus retinitis
- Toxoplasmic chorioretinitis
- Endophthalmitis
PORN is often associated with AIDS as a complication of immunocompromised status.

# Causes
Progressive outer retinal necrosis (PORN) is primarily caused by Varicella zoster virus (VZV), and is less commonly caused by Cytomegalovirus (CMV), Herpes simplex virus 1, and rarely BK Virus. PORN usually appears in immunocompromised individuals, usually as a complication of diseases such as AIDS or from chemotherapy.

## Viral
- Varicella zoster virus
- Cytomegalovirus
- Herpes simplex virus 1 (HSV-1)
- BK Virus

# Differentiating Progressive outer retinal necrosis from Other Diseases
- Progressive outer retinal necrosis (PORN) 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.
Acute retinal necrosis
Uveitis
Uveitis
Endophthalmitis
Toxoplasma chorioretinitis
Cytomegalovirus retinitis
Conjunctivitis
Scleritis
Corneal abrasion
Glaucoma
Corneal ulcer
Retinal vasculitis
- Acute retinal necrosis
- Uveitis
- Uveitis
- Endophthalmitis
- Toxoplasma chorioretinitis
- Cytomegalovirus retinitis
- Conjunctivitis
- Scleritis
- Corneal abrasion
- Glaucoma
- Corneal ulcer
- Retinal vasculitis
- PORN is differentiated from acute retinal necrosis by its occurrence primarily in immunocompromised individuals; acute retinal necrosis will also develop in immunocompetent individuals.

# Epidemiology and Demographics
Epidemiological and demographic data for progressive outer retinal necrosis (PORN) are closely tied to that of AIDS, of which PORN is often a complication.

## Gender
- Females are more likely than males to develop progressive outer retinal necrosis.

## Age
- Progressive outer retinal necrosis occurs more frequently in individuals over the age of 35.

## Developing countries
- Incidences of PORN are higher in developing countries, particularly those in Africa, due to the higher local prevalence of AIDS.

# Risk Factors
Risk factors for progressive outer retinal necrosis include the following:
- Immunocompromised status from prior or concurrent disease, particularly AIDS
- Immunosuppresion from extended corticosteroid use or chemotherapy
- Being female
- Being older than 35 years

# Screening
There is no established, diagnostic screening procedure for progressive outer retinal necrosis.

# Natural History, Complications, and Prognosis

## Natural History
- Early clinical findings of progressive outer retinal necrosis (PORN) include white-yellow necrotic peripheral and macular retinal lesions, as well as opacification of non-necrotic tissue, indicative of the onset of disease.
- Without treatment, the necrotic lesions will rapidly coalesce into a unified film, progressing to complete retinal necrosis.
- Complete retinal detachment will usually occur between 30 days and 3 months after onset.
Blindness usually follows between 4 weeks and 6 months after the PORN diagnosis.
- Blindness usually follows between 4 weeks and 6 months after the PORN diagnosis.
- PORN will usually spread to the previously unaffected eye within 4 weeks.

## Complications
The following complications of progressive outer retinal necrosis occur, if left untreated, from complete retinal necrosis:
- Retinal detachment
- Cataracts
- Retinal atrophy
- Permanent vision loss and blindness
- Pigmentation scarring

## Prognosis
- Without treatment, the prognosis for vision acuity in the affected eyes is poor and it is highly likely that it will become bilateral.
Approximately 67% of progressive outer retinal necrosis cases will progress to blindness if left untreated.
Approximately 70% of progressive outer retinal necrosis cases will progress to retinal detachment.
Approximately 61% of progressive outer retinal necrosis cases will become bilateral.
- Approximately 67% of progressive outer retinal necrosis cases will progress to blindness if left untreated.
- Approximately 70% of progressive outer retinal necrosis cases will progress to retinal detachment.
- Approximately 61% of progressive outer retinal necrosis cases will become bilateral.
- With treatment, the prognosis varies:
Foscarnet and ganciclovir antiviral intravenous therapy can improve the prognosis if administered during the early stages of the disease.
Approximately 45% of eyes treated with antiviral therapy will resolve at a visual acuity of 20/80 or better.
Vitrectomy can successfully prevent retinal detachment.
- Foscarnet and ganciclovir antiviral intravenous therapy can improve the prognosis if administered during the early stages of the disease.
Approximately 45% of eyes treated with antiviral therapy will resolve at a visual acuity of 20/80 or better.
- Approximately 45% of eyes treated with antiviral therapy will resolve at a visual acuity of 20/80 or better.
- Vitrectomy can successfully prevent retinal detachment.

# Diagnosis

## Diagnostic Criteria
The following standardized criteria are used to officially diagnose progessive outer retinal necrosis:
- Presence of multifocal lesions without granular borders in the deep retinal layers
- Evidence that the infection started in the peripheral retina with or without focal involvement
- Extremely rapid progression
- Presence of minimal intraocular infection

## History and Symptoms

### History
A history of immunocompromising disease and/or therapy may be present in progressive outer retinal necrosis patients, particularly the following:
- AIDS
- Diabetes mellitus
- Chemotherapy

### Symptoms
Symptoms of progressive outer retinal necrosis include the following:
- Blurred vision
- Loss of peripheral vision
- Blindness
- Floaters
- Flashes

## Physical Examination
Physical examination for progressive outer retinal necrosis may be remarkable for the following:
- White-yellow necrotic peripheral and macular retinal lesions, coalescing to form a single film
The fovea is a point of convergence and is usually starkly contrasted in redness
- The fovea is a point of convergence and is usually starkly contrasted in redness
- Deep opacification of the peripheral retina
- Abnormal retinal pigmentation
- Absence or minimal presence of anterior chamber or vitreous inflammation, as well as absence of scleritis
This is an important for differentiating progressive outer retinal necrosis from acute retinal necrosis
- This is an important for differentiating progressive outer retinal necrosis from acute retinal necrosis

## Laboratory Findings
Laboratory findings associated with progressive outer retinal necrosis (PORN) are those used to confirm the Varicella zoster virus (VZV) infection, obtained from aqueous humor or the vitreous. Useful laboratory techniques may include:
- Qualitative and real-time polymerase chain reaction may produce genomic evidence of VZV infection with high specificity
- Viral cultures may reveal evidence of VZV infection indicative of PORN
Retinochoroidal biopsy may be performed to obtain a culture sample, in addition to direct sampling from the aqueous humor
Diagnosis via viral culture alone is not recommended due to the low specificity and sensitivity (53.7% and 46.3%, respectively), indicating a high chance of obtaining a false-negative.
- Retinochoroidal biopsy may be performed to obtain a culture sample, in addition to direct sampling from the aqueous humor
- Diagnosis via viral culture alone is not recommended due to the low specificity and sensitivity (53.7% and 46.3%, respectively), indicating a high chance of obtaining a false-negative.
- Immunofluorescence may reveal antibodies indicative of VZV infection
- Detection of indicative Varicella zoster virus antibodies via Goldmann-Witmer coefficient

## Imaging Findings
- Ophthalmoscopy is the imaging modality of choice for progressive outer retinal necrosis and is characterized by the following findings:
Retinal opacity
Superficial retinal hemorrhage
Optic disk swelling
Vitritis
Retinal and choroidal detachment
White-yellow, multifocal retinal lesions with "cherry red spot" central macula
Absence of vitreous or anterior chamber inflammation, which is important in differentiating PORN from acute retinal necrosis
- Retinal opacity
- Superficial retinal hemorrhage
- Optic disk swelling
- Vitritis
- Retinal and choroidal detachment
- White-yellow, multifocal retinal lesions with "cherry red spot" central macula
- Absence of vitreous or anterior chamber inflammation, which is important in differentiating PORN from acute retinal necrosis
- Fundus autofluorescence may present with the following findings, indicative of progressive outer retinal necrosis:
Hyper- and hypo-fluorescence of the retina from visible tissue degradation from the accumulation of lipofuscin
The changes are indicative of photoreceptor death and inflammatory tissue
- Hyper- and hypo-fluorescence of the retina from visible tissue degradation from the accumulation of lipofuscin
The changes are indicative of photoreceptor death and inflammatory tissue
- The changes are indicative of photoreceptor death and inflammatory tissue
- Optical coherence tomography may present with the following findings:
Thickened retinal opacification
Lower reflectivity and disorganization of the outer retina, displaying signs of inflammation and degradation
- Thickened retinal opacification
- Lower reflectivity and disorganization of the outer retina, displaying signs of inflammation and degradation

## Other Diagnostic Studies
There are no other diagnostic studies associated with progressive outer retinal necrosis.

# Treatment

## Medical Therapy
The mainstay of therapy for progressive outer retinal necrosis (PORN) is Highly Active Anti-Retroviral Therapy (HAART), consisting of the following regimens:
- Empiric antimicrobrial therapy
Preferred regimen: Ganciclovir 5mg/kg IV q24h AND Foscarnet 90-120mg/kg IV q24h
Alternative regimen (1): Ganciclovir 5mg/kg IV q12h for 1-2 weeks, followed by Ganciclovir 5mg/kg IV q24h OR Foscarnet 60 mg/kg q8h for 2 weeks, then 90-120 mg/kg q24h
Alternative regimen (2): Acyclovir 15 mg/kg IV q8h OR Acyclovir 15 mg/kg IV q8h
- Preferred regimen: Ganciclovir 5mg/kg IV q24h AND Foscarnet 90-120mg/kg IV q24h
- Alternative regimen (1): Ganciclovir 5mg/kg IV q12h for 1-2 weeks, followed by Ganciclovir 5mg/kg IV q24h OR Foscarnet 60 mg/kg q8h for 2 weeks, then 90-120 mg/kg q24h
- Alternative regimen (2): Acyclovir 15 mg/kg IV q8h OR Acyclovir 15 mg/kg IV q8h
- Note: The combination antimicrobial therapy of Ganciclovir and Foscarnet is recommended as the most effective treatment regiment for halting the progression of PORN. Single antimicrobrial therapy is not usually recommended.

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

## Vitrectomy
- Vitrectomy may be indicated both before and after occurrence of retinal detachment to improve visual prognosis.
Prophylactic vitrectomy can be effective in removing inflammation factors and preventing retinal detachment by removing or preventing the spread of pre-existing lesions and necrotic tissue.
Remedial vitrectomy in patients experiencing retinal detachment can lead to improved visual prognosis by retinal reattachment.
- Prophylactic vitrectomy can be effective in removing inflammation factors and preventing retinal detachment by removing or preventing the spread of pre-existing lesions and necrotic tissue.
- Remedial vitrectomy in patients experiencing retinal detachment can lead to improved visual prognosis by retinal reattachment.

## Prophylactic Laser Retinopexy
- Prophylactic laser retinopexy may be indicated to prevent retinal detachment by photocoagulation, creating posterior chorioretinal adhesions.
The procedure is contraindicated if there is vitreous inflammation or obstructed view of and access to the posterior pole.
- The procedure is contraindicated if there is vitreous inflammation or obstructed view of and access to the posterior pole.
- Due to reported occurrences of retinal detachment from prophylactic laser photocoagulation, more research is necessary to determine the ideal indications for the procedure.
If performed on patients with excessive inflammation and vitreous opacity, there is evidence of photocoagulation worsening prognosis of Progressive outer retinal necrosis, leading to retinal detachment and blindness.
- If performed on patients with excessive inflammation and vitreous opacity, there is evidence of photocoagulation worsening prognosis of Progressive outer retinal necrosis, leading to retinal detachment and blindness.

## Prevention
Effective measures for the prevention of progressive outer retinal necrosis include the following:
- Avoiding proximity to individuals infected with Varicella zoster virus (VZV) to avoid fluid contact and contact with pathogenic respiratory droplets
- Preventative measures to avoid HIV infection and other infectious sources of immunocompromised status

# Source
American Academy of Ophthalmology