REMISSION OF NONPARANEOPLASTIC AUTOIMMUNE RETINOPATHY AFTER MINIMAL STEROID TREATMENT Lulu L. C. D. Bursztyn, MD, MSc,*† Jillian C. Belrose, PhD,* Stuart G. Coupland, PhD,‡ J. Alexander Fraser, MD,*†§ Alain A. Proulx, MD*†
Purpose: To describe the clinical findings in a patient demonstrating recovery from nonparaneoplastic autoimmune retinopathy after a minimal course of steroid treatment. Methods: Clinical presentation was documented, and paraclinical tests were obtained using Humphrey automated perimetry for visual fields, Western blotting for antiretinal antibodies, and electroretinography for evaluation of rod and cone function. Results: Initial presentation revealed marked visual field deficits, electroretinographic dysfunction, and the presence of a-enolase autoantibodies. After a brief course of oral corticosteroids, the patient demonstrated improvement in visual fields, disappearance of a-enolase autoantibodies, partial recovery of the cone on-response, and complete recovery of the rod response. Conclusion: This case is distinguished from previous reports by the rapidity and degree of recovery, the brevity of treatment required, and the unique electroretinographic recovery pattern with concomitant disappearance of a-enolase autoantibodies. These findings suggest a pathologic role for a-enolase autoantibodies in autoimmune rod bipolar cell dysfunction. Identification of other cases exhibiting such improvements and associated autoantibody activity may expand our understanding of nonparaneoplastic autoimmune retinopathy disease pathogenesis. RETINAL CASES & BRIEF REPORTS 9:173–176, 2015
retinal autoantibodies, such as anti-a-enolase, and evidence of retinal degeneration, which may be detected by electroretinographic (ERG) changes and/or optical coherence tomography,3 in the absence of malignancy. Clinical features include photopsias and rapidly progressive painless visual loss.3 Typically, visual prognosis is quite poor, with severe vision loss the norm, despite treatment.3 Visual field improvements may be observed after 3 months or more of immunosuppression.1 We report a case of anti-a-enolase–mediated npAIR, causing severe rod and cone dysfunction on ERG and significant visual field loss, but which resolved after a short course of oral corticosteroids, with concomitant disappearance of a-enolase autoantibodies and selective recovery of rod bipolar function.
From the *Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; †Department of Ophthalmology, Ivey Eye Institute, Western University, London, Ontario, Canada; ‡Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada; and §Department of Clinical Neurological Sciences, Western University, London, Ontario, Canada.
A
utoimmune retinopathies are rare disorders subclassified into cancer-associated retinopathy, melanoma-associated retinopathy, and nonparaneoplastic autoimmune retinopathy (npAIR).1,2 Diagnosis of npAIR is based on the detection of circulating
L. L. C. D. Bursztyn and J. C. Belrose contributed equally to this work. None of the authors have any financial/conflicting interests to disclose. Reprint requests: Lulu L. C. D. Bursztyn, MD, MSc, Ivey Eye Institute, St. Joseph’s Hospital, 268 Grosvenor Street, London, Ontario, Canada N6A 4V2; e-mail: [email protected]
Case Report A 64-year-old man presented with 3 weeks of worsening photophobia and peripheral visual field disturbance. He described “enhancement of edges” and “oscillations” in his peripheral vision. He
173
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RETINAL CASES & BRIEF REPORTS´ 2015 VOLUME 9 NUMBER 2
was otherwise well, took no medications, and had no family history of autoimmune disease. Visual acuity was 20/25 in both eyes. Pupils, slit-lamp, and dilated fundus examination were all unremarkable. Humphrey automated perimetry showed bilateral concentric visual field loss (Figure 1A). Electroretinography was abnormal to scotopic flash, photopic flash, and 30 Hz flicker stimulation (Figure 2), with a definite negative ERG appearance noted on scotopic bright flash (Figure 2B) associated with a supranormal a-wave amplitude, indicating dysfunction of both rod and cone systems. On–off ERG testing using 8 Hz sawtooth flicker demonstrated complete loss of the cone on-response (Figure 3A) with preservation of a normal off-response (Figure 3C), suggesting selective loss of cone depolarizing bipolar cells in the inner retina. Antiretinal autoantibody testing by Western blot was positive for 46 kDa (a-enolase), 50 kDa, and 62 kDa proteins. An optical coherence tomography was not obtained at the time of presentation. A full body positron emission tomography-computed tomography (PET/CT) scan demonstrated no occult focus of malignancy. A complete skin examination by a dermatologist revealed a single suspicious lesion on the dorsum of the right hand; however, biopsy of this lesion was consistent with a simple benign solar lentigo. The patient was therefore diagnosed with npAIR. The patient started oral prednisone 50 mg daily. His symptoms improved within 2 weeks, and the dose was tapered off over the following month. One year later, with no further treatment, the patient had no symptoms and remarkable improvement in visual fields (Figure 1B). Follow-up ERG showed recovery of rod function to scotopic flash (Figure 4A). The scotopic bright flash (Figure 4B) showed improvement in b-wave amplitude, which was within normal limits. The supranormal a-wave amplitude was unchanged. This amplitude, while exceeding 2 standard deviation units, was within 3 standard deviations as would be expected in 1% to 5% of the normal population. Given that there was no significant change in a-wave amplitude over a 12-month period, we assume that this is the normal value for our patient. Photopic cone function was still abnormal as
Fig. 2. Electroretinography at initial presentation. Electroretinographies obtained from both eyes using International Society for Clinical Electrophysiology of Vision (ISCEV) standard recording of scotopic rod response (A), combined rod/cone response (B), photopic cone (C), and 30 Hz flicker response (D). The patient ERG waveforms are shown with single traces from multiple flashes superimposed to show repeatability. The rectangles represent mean ± 2 SD for implicit time and amplitude of a-wave and b-wave. The scotopic rod ERGs (A) are significantly reduced in b-wave amplitude. The combined rod/cone response (B) demonstrates the “negative ERG” appearance, with a reduced b-wave amplitude and supranormal a-wave amplitude. Photopic cone ERGs (C) and 30 Hz flicker (D) are reduced in amplitude.
was the 30 Hz flicker ERG (Figure 4, C and D). Improved but reduced cone on-response and normal off-response was found (Figure 5). Repeat antiretinal antibody testing demonstrated 50 kDa, 62 kDa, and 68 kDa proteins. Importantly, the previously identified 46 kDa a-enolase reactive band was not observed.
Discussion
Fig. 1. Visual fields. A. 30–2 Humphrey visual field showed bilateral concentric visual field loss. B. Visual field showing marked improvement 1 year later.
Although spontaneous improvement has been reported in melanoma-associated retinopathy,4 full recovery in npAIR patients is extremely rare.3 The majority of npAIR patients with a-enolase autoantibodies experience inexorable visual loss, despite immunosuppressive therapy.3 In marked contrast, our patient demonstrated significant clinical and ERG improvement with minimal prednisone, indicating a more treatment-responsive form of the disease. Such a rapid ERG recovery of initially severe rod and cone on-bipolar cell dysfunction is not the typical course of
Copyright ª by Ophthalmic Communications Society, Inc. Unauthorized reproduction of this article is prohibited.
RECOVERY IN A CASE OF
NPAIR
175
Fig. 4. Electroretinography at 1-year follow-up. A complete normalization of scotopic rod response was seen in both eyes at 1-year followup (A). The combined rod/cone ERG (B) also showed some improvement and now has a b-wave amplitude that falls within normal limits. The a-wave amplitude remained supranormal. Photopic cone ERG (C) and 30 Hz flicker ERG (D) remained abnormal. Fig. 3. On-ERGs and Off-ERGs at initial presentation. Electroretinographies obtained from both eyes using 8 Hz sawtooth (rapid-on and rapid-off) stimulation. This patient’s cone on-bipolar response was not detectible at initial presentation (A) in the presence of a normal appearing off-bipolar response (C). Representative normal cone onbipolar and off-bipolar ERGs are shown in (B) and (D).
anti-a-enolase–associated npAIR5 and seems to represent a more benign end of the disease spectrum. In the current case, both rod and cone dysfunction was noted with initial ERG investigations. One year after presentation, ERG examination showed partial recovery in on-cone ERG to flash, in contrast to full recovery of the rod ERG. Rod photoreceptors are unique in that they synapse with only one bipolar cell type, the rod bipolar. Consequently, rod ERG b-wave amplitude directly reflects rod on-bipolar function. Complete recovery of rod on-bipolar cells, despite little recovery of cone on-bipolar function, has not been previously reported. It should be noted that this contrasts with a previous report, which concluded that the ERG examination in individuals with a-enolase autoantibodies often reveals cone dysfunction with normal rod response.6 The current case highlights the need for further examination of autoantibody reactivity and investigation to assess whether antibodies targeting different a-enolase epitopes may trigger dysfunction or degeneration in different retinal cell populations.
Fig. 5. On-response and off-response at 1-year follow-up. Some partial recovery of cone on-bipolar response was observed (A), but responses were still abnormal when compared with normal cone on-bipolar response (B). The patient’s cone off-bipolar response remained normal (C) when compared with normal control patient (D).
Copyright ª by Ophthalmic Communications Society, Inc. Unauthorized reproduction of this article is prohibited.
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RETINAL CASES & BRIEF REPORTS´ 2015 VOLUME 9 NUMBER 2
Decreases in antiretinal antibodies after treatment have been reported3,5; however, this is the first reported case to correlate the loss of a-enolase reactivity in npAIR with recovery of rod function after minimal steroid treatment. Our case illustrates a more treatment-responsive form of npAIR and expands the prognostic spectrum of the disease. This correspondence between a-enolase autoantibody activity and retinal disease supports a pathologic role for a-enolase autoantibodies. Identification of cases, which exhibit such remarkable improvements, may expand our understanding of disease pathogenesis, progression, and treatment. Key words: alpha-enolase, autoimmune retinopathy, electroretinography, rod photoreceptors.
References 1. Heckenlively JR, Ferreyra HA. Autoimmune retinopathy: a review and summary. Semin Immunopathol 2008;30:127–134. 2. Braithwaite T, Vugler A, Tufail A. Autoimmune retinopathy. Ophthalmologica 2012;228:131–142. 3. Ferreyra HA, Jayasundera T, Khan NW, et al. Management of autoimmune retinopathies with immunosuppression. Arch Ophthalmol 2009;127:390–397. 4. Kim LS, Alexander KR, Fishman GA. Spontaneous improvement of rod system function in a patient with melanoma-associated retinopathy. Retin Cases Brief Rep 2008;2:166–171. 5. Hooks JJ, Tso MO, Detrick B. Retinopathies associated with antiretinal antibodies. Clin Diagn Lab Immunol 2001;8: 853–858. 6. Weleber RG, Watzke RC, Shults WT, et al. Clinical and electrophysiologic characterization of paraneoplastic and autoimmune retinopathies associated with antienolase antibodies. Am J Ophthalmol 2005;139:780–794.
Copyright ª by Ophthalmic Communications Society, Inc. Unauthorized reproduction of this article is prohibited.
Purpose: To describe the clinical findings in a patient demonstrating recovery from nonparaneoplastic autoimmune retinopathy after a minimal course of steroid treatment. Methods: Clinical presentation was documented, and paraclinical tests were obtained using Humphrey automated perimetry for visual fields, Western blotting for antiretinal antibodies, and electroretinography for evaluation of rod and cone function. Results: Initial presentation revealed marked visual field deficits, electroretinographic dysfunction, and the presence of a-enolase autoantibodies. After a brief course of oral corticosteroids, the patient demonstrated improvement in visual fields, disappearance of a-enolase autoantibodies, partial recovery of the cone on-response, and complete recovery of the rod response. Conclusion: This case is distinguished from previous reports by the rapidity and degree of recovery, the brevity of treatment required, and the unique electroretinographic recovery pattern with concomitant disappearance of a-enolase autoantibodies. These findings suggest a pathologic role for a-enolase autoantibodies in autoimmune rod bipolar cell dysfunction. Identification of other cases exhibiting such improvements and associated autoantibody activity may expand our understanding of nonparaneoplastic autoimmune retinopathy disease pathogenesis. RETINAL CASES & BRIEF REPORTS 9:173–176, 2015
retinal autoantibodies, such as anti-a-enolase, and evidence of retinal degeneration, which may be detected by electroretinographic (ERG) changes and/or optical coherence tomography,3 in the absence of malignancy. Clinical features include photopsias and rapidly progressive painless visual loss.3 Typically, visual prognosis is quite poor, with severe vision loss the norm, despite treatment.3 Visual field improvements may be observed after 3 months or more of immunosuppression.1 We report a case of anti-a-enolase–mediated npAIR, causing severe rod and cone dysfunction on ERG and significant visual field loss, but which resolved after a short course of oral corticosteroids, with concomitant disappearance of a-enolase autoantibodies and selective recovery of rod bipolar function.
From the *Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; †Department of Ophthalmology, Ivey Eye Institute, Western University, London, Ontario, Canada; ‡Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada; and §Department of Clinical Neurological Sciences, Western University, London, Ontario, Canada.
A
utoimmune retinopathies are rare disorders subclassified into cancer-associated retinopathy, melanoma-associated retinopathy, and nonparaneoplastic autoimmune retinopathy (npAIR).1,2 Diagnosis of npAIR is based on the detection of circulating
L. L. C. D. Bursztyn and J. C. Belrose contributed equally to this work. None of the authors have any financial/conflicting interests to disclose. Reprint requests: Lulu L. C. D. Bursztyn, MD, MSc, Ivey Eye Institute, St. Joseph’s Hospital, 268 Grosvenor Street, London, Ontario, Canada N6A 4V2; e-mail: [email protected]
Case Report A 64-year-old man presented with 3 weeks of worsening photophobia and peripheral visual field disturbance. He described “enhancement of edges” and “oscillations” in his peripheral vision. He
173
Copyright ª by Ophthalmic Communications Society, Inc. Unauthorized reproduction of this article is prohibited.
174
RETINAL CASES & BRIEF REPORTS´ 2015 VOLUME 9 NUMBER 2
was otherwise well, took no medications, and had no family history of autoimmune disease. Visual acuity was 20/25 in both eyes. Pupils, slit-lamp, and dilated fundus examination were all unremarkable. Humphrey automated perimetry showed bilateral concentric visual field loss (Figure 1A). Electroretinography was abnormal to scotopic flash, photopic flash, and 30 Hz flicker stimulation (Figure 2), with a definite negative ERG appearance noted on scotopic bright flash (Figure 2B) associated with a supranormal a-wave amplitude, indicating dysfunction of both rod and cone systems. On–off ERG testing using 8 Hz sawtooth flicker demonstrated complete loss of the cone on-response (Figure 3A) with preservation of a normal off-response (Figure 3C), suggesting selective loss of cone depolarizing bipolar cells in the inner retina. Antiretinal autoantibody testing by Western blot was positive for 46 kDa (a-enolase), 50 kDa, and 62 kDa proteins. An optical coherence tomography was not obtained at the time of presentation. A full body positron emission tomography-computed tomography (PET/CT) scan demonstrated no occult focus of malignancy. A complete skin examination by a dermatologist revealed a single suspicious lesion on the dorsum of the right hand; however, biopsy of this lesion was consistent with a simple benign solar lentigo. The patient was therefore diagnosed with npAIR. The patient started oral prednisone 50 mg daily. His symptoms improved within 2 weeks, and the dose was tapered off over the following month. One year later, with no further treatment, the patient had no symptoms and remarkable improvement in visual fields (Figure 1B). Follow-up ERG showed recovery of rod function to scotopic flash (Figure 4A). The scotopic bright flash (Figure 4B) showed improvement in b-wave amplitude, which was within normal limits. The supranormal a-wave amplitude was unchanged. This amplitude, while exceeding 2 standard deviation units, was within 3 standard deviations as would be expected in 1% to 5% of the normal population. Given that there was no significant change in a-wave amplitude over a 12-month period, we assume that this is the normal value for our patient. Photopic cone function was still abnormal as
Fig. 2. Electroretinography at initial presentation. Electroretinographies obtained from both eyes using International Society for Clinical Electrophysiology of Vision (ISCEV) standard recording of scotopic rod response (A), combined rod/cone response (B), photopic cone (C), and 30 Hz flicker response (D). The patient ERG waveforms are shown with single traces from multiple flashes superimposed to show repeatability. The rectangles represent mean ± 2 SD for implicit time and amplitude of a-wave and b-wave. The scotopic rod ERGs (A) are significantly reduced in b-wave amplitude. The combined rod/cone response (B) demonstrates the “negative ERG” appearance, with a reduced b-wave amplitude and supranormal a-wave amplitude. Photopic cone ERGs (C) and 30 Hz flicker (D) are reduced in amplitude.
was the 30 Hz flicker ERG (Figure 4, C and D). Improved but reduced cone on-response and normal off-response was found (Figure 5). Repeat antiretinal antibody testing demonstrated 50 kDa, 62 kDa, and 68 kDa proteins. Importantly, the previously identified 46 kDa a-enolase reactive band was not observed.
Discussion
Fig. 1. Visual fields. A. 30–2 Humphrey visual field showed bilateral concentric visual field loss. B. Visual field showing marked improvement 1 year later.
Although spontaneous improvement has been reported in melanoma-associated retinopathy,4 full recovery in npAIR patients is extremely rare.3 The majority of npAIR patients with a-enolase autoantibodies experience inexorable visual loss, despite immunosuppressive therapy.3 In marked contrast, our patient demonstrated significant clinical and ERG improvement with minimal prednisone, indicating a more treatment-responsive form of the disease. Such a rapid ERG recovery of initially severe rod and cone on-bipolar cell dysfunction is not the typical course of
Copyright ª by Ophthalmic Communications Society, Inc. Unauthorized reproduction of this article is prohibited.
RECOVERY IN A CASE OF
NPAIR
175
Fig. 4. Electroretinography at 1-year follow-up. A complete normalization of scotopic rod response was seen in both eyes at 1-year followup (A). The combined rod/cone ERG (B) also showed some improvement and now has a b-wave amplitude that falls within normal limits. The a-wave amplitude remained supranormal. Photopic cone ERG (C) and 30 Hz flicker ERG (D) remained abnormal. Fig. 3. On-ERGs and Off-ERGs at initial presentation. Electroretinographies obtained from both eyes using 8 Hz sawtooth (rapid-on and rapid-off) stimulation. This patient’s cone on-bipolar response was not detectible at initial presentation (A) in the presence of a normal appearing off-bipolar response (C). Representative normal cone onbipolar and off-bipolar ERGs are shown in (B) and (D).
anti-a-enolase–associated npAIR5 and seems to represent a more benign end of the disease spectrum. In the current case, both rod and cone dysfunction was noted with initial ERG investigations. One year after presentation, ERG examination showed partial recovery in on-cone ERG to flash, in contrast to full recovery of the rod ERG. Rod photoreceptors are unique in that they synapse with only one bipolar cell type, the rod bipolar. Consequently, rod ERG b-wave amplitude directly reflects rod on-bipolar function. Complete recovery of rod on-bipolar cells, despite little recovery of cone on-bipolar function, has not been previously reported. It should be noted that this contrasts with a previous report, which concluded that the ERG examination in individuals with a-enolase autoantibodies often reveals cone dysfunction with normal rod response.6 The current case highlights the need for further examination of autoantibody reactivity and investigation to assess whether antibodies targeting different a-enolase epitopes may trigger dysfunction or degeneration in different retinal cell populations.
Fig. 5. On-response and off-response at 1-year follow-up. Some partial recovery of cone on-bipolar response was observed (A), but responses were still abnormal when compared with normal cone on-bipolar response (B). The patient’s cone off-bipolar response remained normal (C) when compared with normal control patient (D).
Copyright ª by Ophthalmic Communications Society, Inc. Unauthorized reproduction of this article is prohibited.
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RETINAL CASES & BRIEF REPORTS´ 2015 VOLUME 9 NUMBER 2
Decreases in antiretinal antibodies after treatment have been reported3,5; however, this is the first reported case to correlate the loss of a-enolase reactivity in npAIR with recovery of rod function after minimal steroid treatment. Our case illustrates a more treatment-responsive form of npAIR and expands the prognostic spectrum of the disease. This correspondence between a-enolase autoantibody activity and retinal disease supports a pathologic role for a-enolase autoantibodies. Identification of cases, which exhibit such remarkable improvements, may expand our understanding of disease pathogenesis, progression, and treatment. Key words: alpha-enolase, autoimmune retinopathy, electroretinography, rod photoreceptors.
References 1. Heckenlively JR, Ferreyra HA. Autoimmune retinopathy: a review and summary. Semin Immunopathol 2008;30:127–134. 2. Braithwaite T, Vugler A, Tufail A. Autoimmune retinopathy. Ophthalmologica 2012;228:131–142. 3. Ferreyra HA, Jayasundera T, Khan NW, et al. Management of autoimmune retinopathies with immunosuppression. Arch Ophthalmol 2009;127:390–397. 4. Kim LS, Alexander KR, Fishman GA. Spontaneous improvement of rod system function in a patient with melanoma-associated retinopathy. Retin Cases Brief Rep 2008;2:166–171. 5. Hooks JJ, Tso MO, Detrick B. Retinopathies associated with antiretinal antibodies. Clin Diagn Lab Immunol 2001;8: 853–858. 6. Weleber RG, Watzke RC, Shults WT, et al. Clinical and electrophysiologic characterization of paraneoplastic and autoimmune retinopathies associated with antienolase antibodies. Am J Ophthalmol 2005;139:780–794.
Copyright ª by Ophthalmic Communications Society, Inc. Unauthorized reproduction of this article is prohibited.
