Autoimmune-Related Retinopathy and Optic Neuropathy (ARRON)

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Article initiated by:

Andrew Go Lee, MD, Peter W. Mortensen, MD, Subahari Raviskanthan, MBBS, Vivian Paraskevi Douglas, MD, DVM, MBA, Seth E. Buscho, BS

All contributors:

Nagham Al-Zubidi, MD, Subahari Raviskanthan, MBBS, Pamela Davila-Siliezar, MD

Assigned editor:

Nagham Al-Zubidi, MD

Review:

Assigned status Up to Date

 by Nagham Al-Zubidi, MD on October 8, 2024.

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Clinicians should consider ARRON in patients with unexplained optic neuropathy and retinopathy. Laboratory studies for alternative etiologies should be performed prior to consideration of ARRON. Electrophysiologic studies (e.g., ERG or mERG) are helpful in defining the presence of retinopathy in addition to optic neuropathy in ARRON. Initial ophthalmoscopic findings may be normal or minimal and nonspecific. A thorough search for neoplasm to exclude paraneoplastic disease is recommended in patients with suspected ARRON as the clinical presentations may be indistinguishable. Serum antibodies against retina and optic nerve antigens may be helpful in making the diagnosis but the pathogenic versus epiphenomenon nature of these antibodies remains debated. Immunosuppressive therapy and IVIG or PLEX have been used to treat ARRON with variable and anecdotal success.

Disease Entity

Autoimmune-Related Retinopathy and Optic Neuropathy (ARRON) is a rare, autoimmune, ophthalmic disorder characterized by painless, typically bilateral, vision loss and evidence clinically for both retinopathy and optic neuropathy. In contrast to paraneoplastic retinopathy and optic neuropathy, there is no evidence for a neoplastic process but similar to paraneoplastic disease there are serum antibodies present against retina and optic nerve antigens. ARRON is a disease of exclusion and requires appropriate workup of other causes of neuropathy/retinopathy (especially paraneoplastic disease). Autoimmune retinopathy (AIR) and non-paraneoplastic autoimmune retinopathy or optic neuropathy are other terms to describe the same or similar conditions.

Epidemiology

Due to the rarity of this disease the true incidence and prevalence are unknown. Keltner et al described 12 patients with ARRON and in their series the disorder was more common in women than in men with a mean age of presentation is 50 years (range: 37-75 years).

Pathophysiology

The pathophysiological mechanisms of ARRON remain ill defined but autoantibodies against optic nerve and/or retina have been presumed to be pathogenic in ARRON. Alternatively however these autoantibodies could represent an epiphenomenon of the underlying process or normal immune response after exposure to previously immune privileged sites such as the retina. Although autoantibodies are present in both ARRON and paraneoplastic retinopathy and optic neuropathy, some retinal antigens (e.g., 23kDa retinal antigen, recoverin) are more likely to be due to malignancy. Ferreyra et al reported that other autoimmune disorders and family history of autoimmune disease were more common in ARRON (e.g., systemic lupus erythematosus, Crohn disease, asthma and multiple sclerosis).

Clinical presentation

Patients with ARRON typically present with features suggestive of both retinopathy and optic neuropathy (e.g., visual acuity or visual field loss, relative afferent pupillary defect, and optic atrophy). The history in ARRON should include questions regarding prior malignancy and autoimmune comorbidities. Patients with ARRON commonly present with bilateral subacute painless and often asymmetric vision loss with features of both retinopathy and neuropathy. These can include photopsias or other positive visual phenomenon, nyctanopia (night blindness) or hemeranopia (day blindness), visual field defects (e.g., central, paracentral and midperipheral scotomas), dyschromatopsia, and photosensitivity. Presentation is often delayed due to the insidious progression of symptoms. Photopsias, nyctanopia or hemeranopia, and visual loss however are features common to both ARRON and paraneoplastic conditions including cancer associated retinopathy (CAR) or melanoma associated retinopathy (MAR).

On examination, the best corrected visual acuity may range from 20/20 to no light perception. There may be a relative afferent pupillary defect (RAPD) if there is unilateral (rare) or bilateral but asymmetric disease. Any visual field deficit should be confirmed with automated perimetry. Slit lamp biomicroscopy should be performed to look for anterior or posterior uveitis. On dilated fundus examination, optic disc pallor may be seen, as well as non-specific retinal or retinal pigment epithelial changes. Cystoid macular edema may also be present.

Investigations / Workup

Electroretinography (ERG) abnormalities may be seen on both full field (diffuse) and multifocal (central) ERG confirming a retinopathy but the ERG features are not specific for ARRON. These ERG findings may be similar to those seen in CAR (diffuse reduction) or MAR (loss of ERG b wave) patients, and can include abnormalities in dark adapted, light adapted and bipolar cell responses. Optical coherence tomography (OCT) can also aid in the evaluation of optic nerve and retina pathology. Again, these findings are not specific for ARRON compared with MAR and CAR.

In cases of vision loss without clear cause, especially where there are features of unexplained optic neuropathy, imaging of the brain, typically with magnetic resonance imaging of the brain and orbits with gadolinium contrast, may assist in ruling out compressive lesions/other etiologies.

Laboratory workup for infectious, inflammatory, and neoplastic etiologies should be considered as well as the paraneoplastic and autoimmune retinopathy and optic neuropathy panels. Detection of antibodies against recoverin protein, which is found in the photoreceptors, as well as against α-enolase, Muller cells, glutamic acid decarboxylase (GAD) in serum have been reported in cases of presumed ARRON.

Consideration of malignancy screening may also be appropriate.While CAR and MAR are rare paraneoplastic retinopathies, one should always consider them in the differential diagnosis. It has been shown that in about half of patients diagnosed with CAR the visual symptoms precede the diagnosis of an underlying neoplastic process with small-cell lung carcinoma, breast, ovarian, cervical and endometrial malignancies being the most common. Patients with MAR typically already have an established diagnosis of melanoma - the vast majority of cases are cutaneous melanoma. In terms of gender predilection, it has been suggested that there is a female predilection for CAR and ARRON while males are more likely to be affected by MAR.

Diagnosis

In an effort to better define and support a diagnosis of ARRON, Oyama et al. published suggestive diagnostic criteria in 2009.

Table - Suggested diagnostic criteria for ARRON
All the following criteria must be met
Visual loss as demonstrated either by visual acuity or visual field examination
No malignancy found after extensive evaluation*
Evidence of optic nerve or retinal abnormalities
No identifiable cause for optic neuropathy and/or retinopathy
And one of the following
Serum autoantibodies against retina and/or optic nerve not usually found in normal healthy individuals**
Response to immunomodulation demonstrated either by stabilization, slowing, or reversal of visual field deficit
Modifiers
Type A: Associated with other autoimmune disease
Type B: Not associated with other autoimmune disease
* Includes a history of remote malignancy that may better explain visual loss as being associated with CAR, PON, or MAR.
** The presence of autoantibodies to retina and/or optic nerve antigens does not prove causality.

Management

While currently there is no consensus on the treatment of ARRON, studies have shown that patients could benefit from immunosuppressive treatment. In cases where ARRON coincides with an autoimmune disease the autoimmune condition should be primarily addressed. Where there is no clear other autoimmune pathology, steroids can be considered as first-line treatment followed by immunomodulatory agents such as methotrexate and cyclophosphamide. CD20+ monoclonal antibody, rituximab, has also been used with anecdotal success due to the presumed pathogenic role of antibodies. Intravenous immunoglobulins (IVIG) and plasma exchange (PLEX) can be considered for refractory disease. There has been one case of autologous hemotopoietic stem cell transplantation treatment in a patient with ARRON.

Prognosis

The natural course of ARRON varies among cases and can range from relative improvement to slow deterioration of vision over months or years. Given the rarity of the condition, the insidious presentation and typically prolonged time to diagnosis, as well as the multitude of immunosuppressive treatment options, overall prognosis is challenging to predict.