Ocular Immunology and Inflammation
ISSN: 0927-3948 (Print) 1744-5078 (Online) Journal homepage: http://www.tandfonline.com/loi/ioii20
Clinical and Histological Features of Small Cell Lung Cancer Paraneoplastic Inflammatory Uveitis E. J. Casswell MBBS, iBSc (Hons), E. Pringle MRCP, FRCOphth, C. Thuang FRCOphth, FRCPath, DPhil, M. D. Sanders FRCS, FRCP, FRCOphth & E. M. Graham FRCP, FRCOphth To cite this article: E. J. Casswell MBBS, iBSc (Hons), E. Pringle MRCP, FRCOphth, C. Thuang FRCOphth, FRCPath, DPhil, M. D. Sanders FRCS, FRCP, FRCOphth & E. M. Graham FRCP, FRCOphth (2015): Clinical and Histological Features of Small Cell Lung Cancer Paraneoplastic Inflammatory Uveitis, Ocular Immunology and Inflammation, DOI: 10.3109/09273948.2015.1012296 To link to this article: http://dx.doi.org/10.3109/09273948.2015.1012296
Published online: 14 Jul 2015.
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Date: 20 September 2015, At: 06:28
Ocular Immunology & Inflammation, Early Online, 1–5, 2015 ! Informa Healthcare USA, Inc. ISSN: 0927-3948 print / 1744-5078 online DOI: 10.3109/09273948.2015.1012296
ORIGINAL ARTICLE
Clinical and Histological Features of Small Cell Lung Cancer Paraneoplastic Inflammatory Uveitis E. J. Casswell, MBBS, iBSc (Hons)1, E. Pringle, MRCP, FRCOphth2, C. Thuang, FRCOphth, FRCPath, DPhil3, M. D. Sanders, FRCS, FRCP, FRCOphth4, and E. M. Graham, FRCP, FRCOphth5
Downloaded by [University of Otago] at 06:28 20 September 2015
1
Western Eye Hospital, London, UK, 2Kings College Hospital, London, UK, 3Department of Ocular Biology and Therapeutics, UCL Institute of Ophthalmology, London, UK, 4National Hospital of Neurology & Neurosurgery, Queen’s Square, London, UK, and 5St Thomas’ Hospital, London, UK
ABSTRACT Purpose: Paraneoplastic ocular inflammation can be associated with the autoantibody against collapsin response-mediator protein-5 (anti-CRMP-5). We describe the clinical and histological features of 2 rare cases of small cell lung carcinoma (SCLC) presenting with intraocular inflammation: the first was anti-CRMP-5 positive and the second preceded the auto-antibody’s discovery but with remarkably similar features. The previously unreported retinal histology is described. Methods: Case notes review. Results: Both cases presented with bilateral visual loss, constricted visual fields, vitritis, and pale, swollen optic discs. Fundal fluorescein angiographies showed optic disc leakage. Retinal histology of both cases revealed predominantly inner retinal inflammation. Following their diagnosis with SCLC, serology for case 1 was positive for anti-CRMP-5 but case 2 pre-dated its discovery. Conclusions: CRMP-5 inflammatory eye disease presents with a distinct pattern of clinical and histological features, which may be the first sign of their underlying cancer. Retinal histology revealed predominantly inner retinal inflammation. Keywords: CRMP-5, histology, inflammation, paraneoplastic, visual loss
described, which has not previously been reported in CRMP-5-associated eye disease.
Patients with small cell lung carcinoma can present with a paraneoplastic syndrome that produces an optic neuropathy and ‘‘retinitis,’’ distinct from carcinoma-associated retinopathy. This syndrome has been associated with the paraneoplastic autoantibody to collapsin response-mediator protein-5 (CRMP-5).1 This paper describes 2 cases of ocular inflammation associated with small cell carcinoma: the first is confirmed as CRMP-5 positive and the second preceded the discovery of the autoantibody but has remarkably similar features. Although unconfirmed, the latter may represent one of the earliest known cases of a paraneoplastic inflammatory eye disease. Both patients presented prior to their cancer diagnoses, underlying the importance of early recognition of this clinical picture. The retinal histology is
MATERIALS AND METHODS Case notes review.
RESULTS Case 1 A 52-year-old female smoker presented in February 2008 with progressive painless visual loss in both eyes over 4 months to the point where she was only able to read newspaper headlines. Her corrected visual acuity
Received 28 April 2014; revised 19 January 2015; accepted 22 January 2015; published online 10 July 2015 Correspondence: Edward Casswell, Western Eye Hospital, London NW1 5QH, UK. E-mail: [email protected]
1
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E. Casswell et al.
was 6/60 OD, 3/60 OS. Despite this she could identify 13 out of 16 Ishihara color plates with the left eye but was only able to identify the control plate on the right. Her visual fields were constricted bilaterally with central scotomata. Although the anterior chambers were not inflamed, she had a moderate vitritis in both eyes. Both optic discs were pale and swollen (Figure 1a) and clinically the retina had a diffuse odd sheen. The fundus fluorescein angiogram (FFA) showed diffuse leakage from the optic disc capillaries (Figure 1b) and from some retinal capillaries. There was no cystoid macular edema or leakage from the macula on FFA; indeed, the fovea appeared atrophic on optical coherence tomography (OCT) (Figure 1c). More recent spectral-domain OCT revealed bilateral foveal atrophy, with disruption of the IS/OS junction (Figure 2). Magnetic resonance imaging (MRI) of the brain and orbits was unremarkable and cerebrospinal fluid (CSF) examination revealed a normal white cell
count, but marginally raised protein (0.5 mg/L) with unmatched oligoclonal bands. All routine blood tests were normal and treponemal serology was negative. Given this atypical presentation, a diagnostic vitrectomy and superonasal choroidoretinal biopsy was performed to exclude lymphoma. The vitreous cytology showed occasional lymphocytes, plasma, and mononuclear cells but no malignant cells. The retina shows a mild chronic inflammatory infiltrate predominantly of the inner retinal layers (Figure 3). A paraneoplastic syndrome was suspected and the patient was treated with periorbital and systemic steroids, though her vision did not recover. A CT chest identified a left lower lobe lesion and subsequent biopsy of paratracheal lymph nodes identified metastatic small cell carcinoma. Her peripheral blood serology was negative for anti-recoverin but positive for anti-CRMP-5 antibodies as well as amphiphysin and Hu. She has completed her chemotherapy and remains in remission.
FIGURE 1. Optic discs and macular OCT (case 1): (a) Colour fundus photographs showing pale and swollen optic discs. (b) Fundus fluorescein angiography revealed leaking disc capillaries. (c) Time-domain optical coherence tomography (OCT) scan demonstrates thinning at the fovea rather than oedema. Ocular Immunology & Inflammation
Downloaded by [University of Otago] at 06:28 20 September 2015
Features of CRMP-5 Paraneoplastic Eye Disease
3
FIGURE 2. SD-OCT of both maculae (case 1): Spectral domain optical coherence tomography (OCT) scans of the right (a) and left (b) eyes reveal atrophic thinning at the fovea and disruption of the IS/OS junction.
FIGURE 3. Retinal histology (case 1): This histopathology image shows a light infiltrate of chronic inflammatory cells, predominantly within the inner retina and accentuated around blood vessels. There is some loss of nuclei within the ganglion cell and inner nuclear layers, but the outer nuclear layer and photoreceptor segments are well preserved. (Haematoxylin and eosin, x 20 objective).
Case 2 A 58-year-old male smoker presented in 1973 with an 18-month history of weakness and numbness affecting both legs, and a 6-month history of painless, rapidly progressive loss of vision in both eyes. On examination his visual acuity was 6/60 OD and counting fingers OS. He was unable to read print size N48 with either eye and could not recognize any of the Ishihara color plates. The visual field in the right eye was markedly constricted; the left eye field was constricted and had a dense central scotoma. Anterior chambers were quiet but there was a !
2015 Informa Healthcare USA, Inc.
moderate vitritis in both eyes. Both optic discs were pale and swollen (Figure 4a). Clinically, both retinae were described as ‘‘boggy’’ (diffusely thickened with loss of normal retinal reflection). The fundus fluorescein angiography (FFA) showed diffuse leakage from the capillaries of the optic disc and marked leakage from peripheral vessels (Figure 4b) but with no macular edema. Neurological examination revealed a peripheral neuropathy. Investigations showed a raised ESR 68, but negative treponemal serology. The CSF showed 4 white cells/mL, a raised protein of 68 mg/L, and a high CSF IgG of 25.5%. The chest radiograph showed hilar lymphadenopathy, which on biopsy revealed small cell carcinoma. The patient died soon afterward. At autopsy, the histopathology of the eye was reported by Norman Ashton (Personal Communication).2 He noted a ‘‘remarkable picture in which the uvea and retina are densely infiltrated with lymphocytes and plasma cytoid cells,’’ unlike carcinomatosis. Lymphocytes are seen lining up along the inner limiting membrane and in a perivascular distribution (Figure 5).
DISCUSSION Both of these cases presented with bilateral intraocular inflammation and subsequently were diagnosed with small cell lung cancer. They both experienced a bilateral progressive visual loss, constricted visual fields with moderate vitritis, pale swollen optic discs, and a combination of retinal and optic nerve disease. The combination of a bilateral vitritis with pale swollen discs and poor optic nerve function is
Downloaded by [University of Otago] at 06:28 20 September 2015
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E. Casswell et al.
FIGURE 4. Fundal photo and fluorescein angiography (case 2): (a) Fundal photos show bilateral swollen pale optic discs. (b) Fundus fluorescein angiography (FFA) showed diffuse leakage from the capillaries of the optic disc with marked leakage from vessels in the periphery.
FIGURE 5. Retinal and Optic Disc histology (case 2): (a) Lymphocytes are seen along the inner limiting membrane and in a perivascular distribution. There is shortening of the photoreceptor segments, but the outer nuclear layer is better preserved than the inner nuclear layer (Haematoxylin and eosin, x 20 objective). (b) The optic nerve and adjacent tissue demonstrates a cellular infiltrate extending through the lamina cribrosa (Haematoxylin and eosin, x2 objective).
unusual. The differential diagnosis includes sarcoidosis, syphilis, and lymphoproliferative infiltration. Cross et al.1 reported a case series of 16 patients with CRMP-5 IgG and a paraneoplastic optic
neuropathy. They documented a ‘‘retinitis’’ in 5 cases from this series, all of whom had electroretinogram abnormalities, though no further clinical retinal details were given. This description may be Ocular Immunology & Inflammation
Downloaded by [University of Otago] at 06:28 20 September 2015
Features of CRMP-5 Paraneoplastic Eye Disease misleading as ophthalmologists generally reserve the term ‘‘retinitis’’ for an area of fluffy retinal whitening with vitritis seen in patients with retinal infections or Behc¸et disease,3 unlike what was seen in our cases. The retinal histology has not previously been reported in CRMP-5-associated eye disease. There is a striking retinal inflammatory process in the inner retinal layers, with lymphocytes lining up along the internal limiting membrane and in a perivascular distribution (Figures 3 and 5). This histological retinitis was correctly predicted by Cross et al., but should be differentiated from the clinical ‘‘retinitis’’ described in retinal infections and Behc¸et disease. Ashton’s prediction in 19752 was equally pertinent. Reporting the histology of case 2 prior to the identification of paraneoplastic optic neuropathies, he concluded the histology of our second case was not carcinomatous infiltration, and suggested this may represent an abnormality of the reticuloendothelial system. Cross et al. found in healthy retina that the CRMP-5 antigen was present in the ganglion cells, nerve fiber layer, and photoceptors.1 These locations may explain the inflammation along the internal limiting membrane seen in our cases (Figures 3 and 5), in addition to the disruption to the IS/OS junction shown on the OCT of case 1 (Figure 2). These changes are unlikely to be due to the other anti-antibodies (amphiphysin and Hu) as these are not normally associated with ocular inflammation in the absence of anti-CRMP-5.1 Previous histological examination of the optic nerve of patients with CRMP-5-associated inflammatory eye disease has revealed a predominantly CD8+ T-cell inflammatory reaction,1 although a subsequent report described a predominantly B-cell CD20 reaction.7 The mechanism remains unclear, but it may be that the CRMP-5 expressed by the SCLC tumor cells leads to a combination of cytotoxic T-cell and B-cell activation, resulting in optic nerve and retinal inflammation. Recently, Saito et al.4 reported a case of CRMP5-positive bilateral optic neuropathy with unilateral neuroretinitis in a patient with small cell carcinoma. Again, this case lacked the retinal whitening seen in clinical retinitis, although OCT scans revealed focal fibrin-like inflammation in the outer retinal layers at the fovea, not found in our cases (Figures 1 and 2). As the authors suggest, however, this may have been due to additional paraneoplastic auto-antibodies that were also present. De La Sayette identified the anti-CV2 antibody in 1998,4 25 years after the presentation of case 2. Their patient had a paraneoplastic syndrome causing a bilateral optic neuropathy and a cerebellar syndrome.
!
2015 Informa Healthcare USA, Inc.
5
This antibody has subsequently been defined as an IgG antibody against the intracellular protein CRMP-5. Given the similarities in clinical presentation, we postulate that the elevated CSF IgG level identified in our second case may have included the anti-CRMP-5 autoantibody. Although not recognized at the time, this may represent one of the earliest unconfirmed cases of a paraneoplastic inflammatory eye disease.
CONCLUSIONS When presented with smokers with progressive bilateral visual loss and pale swollen optic discs with vitritis and ‘‘boggy’’ retinae, a paraneoplastic process should be considered. Both of our cases presented prior to their diagnosis of lung cancer and early diagnosis helps to improve outcome.6 Retinal histology of CRMP-5-associated inflammatory eye disease revealed predominantly inner retinal inflammation.
DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
REFERENCES 1. Cross SA, Salomao DR, Parisi JE, et al. Paraneoplastic autoimmune optic neuritis with retinitis defined by CRMP-5-IgG. Ann Neurol. 2003;54:38–50. 2. Ashton N. Personal communication (histology report). 2nd Jan 1975. 3. Davis JL. Diagnostic dilemmas in retinitis and endophthalmitis. Eye (Lond). 2012;26:194–201. 4. Saito M, Saito W, Kanda A, et al. A case of paraneoplastic optic neuropathy and outer retinitis positive for autoantibodies against collapsin response mediator protein-5, recoverin, and a-enolase. BMC Ophthalmol. 2014;14:5. doi: 10.1186/1471-2415-14-5. 5. de la Sayette V, Bertran F, Honnorat J, et al. Paraneoplastic cerebellar syndrome and optic neuritis with anti-CV2 antibodies: clinical response to excision of the primary tumor. Arch Neurol. 1998;55:405–408. 6. Lin RS, Plevritis SK. Comparing the benefits of screening for breast cancer and lung cancer using a novel natural history model. Cancer Causes Control. 2012;23:175–185. 7. Sheorajpanday R, Slabbynck H, Van De Sompel W, et al. Small cell lung carcinoma presenting as collapsin response-mediating protein (CRMP) -5 paraneoplastic optic neuropathy. J Neuroophthalmol. 2006;26:168–172.
ISSN: 0927-3948 (Print) 1744-5078 (Online) Journal homepage: http://www.tandfonline.com/loi/ioii20
Clinical and Histological Features of Small Cell Lung Cancer Paraneoplastic Inflammatory Uveitis E. J. Casswell MBBS, iBSc (Hons), E. Pringle MRCP, FRCOphth, C. Thuang FRCOphth, FRCPath, DPhil, M. D. Sanders FRCS, FRCP, FRCOphth & E. M. Graham FRCP, FRCOphth To cite this article: E. J. Casswell MBBS, iBSc (Hons), E. Pringle MRCP, FRCOphth, C. Thuang FRCOphth, FRCPath, DPhil, M. D. Sanders FRCS, FRCP, FRCOphth & E. M. Graham FRCP, FRCOphth (2015): Clinical and Histological Features of Small Cell Lung Cancer Paraneoplastic Inflammatory Uveitis, Ocular Immunology and Inflammation, DOI: 10.3109/09273948.2015.1012296 To link to this article: http://dx.doi.org/10.3109/09273948.2015.1012296
Published online: 14 Jul 2015.
Submit your article to this journal
Article views: 17
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ioii20 Download by: [University of Otago]
Date: 20 September 2015, At: 06:28
Ocular Immunology & Inflammation, Early Online, 1–5, 2015 ! Informa Healthcare USA, Inc. ISSN: 0927-3948 print / 1744-5078 online DOI: 10.3109/09273948.2015.1012296
ORIGINAL ARTICLE
Clinical and Histological Features of Small Cell Lung Cancer Paraneoplastic Inflammatory Uveitis E. J. Casswell, MBBS, iBSc (Hons)1, E. Pringle, MRCP, FRCOphth2, C. Thuang, FRCOphth, FRCPath, DPhil3, M. D. Sanders, FRCS, FRCP, FRCOphth4, and E. M. Graham, FRCP, FRCOphth5
Downloaded by [University of Otago] at 06:28 20 September 2015
1
Western Eye Hospital, London, UK, 2Kings College Hospital, London, UK, 3Department of Ocular Biology and Therapeutics, UCL Institute of Ophthalmology, London, UK, 4National Hospital of Neurology & Neurosurgery, Queen’s Square, London, UK, and 5St Thomas’ Hospital, London, UK
ABSTRACT Purpose: Paraneoplastic ocular inflammation can be associated with the autoantibody against collapsin response-mediator protein-5 (anti-CRMP-5). We describe the clinical and histological features of 2 rare cases of small cell lung carcinoma (SCLC) presenting with intraocular inflammation: the first was anti-CRMP-5 positive and the second preceded the auto-antibody’s discovery but with remarkably similar features. The previously unreported retinal histology is described. Methods: Case notes review. Results: Both cases presented with bilateral visual loss, constricted visual fields, vitritis, and pale, swollen optic discs. Fundal fluorescein angiographies showed optic disc leakage. Retinal histology of both cases revealed predominantly inner retinal inflammation. Following their diagnosis with SCLC, serology for case 1 was positive for anti-CRMP-5 but case 2 pre-dated its discovery. Conclusions: CRMP-5 inflammatory eye disease presents with a distinct pattern of clinical and histological features, which may be the first sign of their underlying cancer. Retinal histology revealed predominantly inner retinal inflammation. Keywords: CRMP-5, histology, inflammation, paraneoplastic, visual loss
described, which has not previously been reported in CRMP-5-associated eye disease.
Patients with small cell lung carcinoma can present with a paraneoplastic syndrome that produces an optic neuropathy and ‘‘retinitis,’’ distinct from carcinoma-associated retinopathy. This syndrome has been associated with the paraneoplastic autoantibody to collapsin response-mediator protein-5 (CRMP-5).1 This paper describes 2 cases of ocular inflammation associated with small cell carcinoma: the first is confirmed as CRMP-5 positive and the second preceded the discovery of the autoantibody but has remarkably similar features. Although unconfirmed, the latter may represent one of the earliest known cases of a paraneoplastic inflammatory eye disease. Both patients presented prior to their cancer diagnoses, underlying the importance of early recognition of this clinical picture. The retinal histology is
MATERIALS AND METHODS Case notes review.
RESULTS Case 1 A 52-year-old female smoker presented in February 2008 with progressive painless visual loss in both eyes over 4 months to the point where she was only able to read newspaper headlines. Her corrected visual acuity
Received 28 April 2014; revised 19 January 2015; accepted 22 January 2015; published online 10 July 2015 Correspondence: Edward Casswell, Western Eye Hospital, London NW1 5QH, UK. E-mail: [email protected]
1
Downloaded by [University of Otago] at 06:28 20 September 2015
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E. Casswell et al.
was 6/60 OD, 3/60 OS. Despite this she could identify 13 out of 16 Ishihara color plates with the left eye but was only able to identify the control plate on the right. Her visual fields were constricted bilaterally with central scotomata. Although the anterior chambers were not inflamed, she had a moderate vitritis in both eyes. Both optic discs were pale and swollen (Figure 1a) and clinically the retina had a diffuse odd sheen. The fundus fluorescein angiogram (FFA) showed diffuse leakage from the optic disc capillaries (Figure 1b) and from some retinal capillaries. There was no cystoid macular edema or leakage from the macula on FFA; indeed, the fovea appeared atrophic on optical coherence tomography (OCT) (Figure 1c). More recent spectral-domain OCT revealed bilateral foveal atrophy, with disruption of the IS/OS junction (Figure 2). Magnetic resonance imaging (MRI) of the brain and orbits was unremarkable and cerebrospinal fluid (CSF) examination revealed a normal white cell
count, but marginally raised protein (0.5 mg/L) with unmatched oligoclonal bands. All routine blood tests were normal and treponemal serology was negative. Given this atypical presentation, a diagnostic vitrectomy and superonasal choroidoretinal biopsy was performed to exclude lymphoma. The vitreous cytology showed occasional lymphocytes, plasma, and mononuclear cells but no malignant cells. The retina shows a mild chronic inflammatory infiltrate predominantly of the inner retinal layers (Figure 3). A paraneoplastic syndrome was suspected and the patient was treated with periorbital and systemic steroids, though her vision did not recover. A CT chest identified a left lower lobe lesion and subsequent biopsy of paratracheal lymph nodes identified metastatic small cell carcinoma. Her peripheral blood serology was negative for anti-recoverin but positive for anti-CRMP-5 antibodies as well as amphiphysin and Hu. She has completed her chemotherapy and remains in remission.
FIGURE 1. Optic discs and macular OCT (case 1): (a) Colour fundus photographs showing pale and swollen optic discs. (b) Fundus fluorescein angiography revealed leaking disc capillaries. (c) Time-domain optical coherence tomography (OCT) scan demonstrates thinning at the fovea rather than oedema. Ocular Immunology & Inflammation
Downloaded by [University of Otago] at 06:28 20 September 2015
Features of CRMP-5 Paraneoplastic Eye Disease
3
FIGURE 2. SD-OCT of both maculae (case 1): Spectral domain optical coherence tomography (OCT) scans of the right (a) and left (b) eyes reveal atrophic thinning at the fovea and disruption of the IS/OS junction.
FIGURE 3. Retinal histology (case 1): This histopathology image shows a light infiltrate of chronic inflammatory cells, predominantly within the inner retina and accentuated around blood vessels. There is some loss of nuclei within the ganglion cell and inner nuclear layers, but the outer nuclear layer and photoreceptor segments are well preserved. (Haematoxylin and eosin, x 20 objective).
Case 2 A 58-year-old male smoker presented in 1973 with an 18-month history of weakness and numbness affecting both legs, and a 6-month history of painless, rapidly progressive loss of vision in both eyes. On examination his visual acuity was 6/60 OD and counting fingers OS. He was unable to read print size N48 with either eye and could not recognize any of the Ishihara color plates. The visual field in the right eye was markedly constricted; the left eye field was constricted and had a dense central scotoma. Anterior chambers were quiet but there was a !
2015 Informa Healthcare USA, Inc.
moderate vitritis in both eyes. Both optic discs were pale and swollen (Figure 4a). Clinically, both retinae were described as ‘‘boggy’’ (diffusely thickened with loss of normal retinal reflection). The fundus fluorescein angiography (FFA) showed diffuse leakage from the capillaries of the optic disc and marked leakage from peripheral vessels (Figure 4b) but with no macular edema. Neurological examination revealed a peripheral neuropathy. Investigations showed a raised ESR 68, but negative treponemal serology. The CSF showed 4 white cells/mL, a raised protein of 68 mg/L, and a high CSF IgG of 25.5%. The chest radiograph showed hilar lymphadenopathy, which on biopsy revealed small cell carcinoma. The patient died soon afterward. At autopsy, the histopathology of the eye was reported by Norman Ashton (Personal Communication).2 He noted a ‘‘remarkable picture in which the uvea and retina are densely infiltrated with lymphocytes and plasma cytoid cells,’’ unlike carcinomatosis. Lymphocytes are seen lining up along the inner limiting membrane and in a perivascular distribution (Figure 5).
DISCUSSION Both of these cases presented with bilateral intraocular inflammation and subsequently were diagnosed with small cell lung cancer. They both experienced a bilateral progressive visual loss, constricted visual fields with moderate vitritis, pale swollen optic discs, and a combination of retinal and optic nerve disease. The combination of a bilateral vitritis with pale swollen discs and poor optic nerve function is
Downloaded by [University of Otago] at 06:28 20 September 2015
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E. Casswell et al.
FIGURE 4. Fundal photo and fluorescein angiography (case 2): (a) Fundal photos show bilateral swollen pale optic discs. (b) Fundus fluorescein angiography (FFA) showed diffuse leakage from the capillaries of the optic disc with marked leakage from vessels in the periphery.
FIGURE 5. Retinal and Optic Disc histology (case 2): (a) Lymphocytes are seen along the inner limiting membrane and in a perivascular distribution. There is shortening of the photoreceptor segments, but the outer nuclear layer is better preserved than the inner nuclear layer (Haematoxylin and eosin, x 20 objective). (b) The optic nerve and adjacent tissue demonstrates a cellular infiltrate extending through the lamina cribrosa (Haematoxylin and eosin, x2 objective).
unusual. The differential diagnosis includes sarcoidosis, syphilis, and lymphoproliferative infiltration. Cross et al.1 reported a case series of 16 patients with CRMP-5 IgG and a paraneoplastic optic
neuropathy. They documented a ‘‘retinitis’’ in 5 cases from this series, all of whom had electroretinogram abnormalities, though no further clinical retinal details were given. This description may be Ocular Immunology & Inflammation
Downloaded by [University of Otago] at 06:28 20 September 2015
Features of CRMP-5 Paraneoplastic Eye Disease misleading as ophthalmologists generally reserve the term ‘‘retinitis’’ for an area of fluffy retinal whitening with vitritis seen in patients with retinal infections or Behc¸et disease,3 unlike what was seen in our cases. The retinal histology has not previously been reported in CRMP-5-associated eye disease. There is a striking retinal inflammatory process in the inner retinal layers, with lymphocytes lining up along the internal limiting membrane and in a perivascular distribution (Figures 3 and 5). This histological retinitis was correctly predicted by Cross et al., but should be differentiated from the clinical ‘‘retinitis’’ described in retinal infections and Behc¸et disease. Ashton’s prediction in 19752 was equally pertinent. Reporting the histology of case 2 prior to the identification of paraneoplastic optic neuropathies, he concluded the histology of our second case was not carcinomatous infiltration, and suggested this may represent an abnormality of the reticuloendothelial system. Cross et al. found in healthy retina that the CRMP-5 antigen was present in the ganglion cells, nerve fiber layer, and photoceptors.1 These locations may explain the inflammation along the internal limiting membrane seen in our cases (Figures 3 and 5), in addition to the disruption to the IS/OS junction shown on the OCT of case 1 (Figure 2). These changes are unlikely to be due to the other anti-antibodies (amphiphysin and Hu) as these are not normally associated with ocular inflammation in the absence of anti-CRMP-5.1 Previous histological examination of the optic nerve of patients with CRMP-5-associated inflammatory eye disease has revealed a predominantly CD8+ T-cell inflammatory reaction,1 although a subsequent report described a predominantly B-cell CD20 reaction.7 The mechanism remains unclear, but it may be that the CRMP-5 expressed by the SCLC tumor cells leads to a combination of cytotoxic T-cell and B-cell activation, resulting in optic nerve and retinal inflammation. Recently, Saito et al.4 reported a case of CRMP5-positive bilateral optic neuropathy with unilateral neuroretinitis in a patient with small cell carcinoma. Again, this case lacked the retinal whitening seen in clinical retinitis, although OCT scans revealed focal fibrin-like inflammation in the outer retinal layers at the fovea, not found in our cases (Figures 1 and 2). As the authors suggest, however, this may have been due to additional paraneoplastic auto-antibodies that were also present. De La Sayette identified the anti-CV2 antibody in 1998,4 25 years after the presentation of case 2. Their patient had a paraneoplastic syndrome causing a bilateral optic neuropathy and a cerebellar syndrome.
!
2015 Informa Healthcare USA, Inc.
5
This antibody has subsequently been defined as an IgG antibody against the intracellular protein CRMP-5. Given the similarities in clinical presentation, we postulate that the elevated CSF IgG level identified in our second case may have included the anti-CRMP-5 autoantibody. Although not recognized at the time, this may represent one of the earliest unconfirmed cases of a paraneoplastic inflammatory eye disease.
CONCLUSIONS When presented with smokers with progressive bilateral visual loss and pale swollen optic discs with vitritis and ‘‘boggy’’ retinae, a paraneoplastic process should be considered. Both of our cases presented prior to their diagnosis of lung cancer and early diagnosis helps to improve outcome.6 Retinal histology of CRMP-5-associated inflammatory eye disease revealed predominantly inner retinal inflammation.
DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
REFERENCES 1. Cross SA, Salomao DR, Parisi JE, et al. Paraneoplastic autoimmune optic neuritis with retinitis defined by CRMP-5-IgG. Ann Neurol. 2003;54:38–50. 2. Ashton N. Personal communication (histology report). 2nd Jan 1975. 3. Davis JL. Diagnostic dilemmas in retinitis and endophthalmitis. Eye (Lond). 2012;26:194–201. 4. Saito M, Saito W, Kanda A, et al. A case of paraneoplastic optic neuropathy and outer retinitis positive for autoantibodies against collapsin response mediator protein-5, recoverin, and a-enolase. BMC Ophthalmol. 2014;14:5. doi: 10.1186/1471-2415-14-5. 5. de la Sayette V, Bertran F, Honnorat J, et al. Paraneoplastic cerebellar syndrome and optic neuritis with anti-CV2 antibodies: clinical response to excision of the primary tumor. Arch Neurol. 1998;55:405–408. 6. Lin RS, Plevritis SK. Comparing the benefits of screening for breast cancer and lung cancer using a novel natural history model. Cancer Causes Control. 2012;23:175–185. 7. Sheorajpanday R, Slabbynck H, Van De Sompel W, et al. Small cell lung carcinoma presenting as collapsin response-mediating protein (CRMP) -5 paraneoplastic optic neuropathy. J Neuroophthalmol. 2006;26:168–172.
