Non-Paraneoplastic Autoimmune Retinopathy

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Article initiated by:

Eric Kim, Francisco Serdoura Alves, Nicole Lifson MD, Spandana Jarmale, Viren Rana, DO

All contributors:

Guilherme J. C. dos S. Portas de Almeida, Shivani Rana MS., Viren Rana, DO, Ghazala D. O'Keefe, MD, Viren Rana, DO, Nicole Lifson MD, Francisco Serdoura Alves

Assigned editor:

Olena Hurzhii, MD

Review:

Assigned status Update Pending

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Introduction

Autoimmune retinopathies are a rare set of diseases that often lead to retinal degeneration. The two main types of autoimmune retinopathy are paraneoplastic retinopathy, which is associated with an underlying malignancy, and non-paraneoplastic autoimmune retinopathy (npAIR) which arises independently of cancer.

npAIR is characterized by bilateral, rapidly progressive vision loss, visual field defects, and photoreceptor dysfunction . It is caused by cross-reactivity of serum autoantibodies to the retina and retinal photoreceptor antigens.

Diagnosis of npAIR is one of exclusion, and is often difficult and delayed given a wide variety of clinical findings and symptoms associated with the disease. Variable disease expression is thought to be due to the different permutations of autoantibodies in patients. Given this delay in diagnosis and treatment initiation, the visual prognosis in npAIR is often poor.

Historical Background

The first case report of paraneoplastic AIR (specifically, cancer-associated retinopathy) was published in 1976 by Sawyer et al. but the term “paraneoplastic retinopathy” was used to describe malignancy-associated AIRs by Klingele et al. later in 1984. In 1997, the first case of npAIR was described and its clinical similarity to cancer associate retinopathy (CAR) was noted.

Epidemiology

The prevalence of npAIR is unknown. The disease is more prevalent in females (63–66%) and typically occurs between the fifth and sixth decade of life. npAIR is associated with autoimmune disease, most commonly hypothyroidism.

Pathophysiology

Although the mechanism of the disease is not yet fully understood, it is thought to be caused by circulating autoantibodies against the retina causing destruction of photoreceptors and widespread degenerative changes in the retina and retinal pigment epithelium (RPE) . Given that the RPE is a major component of the blood-retinal barrier and contributes to immune regulation, it is often the target of the degenerative progress . There have been a number of anti-retinal antibodies found to be associated with npAIR with the most significant being anti-recoverin, anti-carbonic anhydrase II, anti-α-enolase, and anti-rod transducin-α antibodies .

A bacterial or viral infection may trigger the cross reaction of retinal protein and bacterial/viral protein. Retinal damage of photoreceptors, ganglion cells, and bipolar cells occurs through caspases and intracellular calcium influx apoptotic mechanisms.

Diagnosis

Clinical findings

The diagnosis of npAIR is challenging given its rarity, various clinical manifestations, and non-specific findings. Typically patients present with vague and subtle symptoms that are often bilateral and asymmetric including photopsias, dyschromatopsia and nyctalopia. Spontaneous improvement of these symptoms are possible Fundus exam may appear benign, however, some non-specific findings may be present, such as pigmentary changes, retinal vascular attenuation, optic disc pallor, macular edema, retinal atrophy, or retinal pigmentary depositionTypically there is minimal to no intraocular inflammation.

Associated Systemic Diseases

It is common for patients who have npAIR to have associated systemic pathologies, particularly related to autoimmune dysfunction. In a series, the most commonly associated finding was hypothyroidism, however, there are other associations described, such as rheumatoid arthritis, multiple sclerosis, autoimmune hepatitis, Hashimoto´s Thyroiditis, myasthenia gravis and graves disease. Given the circumstances, it is important for the clinician to bear in mind this fact in its diagnostic work-up, given the rarity of npAIR, and to exclude neoplasm.

Fundus Autofluorescence

Fundus autofluorescence (FAF) can may indicate hyperautofluorescence around the macula and hypoautofluorescence around the optic nerve, hyperautofluorescent ring around the macula and hypoautofluorescent patches in the posterior pole

Visual Fields

In a series, scotoma was described in 61% of cases.. Peripheral constriction, enlarged blind spot and other types of visual field defects (superior, paracentral) were described.

Electrophysiologic Testing

There are no pathognomonic features of AIR. Dysfunction may occur in either cones and/or rods but typically patients develop rod dysfunction as the disease progresses over time. The ERG may completely extinguish. The rate of ERG dysfunction tends to be more rapid in AIR than in retinal degenerative diseases.

Serology

Numerous ARAs have been identified including antibodies against recoverin, α-enolase, rod transducin-α, Carbonic Anhydrase II, the inner retinal layer, arrestin, interphotoreceptor-binding protein) Not all patients with npAIR have detectable antibodies, and retinal autoantibodies can be elevated in other diseases, such as cancer . Immunohistochemistry, Western blot, ELISA, and multiplex assays can all be used in the detection of these antibodies. In addition, anti-retinal antibodies have been detected in other retinopathies (Age-related Macular Degeneration, RP, making this a less specific test.

Optical Coherence Tomography

Multimodal imaging, including spectral domain optical coherence tomography (SD-OCT) can often times reveal non-specific changes, including attenuation of both the Outer Nuclear Layer and the Ellipsoid Zone, Decreased Macular Thickness and Cystoid Macular Edema.

Differential Diagnosis

Differential diagnosis of npAIR includes acute zonal occult outer retinopathy (AZOOR), idiopathic big blind spot syndrome, retinal degenerative disorders such as retinitis pigmentosa (RP) and hereditary cone dystrophies, non-infectious and infectious uveitis, and vitamin A deficiency.

Management

Medical management

Treatment of npAIR is primarily aimed at thwarting the immune response caused by the anti-retinal antibodies and furthering disease progression.

Short-term treatment with corticosteroids include intravitreal Triamcinolone, subtenon injection of depomedrol, or intravenous immunoglobulin (IVIG) infusions. If corticosteroid treatment alone is not enough to stop progression, or if the side effects of long term steroid use become unmanageable, immunosuppressive agents such as Mycophenolate, Azathioprine, Cyclosporine and Infliximab should be considered .

In addition, supplementation with antioxidant vitamins such as β-carotene, vitamin C, and vitamin E may have some effect against progressive retinal degeneration.

Systemic management

It is crucial to differentiate the paraneoplastic AIR from the non-paraneoplastic. A thorough investigation to rule out malignancy should be undertaken in patients who present with signs and symptoms suggestive of autoimmune retinopathy with all age and gender appropriate testing including mammography, abdominal, pelvic, and chest CT,  brain MRI, and colonoscopy .

Monitoring of Disease

Consider monitoring of disease every three to six months with a full ophthalmological evaluation and ERG.