A case of paraneoplastic optic neuropathy and outer retinitis positive for autoantibodies against collapsin response mediator protein-5, recoverin, and α-enolase
© Saito et al.; licensee BioMed Central Ltd. 2014
Received: 2 July 2013
Accepted: 14 January 2014
Published: 16 January 2014
Specific cross-reacting autoimmunity against recoverin or collapsin response mediator protein (CRMP)-5 is known to cause cancer-associated retinopathy or paraneoplastic optic neuropathy, respectively. We report a rare case with small cell lung carcinoma developing bilateral neuroretinitis and unilateral focal outer retinitis positive for these antibodies.
A 67-year-old man developed bilateral neuroretinitis and foveal exudation in the right eye. Optical coherence tomography showed a dome-shaped hyperreflective lesion extending from inner nuclear layer to the photoreceptor layer at the fovea in the right eye. Single-flash electroretinography showed normal a-waves in both eyes and slightly reduced b-wave in the left eye. Results of serological screening tests for infection were within normal limits. The patient’s optic disc swelling and macular exudation rapidly improved after oral administration of prednisolone. Systemic screening detected lung small cell carcinoma and systemic chemotherapy was initiated. Immunoblot analyses using the patient’s serum detected autoantibodies against recoverin, CRMP-5, and α-enolase, but not carbonic anhydrase II. Neuroretinitis once resolved after almost remission of carcinoma on imaging but it recurred following the recurrence of carcinoma.
The development of neuroretinitis in this cancer patient with anti-retinal and anti-optic nerve antibodies depended largely on the cancer activity, suggesting the possible involvement of paraneoplastic mechanisms. Patients with paraneoplastic optic neuropathy and retinopathy are likely to develop autoimmune responses against several antigens, thus leading to various ophthalmic involvements.
KeywordsNeuroretinitis Recoverin Cancer-associated retinopathy Collapsin response mediator protein-5 Outer retinitis
Paraneoplastic retinopathy including cancer-associated retinopathy (CAR) and paraneoplastic optic neuropathy (PON) are autoimmune diseases in which the host response to tumor antigens triggers cross-reactions to an overlapping epitope in the retina and/or the optic nerve . A 23-kDa recoverin protein, localized in photoreceptors, is one of the major antigens linked with CAR [2, 3]. Patients with CAR basically exhibit no abnormal retinal appearances in the initial stage and may later develop diffuse pigment epithelial degeneration similar to retinitis pigmentosa together with photoreceptor degeneration . Multiple ancillary tests including immunoblot analyses using patients’ sera, systemic screening, electroretinography, and perimetry are needed for a diagnosis of CAR. As for autoantigens causing PON, collapsin response mediator protein (CRMP)-5 has been most frequently reported [4–7]. Patients with anti-CRMP-5 antibody-positive PON generally develop funduscopic features of neuroretinitis . On the other hand, some patients with CAR involve inflammatory findings such as retinal vasculitis [1, 8]. In this report, we describe a rare case with small cell lung carcinoma positive for anti-recoverin antibody and anti-CRMP-5 antibody presenting bilateral neuroretinitis and focal outer retinitis.
Two weeks after the first visit, BCVA decreased to 0.02 OD and 0.3 OS, with aggravation of the optic disc swelling OU and development of SRD at the macula OS (Figure 1g). Single bright-flash electroretinography (ERG) showed normal a-wave OU and slightly reduced b-wave OS (Figure 1h). Results of serological screening tests for infection, including syphilis and anti-Bartonella henselae antibody, as well as autoantibodies for autoimmune diseases were within normal limits.
Plasmid construction and protein expression
The human Recoverin cDNA (GenBank No. NM_002903) was subcloned into pGEX4T-2 vector (GE Healthcare, Piscataway, NJ), and glutathione S-transferase (GST) fusion recoverin protein was expressed in Escherichia (E.) coli strain Rosetta-gami 2 (DE3) (Novagen, Madison, WI). GST fusion proteins were purified through binding to Glutathione-Sepharose (GE Healthcare).
Immunoblot analyses for recoverin, CRMP-5, α-enolase, and carbonic anhydrase II
Recombinant human CRMP-5, α-enolase, and carbonic anhydrase II proteins were purchased from Abnova (Taipei, Taiwan), Biovision (Milpitas, CA), and ATGen (Gyeonggi-do, South Korea), respectively. Proteins were solubilized in 2 × SDS (sodium dodecyl sulfate) sample buffer by heating to 100°C for 5 minutes and separated by 10% SDS-PAGE. Then, proteins were transferred to PVDF (polyvinylidene fluoride) membrane by electroblotting, and immunoblot analyses were performed using patient’s and control’s serum (1/2000 dilution), anti-recoverin antibody (1/20000, Millipore, Billerica, MA), anti-CRMP-5 antibody (1/2000, GeneTex, Irvine, CA), anti-α-enolase antibody (1/2000, Santa Cruz Biotechnology, Santa Cruz, CA), and anti-carbonic anhydrase II antibody (1/2000, Abcam, Cambridge, MA), as previously described .
Bilateral neuroretinitis with unilateral focal outer retinitis developed in a cancer patient positive for autoantibodies against recoverin, CRMP-5, and α-enolase. The ocular manifestations depended largely on comorbid cancer activity, suggesting the possible involvement of paraneoplastic mechanisms in the ocular disorder.
Neuroretinitis is an inflammatory disorder characterized by optic disc edema and the surrounding exudation despite with or without RAPD . In the differential diagnosis, papilledema and optic disc tumors were eliminated owing to the lack of abnormal brain or orbital MRI findings. Hypertensive retinopathy was also denied based on the absence of systemic hypertension. Anterior ischemic optic neuropathy was differentiated based on negative RAPD and the presence of anterior vitreous cells and retinal vasculitis. Vogt-Koyanagi-Harada disease was excluded because the patient had no extraocular symptoms of the disease and indocyanine green angiography showed no choroidal inflammation, such as multiple hypofluorescent spots that appear during the middle phase. Infectious neuroretinitis was denied because of the negative serological screening results including Bartonella henselae.
The pathogenesis of neuroretinitis is generally regarded as vasculitis at the optic disc . In this patient, a possible cause of optic disc swelling was thought to be vasculitis rather than neuritis because of several findings such as negative RAPD, normal P100 latency in VEP, and blind spot enlargement in perimetry. Anti-CRMP-5 antibody-positive PON presents optic neuritis or neuroretinitis characterized by optic disc swelling, the leakages of the optic disc and retinal vessels on FA, and anterior vitreous cells [4, 5]. Since the CRMP-5 protein localizes at oligodendrocytes within the myelin sheath of the optic nerve , bilateral neuroretinitis in this patient is thought to result from inflammation at the vicinity of the optic nerve caused by CRMP-5-related autoimmunity.
The present case also involved unilateral focal outer retinal inflammation with suspected fibrin formation at the fovea, which quickly responded to systemic corticosteroid therapy and completely resolved with the remaining loss of the IS/OS line. To our knowledge, no previous reports have shown such findings in patients with anti-CRMP-5 antibody-positive PON [4–7]. Reasonably, autoantibodies other than anti-CRMP-5 antibody were likely to play a role in the pathogenesis of the outer retinal inflammation.
Our case presented with not only the anti-CRMP-5 antibody but also the antibody for recoverin, a major cause of CAR. To our knowledge, only one case with both antibodies has been reported . However, the ophthalmic findings in this case differed from those presented here; the former case had no initial retinal or optic disc abnormalities and later developed optic disc pallor . Basically, anti-recoverin antibody-positive CAR patients have diffuse photoreceptor damage in ERG and OCT . In the present case, however, photoreceptors were preserved except for the fovea OD from these OCT findings and preserved a-wave amplitude on ERG, suggesting an underlying cause distinctly different from typical cases with anti-recoverin antibody-positive CAR.
Recoverin is reported to be highly uveitogenic and antigenic in rodents and cause experimental autoimmune uveitis (EAU) together with recoverin-specific autoantibody induction and severe photoreceptor degeneration [13, 14]. The histopathological analysis in a recoverin-induced EAU has demonstrated focal cell infiltration from the level of the photoreceptor to the outer plexiform layers in the early stage, which were similar to the OCT images of focal outer retinal inflammation in this case (Figure 1e). Moreover, all the aspects of recoverin-induced EAU and photoreceptor degeneration could be reproduced in naïve animals by the adoptive transfer of stimulated lymphocytes from animals previously immunized with recoverin, suggesting a possible association of cellular immunity with the recoverin-induced ocular disorder .
Regarding the pathogenesis by which anti-recoverin antibody causes CAR, it has been demonstrated that the antibody triggers photoreceptor cell death through apoptosis [2, 15]. However, the association of T cell-mediated autoimmunity in CAR remains elusive. A case with CAR-like disease with no malignancy (benign Warthin tumor) was reported to develop bilateral vitritis, optic disc pallor and retinal vascular sheathing in addition to the typical CAR-related sign of non-recordable ERG . Importantly, lymphocyte proliferative responses demonstrated a strong cellular reaction to recoverin, suggesting the validity of recoverin-specific autoimmunity in the pathogenesis of this CAR-like disease, which was then termed “recoverin-associated retinopathy (RAR)” . We have reported the case of a benign tumor with anti-recoverin antibody-positive retinopathy manifesting typical CAR (i.e., photoreceptor degeneration) and retinal vasculitis with macular edema. Surprisingly, colonic adenoma excised from the patient was potently immunopositive for recoverin, leading us to advocate “benign tumor-associated retinopathy (BAR)” .
Thus, the recoverin-mediated autoimmune retinopathies (CAR, RAR and BAR) [8, 16, 17] and ophthalmic findings in the present case potentially harbor inflammatory features; however, in this cancer patient, it remains unclear why photoreceptors were mostly intact despite the induction of antirecoverin antibody. Future research is needed to elucidate the molecular and cellular mechanisms underlying recoverin-associated pathogenesis of vascular inflammation and neurodegeneration.
α-enolase is another antigen that causes CAR or PON, as this protein localizes at both the retina and the optic nerve . Anti-α-enolase antibody-positive CAR patients have relatively mild clinical course that varied from stability to years to slow progression , suggesting its weaker pathogenicity than anti-recoverin antibody. Therefore, this antibody might contribute less than the other antibody present to the development of this patient’s ophthalmic findings.
In conclusion, we encountered a case with small cell lung carcinoma that was thought to be paraneoplastic neuroretinitis and focal outer retinitis. Patients with paraneoplastic optic neuropathy and retinopathy are likely to develop autoimmune responses against several antigens, as shown in the present case, thus leading to various ophthalmic involvements.
Written informed consent was obtained from the next of kin of the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
We thank Ikuyo Hirose and Shiho Namba (Hokkaido University) for technical assistance. This work was supported in part by the Ono Cancer Research Fund.
- Chan JW: Paraneoplastic retinopathies and optic neuropathies. Surv Ophthalmol. 2003, 48: 12-38. 10.1016/S0039-6257(02)00416-2.View ArticlePubMedGoogle Scholar
- Adamus G, Machnicki M, Seigel GM: Apoptotic retinal cell death induced by antirecoverin autoantibodies of cancer-associated retinopathy. Invest Ophthalmol Vis Sci. 1997, 38: 283-291.PubMedGoogle Scholar
- Adamus G: Autoantibody targets and their cancer relationship in the pathogenicity of paraneoplastic retinopathy. Autoimmun Rev. 2009, 8: 410-414. 10.1016/j.autrev.2009.01.002.View ArticlePubMedPubMed CentralGoogle Scholar
- Yu Z, Kryzer TJ, Griesmann GE, Kim K, Benarroch EE, Lennon VA: CRMP-5 neuronal autoantibody: marker of lung cancer and thymoma-related autoimmunity. Ann Neurol. 2001, 49: 146-154. 10.1002/1531-8249(20010201)49:2<146::AID-ANA34>3.0.CO;2-E.View ArticlePubMedGoogle Scholar
- Cross SA, Salomao DR, Palisi JE, Kryzer TJ, Bradley EA, Mines JA, Lam BL, Lennon VA: Paraneoplastic autoimmune optic neuritis with retinitis defined by CRMP-5-IgG. Ann Neurol. 2003, 54: 38-50. 10.1002/ana.10587.View ArticlePubMedGoogle Scholar
- Adamus G, Brown L, Schiffman J, Iannaccone A: Diversity in autoimmunity against retinal, neuronal, and axonal antigens in acquired neuro-retinopathy. J Ophthalmic Inflamm Infect. 2011, 1: 111-121. 10.1007/s12348-011-0028-8.View ArticlePubMedPubMed CentralGoogle Scholar
- Ko MW, Dalmau J, Galleta SL: Neuro-ophthalmologic manifestations of paraneoplastic syndromes. J Neuro-Ophthalmol. 2008, 28: 58-68. 10.1097/WNO.0b013e3181677fcc.View ArticleGoogle Scholar
- Saito W, Kase S, Ohguro H, Furudate N, Ohno S: Slowly progressive cancer-associated retinopathy. Arch Ophthalmol. 2007, 125: 1431-1433. 10.1001/archopht.125.10.1431.View ArticlePubMedGoogle Scholar
- Kanda A, Noda K, Saito W, Ishida S: (Pro)renin receptor is associated with angiogenic activity in proliferative diabetic retinopathy. Diabetologia. 2012, 55: 3104-3113. 10.1007/s00125-012-2702-2.View ArticlePubMedGoogle Scholar
- Purvin V, Sundaram S, Kawasaki A: Neuroretinitis: review of the literature and new observations. J Neuroophthalmol. 2011, 31: 58-68. 10.1097/WNO.0b013e31820cf78a.View ArticlePubMedGoogle Scholar
- Thirkill CE, FitzGerald P, Sergott RC, Roth AM, Tyler NK, Keltner JL: Cancer-associated retinopathy (CAR syndrome) with antibodies reacting with retinal, optic-nerve, and cancer cells. N Engl J Med. 1989, 321: 1589-1594. 10.1056/NEJM198912073212307.View ArticlePubMedGoogle Scholar
- Heckenlively JR, Ferreyra HA: Autoimmune retinopathy: a review and summary. Semin Immunopathol. 2008, 30: 127-134. 10.1007/s00281-008-0114-7.View ArticlePubMedGoogle Scholar
- Adamus G, Ortega H, Witkowska D, Polans A: Recoverin: a potent uveitogen for the induction of photoreceptor degeneration in Lewis rats. Exp Eye Res. 1994, 59: 447-455. 10.1006/exer.1994.1130.View ArticlePubMedGoogle Scholar
- Gery I, Chanaud NP, Anglade E: Recoverin is highly uveitogenic in Lewis rats. Invest Ophthalmol Vis Sci. 1994, 35: 3342-3345.PubMedGoogle Scholar
- Maeda T, Maeda A, Maruyama I, Ogawa KI, Kuroki Y, Sahara H, Sato N, Ohguro H: Mechanisms of photoreceptor cell death in cancer-associated retinopathy. Invest Ophthalmol Vis Sci. 2001, 42: 705-712.PubMedGoogle Scholar
- Whitcup SM, Vistica BP, Milam AH, Nussenblatt RB, Gery I: Recoverin-associated retinopathy: a clinically and immunologically distinctive disease. Am J Ophthalmol. 1998, 126: 230-237. 10.1016/S0002-9394(98)00149-4.View ArticlePubMedGoogle Scholar
- Saito W, Kase S, Ohguro H, Ishida S: Autoimmune retinopathy associated with colonic adenoma. Graefes Arch Clin Exp Ophthalmol. 2013, 251: 1447-1449. 10.1007/s00417-012-2131-4.View ArticlePubMedGoogle Scholar
- Weleber RG, Watzke RC, Shults WT, Trzupek KM, Heckenlively JR, Egan RA, Adamus G: Clinical and electrophysiologic characterization of paraneoplastic and autoimmune retinopathies associated with antienolase antibodies. Am J Ophthalmol. 2005, 139: 780-794. 10.1016/j.ajo.2004.12.104.View ArticlePubMedGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2415/14/5/prepub
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