Clinical and Electrophysiologic Characterization of Paraneoplastic and Autoimmune Retinopathies Associated With Antienolase Antibodies

Article Outline

• Abstract
• Subjects and methods
• Results
  • Case reports
    • Antirecoverin cancer-associated retinopathy wth small cell carcinoma of the lung
    • Case 1. Antienolase antibodies, no cancer
    • Case 2. Antienolase antibodies, no cancer
    • Case 3. Antienolase antibodies and prostate cancer
    • Case 4. Antienolase antibodies, no cancer
• Discussion
• References
• Biography
• Copyright

Purpose

Paraneoplastic and autoimmune retinopathies are immunologically mediated retinal degenerations that are associated with antibodies directed against any of several retinal proteins, including α-enolase. We report the clinical and electrophysiological features of antienolase retinopathy in contrast to the features of antirecoverin retinopathy.

Design

Retrospective, observational case series.

Methods

Patients were referred for evaluation of unexplained acquired visual symptoms, including photopsias, and loss of visual acuity or field considered of possible retinal origin. Full-field and multifocal electroretinograms (ERGs) were performed. Sera from patients were examined for antiretinal antibodies by Western blot analysis using proteins extracted from human retinas and by immunohistochemistry; antienolase was confirmed by incubating patient sera with purified α-enolase.

Results

Of 87 patients with unexplained retinal visual symptoms associated with abnormal ERGs, 37 (43%) demonstrated autoantibodies to retinal antigens, including 12 against α-enolase, of whom 4 had cancer. Initial visual loss was typically central and often asymmetric. The ERGs demonstrated mostly normal rod responses but central cone abnormalities (evident on multifocal ERG) and, for many, global cone abnormalities. Seven patients developed optic disk pallor. Corticosteroid and immunosuppressive therapy, when attempted, was clinically ineffective.

Conclusions

Antienolase retinopathy is a protean autoimmune retinopathy that characteristically presents with cone dysfunction. The visual impairment and course vary from relative stability for years to slow progression with loss of central vision. With time, optic disk pallor can evolve, presumably from attrition of ganglion cells.

Paraneoplastic and autoimmune retinopathies represent significant causes of otherwise unexplained acute or subacute vision loss in adults. Both forms of retinopathy result from a presumed immunologic attack on the retina by antibodies directed against retinal antigens. Cancer-associated retinopathy, or CAR, is the term that has been used for the retinal degeneration first described by Sawyer and associates¹ in 1976 as a distant effect of cancer. The first antigen shown to represent the source of the autoimmunity in CAR patients was the 23-kD retinal protein, recoverin.², ³ The second antigen that was reported to occur in CAR patients was the 46-kD protein, α-enolase.⁴, ⁵ Paraneoplastic retinopathy, a term first used by Klingele and associates in 1984,⁶ has become the more general term used for any of a number of autoimmune retinopathies associated with a malignant tumor.

Autoimmune retinopathy is the preferred term for an acquired, presumed immunologically mediated retinal degeneration with symptoms resembling paraneoplastic retinopathy but without tumor in association with serum antiretinal autoantibodies. The etiology and source of antigenic stimulation vary but are largely unknown. It is possible that the disease is triggered by molecular mimicry between retinal proteins and presumed viral or bacterial proteins or by the acquired alteration of host tissues or antigens so that autoimmunity is induced against retinal proteins. Multiple retinal proteins have been found to be antigenic, including recoverin, α-enolase, arrestin, transducin, TULP1, neurofilament protein, heat-shock protein-70, PNR, and as yet undefined bipolar cell antigens causing melanoma-associated retinopathy (MAR syndrome).⁷

CAR due to antirecoverin antibodies is almost always associated with severe, progressive vision loss and profoundly abnormal electroretinographic responses, both for rods and cones.⁶, ⁸, ⁹, ¹⁰, ¹¹, ¹² The presenting symptoms, ophthalmologic evaluation findings, and electroretinographic test results that characterize the paraneoplastic and autoimmune retinopathies associated with antienolase, however, have not been fully documented or characterized in the literature. We describe the clinical and electrophysiologic findings of 12 patients with antienolase, with presumed associated paraneoplastic or autoimmune retinopathy.

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Subjects and methods 

The study and data accumulation were carried out with approval from the Oregon Health & Science University institutional review board, and informed consent was obtained from the patients in accord with regulations of the Health Insurance Portability and Accountability Act of 1996 (HIPAA). All of the patients were evaluated in Portland, Oregon, by one or more of the authors. Patients generally presented with sudden or subacute vision loss, often associated with visual field defects and photopsias. Those with measurable abnormalities on electroretinogram (ERG) were screened for the presence of antiretinal autoantibodies. Antibody testing was performed using previously described techniques that employed Western blot analysis using proteins extracted from human retinas and immunohistochemistry.⁵ The presence of antienolase antibodies was confirmed by incubating the blot containing purified α-enolase with the patient’s serum.

Full-field ERGs were performed using protocols that conform to the International Society for Clinical Electrophysiology of Vision (ISCEV) Standard.¹³, ¹⁴, ¹⁵ Multifocal ERGs (mfERGs) were performed according to ISCEV guidelines¹⁶ using the Veris system (EDI, San Mateo, California, USA) with a protocol that used 103 hexagons, Burian-Allen bipolar electrodes, dilated pupils, refraction adjusted to the 40-cm test distance, band-pass of 10 Hz to 300 Hz, and a testing time of 8 minutes divided into 60-second segments.

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Results 

Of 87 patients seen over a 10-year period with unexplained retinal visual symptoms associated with abnormal ERGs, 37 patients (43%) demonstrated autoantibodies to retinal antigens, including 3 (8%) with antirecoverin (all CAR patients) and 12 (32%) with anti-α-enolase. Patients’ antibodies reacting with 46-kD protein on retinal proteins blots were retested and confirmed to be specific for retinal α-enolase. Of the 12 patients with anti-α-enolase retinopathy, 4 had cancer and 8 had autoimmune retinopathy without cancer. The clinical and electrophysiologic information for these 12 subjects is presented in Table 1. For all patients, vision was normal before the present illness, and a complete medical and family history failed to disclose suggestion of a genetic form of retinal degeneration or any other cause for retinopathy, except for the history of cancer in 4 patients.

TABLE 1. Presenting Symptoms, Clinical Findings, and Electrophysiology of Patients With Antienolase-Associated Retinopathy

CF = counting fingers; mfERG = multifocal electroretinogram; HFA = Humphrey Field Analyzer; RPE = retinal pigment epithelium; VA = visual acuity.

Patients with antienolase antibodies (Table 1) presented with a range of symptoms, clinical features, and electrophysiologic findings. The symptoms, degree of loss of visual acuity, and findings varied with time. Visual loss was central and initially often unilateral or asymmetric. Patients experienced difficulties with central or pericentral visual tasks, such as reading, shimmering photopsias, loss of color vision centrally, reduced vision in bright light, and sometimes night blindness. Seven patients (cases 1 through 5, 7, and 12), all of whom had both full-field and multifocal ERG studies, had phenotypes that suggested common elements of central or global cone dysfunction, with modest to no rod involvement. Seven patients (cases 1 through 4, 6, 8, and 10) developed optic disk pallor suggesting optic nerve involvement or ganglion cell attrition. Treatment with corticosteroids or immunosuppression did not alleviate the symptoms, degree of loss of visual acuity, or ERG findings for cases 1, 3, and 4 (the other 9 patients were not treated).

Four cases differed notably from the others in this series. In case 5, symptoms developed 17 years after hysterectomy for cervical cancer, and it is unclear whether the patient’s current illness represents paraneoplastic or autoimmune retinopathy. In case 6, the patient had extensive atrophic retinal findings and severity of ERG abnormalities that were unlike any of the other patients and suggested a more widespread retinal degeneration. The patient’s primary vision complaints began at age 78. One year after the detection of antienolase at age 81, she was diagnosed with breast cancer. Case 7 was initially considered possibly to have either the enlarged blind spot syndrome or acute zonal occult outer retinopathy (AZOOR). Case 9 had head trauma of uncertain significance.

To illustrate the differences in the presentations, findings, and electrophysiologic test results between antienolase retinopathy and antirecoverin, we present four patients (cases 1 through 4) whose features we consider to be distinctive and representative of the central to global cone dysfunction characteristic of anti-α-enolase retinopathy in comparison with a typical patient with antirecoverin cancer-associated retinopathy.

Case reports 

A 71-year-old female smoker presented with subacute onset of reduced near vision. Initial visual acuity was 20/80+ OD, 20/50− OS. She was unable to correctly identify any of the Ishihara color plates. Goldmann perimetry disclosed severe visual field loss in each eye (Figure 1, top). One month later, her acuity was 20/80+ OD and 20/70− OS, and she was unable to read any Jaeger type with either eye. Fundus examination, including vessel caliber, was normal. ERG responses were markedly subnormal and prolonged for both rods and cones (Figure 2). SCCL was diagnosed and treated with chemotherapy and radiation. Antibody testing was positive for antirecoverin. Oral prednisone was administered, initially at 60 mg per day but later tapered to 20 mg day. Her acuity improved over the subsequent weeks and remained stable thereafter at 20/40, J4 at near OU. Goldmann perimetry 2 months after initiation of corticosteroids showed improvement (Figure 1, bottom). ERG amplitudes were significantly improved for both rod- and cone-mediated responses 7 months after corticosteroid administration (Figure 2 and Supplemental Material Figure 1S). Naka-Rushton analysis of a stimulus-response series of scotopic responses (Supplemental Material, Figure 2S and Table 1S) demonstrated a significant increase in maximal amplitude, R_max, for the right eye and return to normal for retinal sensitivity, Log K, for each eye. Modest retinal vascular narrowing became evident. The patient died of metastatic cancer 2 years 3 months after her diagnosis, but she was still able to read at the time of her death. This case is a classic example of antirecoverin-associated paraneoplastic retinopathy, with equal involvement of both rod and cone systems on ERG testing.

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• FIGURE 1. 

  Visual field response of antirecoverin CAR patient to corticosteroid therapy. Goldmann perimetric visual fields of patient before (top) and 6 weeks after (bottom) treatment with oral corticosteroids demonstrate significant reduction of the dense ring scotomas in each eye. The very small isopter present centrally for the right eye in top figure is using the I4e test target. Note that this isopter was much larger after treatment with corticosteroids.

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• FIGURE 2. 

  Expanded International Society for Clinical Electrophysiology of Vision protocol full-field electroretinograms (ERGs) of patient with antirecoverin cancer-associated retinopathy (CAR) at time of recognition of her autoimmune retinopathy and 7 months after corticosteroid therapy compared with an age-matched normal subject. In this and subsequent full-field ERGs, the responses from the right and left eye are superimposed. Note that cone and rod ERG responses for this patient are equally subnormal when compared with a normal subject. Oscillatory potentials (OPs) are also severely abnormal. Comparison of patient’s ERG tracings before and 7 months after treatment with oral corticosteroids demonstrates a notable increase in amplitudes of rod responses, dark-adapted cone responses to red flash (arrows), light-adapted cone responses to single flash and 30-Hz flicker, and, to a lesser degree, scotopic bright white flash and the scotopic OPs. The rod and cone implicit times, including 30-Hz flicker (horizontal arrow designates peak timing), remained mildly prolonged.

A 73-year-old man developed severe loss of near and color vision over several days. Initial visual acuity was 20/400 OD, 20/200 OS. Central field loss was evident on Humphrey Field Analyzer (HFA) 10–2 static perimetry, greater for the right eye. A full-field ERG was normal (Figure 3), but an mfERG showed markedly subnormal amplitudes centrally, OD greater than OS. Antienolase antibodies were detected, but a subsequent extensive medical evaluation was negative. A course of prednisone (120 mg/day for 6 days, 20 mg/day for 3 days, and 10 mg/day for 3 days) and a subsequent course of acyclovir had no visual benefit. Six weeks later, acuity was counting fingers (CF) 3′ OD and CF 4′ OS. Fundus findings were normal. Four months later another mfERG (Figure 4) disclosed subnormal responses centrally OD and mildly subnormal, but prolonged OS. Vision fluctuated over the next 2 years, and on subsequent examination, 2 years 2 months after disease onset, acuity was CF 4′ OU and optic disks were markedly pale OU. Repeated full-field and multifocal ERGs were stable for amplitudes with variably prolonged mfERG implicit times OU. Four years later, the patient remains otherwise healthy with stable poor vision. Serum antienolase levels have remained high. The patient’s vision loss is believed to represent an autoimmune retinopathy with central cone dysfunction and secondary optic atrophy related to antienolase antibodies.

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• FIGURE 3. 

  Expanded International Society for Clinical Electrophysiology of Vision protocol full-field electroretinograms (ERGs) for cases 1, 2, and 3, compared with a similar-aged subject with normal ERG. The ERG responses are normal for all protocol steps for case 1. For case 2, rod responses are normal and responses to scotopic bright white flash and the oscillatory potentials (OPs) are mildly and moderately subnormal, respectively. For case 3, rod and scotopic bright flash responses are mildly subnormal, but OPs are markedly subnormal. Cone single flash and 30-Hz flicker responses are moderately subnormal and, at most, mildly prolonged for case 2, and severely subnormal and prolonged (horizontal arrow designates peak timing) for case 3.

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• FIGURE 4. 

  The multifocal electroretinogram (mfERG) first-order tracing arrays (top) and ring averages (bottom) for the right eye for case 1, at age 74 years. The gray tracings represent those of a normal reference. For this and all subsequent mfERGs, the responses were averaged across 6 rings (ring 1 represents the central hexagon, 1 arc degree in diameter; ring 2, 1 to 6 arc degrees in diameter; ring 3, 6 to 12 arc degrees in diameter; ring 4, 12 to 21 arc degrees in diameter; ring 5, 21 to 31 arc degrees in diameter; and ring 6, 31 to 44 arc degrees in diameter). The peripheral mfERG responses are of normal amplitude, but the responses within the central 5 degrees from fixation are subnormal.

A 67-year-old woman presented with poor night vision and gradual loss of reading acuity for 8 to 10 years. Visual acuity was 20/25 to 2, J10 OD and 20/20, J7 OS. Humphrey 24–2 static perimetry disclosed severe central and pericentral loss OD and marked pericentral loss OS (Supplemental Material, Figure 3S). Retinal vessels were markedly attenuated and the optic nerves showed waxy pallor. Full-field ERG showed normal rod responses and moderately subnormal scotopic bright-flash b-wave, dark-adapted subtracted cone responses and 30-Hz flicker cone responses, with mildly prolonged cone implicit times (Figure 3). mfERG responses were severely subnormal OD and mildly subnormal OS but variably prolonged OU (Figure 5). Antienolase antibodies were detected in serum. Medical surveillance has been normal, and 14 months later she remains healthy with stable vision, unchanged visual electrophysiology, and persistent, strongly positive serum antienolase antibodies. This patient’s global and central cone dysfunction is believed to result from an antienolase-associated autoimmune retinopathy. Reading vision was more disturbed than distance visual acuity, probably because of the loss of pericentral retinal sensitivity.

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• FIGURE 5. 

  Multifocal electroretinogram first-order tracings, amplitude density plots, ring averages, and latencies for the left eye (top) and right eye (bottom) of case 2. Peripheral amplitude loss is evident for each eye, greater for the left eye, with prolonged implicit times peripherally for the left eye and pericentrally for the right eye.

An 81-year-old man noted blurred central vision 1 year after radiotherapy and leuprolide for prostate cancer. Initial visual acuity was 20/25 OD, 20/15− OS. Central scotomas were evident on static perimetry. Full-field ERG testing disclosed severe cone and mild to moderate rod loss OU (Figure 3). Antienolase antibodies were detected in serum. A course of high-dose oral prednisone failed to improve his vision. Eight months later, visual acuity decreased to 20/50−, J16 OD and 20/25 J10 OS. A mfERG disclosed profoundly subnormal and delayed P1 responses OU. Mild optic nerve pallor developed. A course of triple immunosuppression (azathioprine, cyclosporine, and prednisone) failed to improve his vision and was discontinued when he developed pneumonia. Throughout this time, his vision continued to worsen; 14 months after symptoms began, acuity was 20/200 OU. The visual acuity and full-field ERG over the subsequent 3.6 years have remained unchanged. Five years after onset, his health and vision loss remain stable. Antienolase antibodies have persisted throughout. This patient presented with global cone dysfunction and secondary optic atrophy as part of antienolase paraneoplastic retinopathy.

A 49-year-old man initially noted blurred vision OS at age 42. Visual acuity was 20/20 OD but fluctuated from 20/40 to 20/100 OS. Pupillary responses and fundus examination were normal. Fluorescein angiogram, magnetic resonance imaging scan, full-field ERG, visually evoked potential (VEP), and repeated Humphrey visual fields were normal over the next 2 years. Five months later, his vision began to blur OD (acuity, 20/50). A mfERG disclosed central cone dysfunction OU. Repeated full-field ERG and pattern VEP were normal, and a diagnosis of occult maculopathy was made. His vision continued to worsen, and he developed light sensitivity. Four years and 8 months after onset, kinetic and static visual field testing showed bilateral enlarged blind spots and central scotomas. Blood screening detected antienolase antibodies. A 3-month trial of oral prednisone, azathioprine, and cyclosporin was without visual benefit. Five years after disease onset, acuity was 20/300 OD and 20/70 OS; repeated full-field ERG testing disclosed a 50% reduction in the amplitude of the photopic ERG OS. When last evaluated 6 years 6 months after the onset, his acuity was 20/200 OD, 20/300 OS. Goldmann perimetry disclosed enlarged blind spots and scattered central and midperipheral scotomas OU. Fundus examination disclosed mildly attenuated retinal vessels, peripapillary pallor, and mild waxy pallor of the optic disks, all greater OS. mfERGs (Figure 6) showed severe central cone dysfunction OD and even greater central and peripheral cone dysfunction OS. The full-field ERG remained normal OD but showed further progression of global cone dysfunction OS (cone amplitudes OS 25% of OD; delayed cone b-wave implicit times). Antienolase antibodies remain unchanged. This patient represents a case of antienolase retinopathy progressing from unilateral central acuity loss to bilateral central cone dysfunction to eventual global cone dysfunction OS.

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• FIGURE 6. 

  Multifocal electroretinogram first-order tracings, amplitude density plots, ring averages, and latencies for the left eye (top) and right eye (bottom) of case 4. Central responses are severely subnormal bilaterally, more so for the left eye. For the left eye, the amplitude loss is more diffuse and extended peripherally, and the pericentral responses show prolonged latencies. For the right eye, peripheral responses are generally normal, but uneven, in amplitude. Note prolongation of latencies temporal to fixation for the right eye in the region associated with the relatively smaller amplitudes; this correlated well with the paracentral scotoma evident on Goldmann perimetry.

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Discussion 

Antienolase antibodies are frequently found in patients with retinopathy resembling CAR symptoms. In 1996, Adamus⁴ first reported the finding of CAR retinopathy related to anti-α-enolase antibodies, a finding that has been confirmed in other laboratories since then.¹⁷, ¹⁸ Antienolase-associated paraneoplastic retinopathy has been associated with numerous kinds of cancer, including lung, breast, bladder, uterine, prostate, salivary gland, and gastrointestinal tract, as well as chronic lymphocytic leukemia. However, in approximately 60% of cases, no neoplasm can be found on extensive evaluation.⁵ Paraneoplastic patients are usually older than patients with autoimmune retinopathy at the onset of visual symptoms.⁵

The significance of antibodies against enolase is made more complex by the finding of similar antibodies in a number of inflammatory, degenerative, and neurologic diseases.¹⁹, ²⁰ These reports have led some authors to question whether antienolase truly causes autoimmune retinopathy and whether the association of antienolase with cancer might be fortuitous.¹² It is possible that the antienolase seen in some of our patients may not be acting alone in the production of the symptoms and associated retinopathy. In ocular disorders, antienolase antibodies can be found in 25% of patients with glaucoma, where it is hypothesized that the associated death of ganglion cells may contribute to low-tension glaucoma and greater risk for progression.²¹, ²² Antienolase can be seen in approximately 10% of healthy subjects.⁴, ¹⁹ However, antibodies present in otherwise healthy subjects usually target different epitopes on enolase when compared with antienolase antibodies of patients’ sera.²³ Moreover, antienolase antibodies that are associated with cancer are cytotoxic and can induce apoptosis, a feature not found with antienolase antibodies from normal subjects.²³, ²⁴, ²⁵ Conversely, administration of antibodies against neuron-specific enolase to rats’ eyes produced retinal dysfunction evident on ERG that had similarities to that seen with injection of N-methy-d-aspartate, suggesting that these antienolase antibodies affect cell function.²⁶

Antirecoverin antibodies bind almost exclusively to rods and cones and some bipolar cells.²⁷ The ERG in antirecoverin retinopathy, as demonstrated by the case report of the patient with SCCL, reflects nearly equal loss of both rod and cone amplitudes with implicit times that are normal or prolonged. Conversely, antienolase antibodies may label several layers and cell types within the retina, primarily retinal ganglion cells, Müller cells, and also cones and rods, and may present different labeling patterns based on their antigenic specificity.⁴, ²¹, ²⁸

The four antienolase cases presented here in greater detail illustrate distinct and characteristic clinical features with representative findings on full-field ERG and mfERG: (1) central cone dysfunction evident on mfERG (case 1 and initially 4); (2) both central and global cone-rod dysfunction of varying degree (case 2); and (3) central vision disturbance associated with a profound degree of both central and global cone dysfunction (case 3). Whereas the full-field ERG and mfERG for cases 1, 2, and 3 have remained stable or changed minimally with time, case 4 presented with only central cone dysfunction for several years before developing significant global cone dysfunction in the left eye. The evolution of optic nerve pallor over time (cases 1 through 4, 6, 8, and 10) suggests the development of axonal attrition, possibly as a consequence of binding of antienolase to ganglion cells with subsequent cell death and axonal loss.

Selective cone ERG loss has only rarely been reported in association with paraneoplastic retinopathy. In 1990, Cogan and associates²⁹ reported symptoms of “achromatopsia” with predominant cone ERG loss in a woman with metastatic pleomorphic carcinoma of presumed uterine origin. Histopathology showed extensive loss of the photoreceptors in the maculae and selective cone loss throughout the remaining retina. In 1992, Campo and associates³⁰ reported a patient with primary small cell carcinoma of the endometrium who had visual acuities of 20/80 OU, central scotomas, and reduced cone ERG responses. Histopathology of the retina showed total loss of photoreceptors in the macular region with, at most, only patchy loss of photoreceptors in other areas of the retina. In 1995, Jacobson and Thirkill³¹ found selective cone ERG loss in a patient who had three recent, but separate, cancers (stomach, colon, and thyroid) in association with antirecoverin (23 kD) and anti-50 kD protein antibodies that the authors indicated could have been antienolase.

The patients reported by Cogan and associates²⁹ and by Campo and associates³⁰ did not have screening for antiretinal antibodies in circulating blood, but in both instances, antibodies to neuronal-specific enolase were detected in the patient’s tumor tissue by immunohistochemistry, suggesting that the tumor was a possible source of antigen. We speculate that the paraneoplastic retinopathy in these two cases may have represented antienolase retinopathy. Based on our findings, we speculate that the selective cone dysfunction in the patient reported by Jacobson and Thirkill³¹ more likely resulted from antienolase antibodies than an antirecoverin response. It has been suggested that tumor be can a source of enolase for autoimmunization in CAR patients. Just recently, Dot and associates³² reported a patient with SCCL for whom serum antienolase antibodies developed after tumor resection by “epitope spreading” with eventual consolidation of antigen specificity; this phenomenon may explain why anti-α-enolase autoantibodies are typically detected after the diagnosis of cancer.

Patients with antirecoverin retinopathy present with symptoms of night blindness, photopsias, loss of peripheral or pericentral visual field, reduced central acuity, and major abnormalities involving both the rod and cone system, indicating widespread retinal dysfunction. Patients with antienolase antibodies experience varying degrees of central or pericentral visual field loss, shimmering photopsias, loss of color vision, reduced vision in bright light, and, less commonly, night blindness. Because of diffuse, albeit uneven, loss of sensitivity of central and pericentral retina, greater difficulty is encountered in both antirecoverin and antienolase retinopathies with near tasks, such as reading, than with distant tasks, such as Snellen acuity.

In our experience, the clinical features of antienolase retinopathy are more protean in nature than antirecoverin retinopathy (Table 2) but almost invariably begin with evidence of central visual dysfunction. Fluctuation of visual acuity with time and gradual progression in the level of vision impairment appear to be characteristic features of antienolase retinopathy. The visual acuity loss from antienolase-associated retinopathy rarely becomes as profound as can be seen with antirecoverin retinopathy and often remains relatively stable for years. Because of pericentral loss of retinal function, reading vision is more severely affected than distance visual acuity. Central and/or pericentral scotomas can usually be defined by static perimetry. Unlike antirecoverin CAR, which often precedes the recognition of the cancer by months to over a year, the paraneoplastic retinopathy associated with antienolase antibodies usually develops months to years after the discovery of the malignancy. The involvement may be asymmetric initially but almost always becomes bilateral and more symmetric with time. Patients may present with a central cone dysfunction evident only by mfERG. Full-field ERGs range from normal or nearly normal to demonstrating marked global cone or cone-rod loss. Some patients evolve global cone dysfunction in one or both eyes. Optic atrophy also can occur with time in association with antienolase retinopathy, further complicating the clinical phenotype.

TABLE 2. Comparison of Features of Retinopathy Associated With Antirecoverin Versus Antienolase Antibodies

ERG = electroretinogram; LP = light perception; NLP = no light perception.

There is no established protocol for the treatment of autoimmune retinopathy. Treatment for CAR involves modulation of the immune system to reduce the autoimmune response. Without treatment, retinopathy associated with antirecoverin antibodies almost always progresses rapidly to severe vision loss (often to no light perception). Antirecoverin-associated retinopathy frequently responds to corticosteroid or immunomodulation therapy, if the disorder is treated early in its course (reviewed in reference 17). Retinopathy associated with antienolase antibodies may remain stable or slowly worsen but uncommonly progresses to a visual acuity less than 20/300. In our experience, vision loss in patients with established antienolase retinopathy has failed to respond to oral corticosteroid therapy or chemotherapy with immunosuppressive agents. However, Guy and Aptsiauri¹⁷ reported a favorable response to intravenous immunoglobulin infusion for one patient with antienolase and a less convincingly favorable response for a second patient. The possible benefit of intravenous immunoglobulin therapy, alone or in combination with corticosteroids, for antienolase retinopathy needs further exploration.

In conclusion, the recognition of the differences between presenting symptoms, natural history, ophthalmologic features, response to corticosteroids and immunosuppression, and electrophysiologic findings of antienolase-associated and antirecoverin-associated retinopathies will help initiate the appropriate medical evaluation and care for affected patients and should provide a greater eventual understanding of how best to manage these two distinct forms of autoimmune retinopathy.

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Richard G. Weleber, M.D., is professor of Ophthalmology and Molecular and Medical Genetics at the Casey Eye Institute of Oregon Health & Science University. He is board certified in both ophthalmology and medical genetics. He is the director of the Oregon Retinal Degeneration Center and the Visual Function Service at OHSU, the laboratory that performs visual electrophysiology for clinical diagnosis and research. Dr. Weleber has published extensively on ophthalmic-genetics, retinal degenerations/dystrophies, and visual electrophysiology.

Grazyna Adamus, Ph.D., is a professor at the Neurological Sciences Institute and the Department of Ophthalmology at Oregon Health & Science University. Her laboratory is conducting NIH-sponsored research on the molecular and cellular bases of autoimmune diseases of the eye in such areas as the role of autoantibodies in retinal degeneration, including CAR syndrome and the role of T cells in autoimmune uveitis. Her work has been published in national and international journals.