| OCR Text |
Show EDITORIAL A CR( I) MP in the Optic Nerve: Recognition and Implications of Paraneoplastic Optic Neuropathy Preston C. Calvert, MD Paraneoplastic optic neuropathy ( PON) is a rare cause of visual loss in patients with cancer. The clinical picture of PON usually begins with subacute or acute loss of vision in one or both eyes ( 1). Visual acuity can be reduced to any degree, sometimes to profound levels. There are other signs of optic nerve dysfunction such as color perception deficits and optic nerve- related visual field loss. Optic disc swelling may occur. A posterior vitreous cellular reaction is frequently present. PON is almost always associated with other evidence of neurologic dysfunction such as cerebellar ataxia, polyneuropathy, dysgeusia, anosmia, involuntary movement disorders, autonomic dysfunction, and myelopathy. PON and associated neurologic manifestations may occur in a patient with known cancer or may be the presenting sign of underlying systemic neoplasia. The underlying tumor is most often small cell lung carcinoma, although the condition has been associated with other tumors, including non- small cell lung carcinoma, renal carcinoma, and thyroid carcinoma ( 1). PON was recognized as a distinct disease entity by its clinical features and by the lack of electrophysiological evidence characteristic of paraneoplastic retinal degeneration. Elec-troretinography does not show abnormalities consistently in patients with PON, although amplitude reduction in photopic responses can be seen ( 2). By contrast, both photopic and scotopic responses are usually markedly attenuated in typical cancer- associated retinopathy ( 3). Melanoma- associated retinopathy has unique electroretinography features that are not seen in patients with PON, particularly attenuation of B waves with relative preservation of A waves in both the scotopic and photopic responses, reflecting functional impairment of rod bipolar pathways in the retina similar to those of congenital stationary night blindness ( 4). In patients with PON, visual evoked potentials often show conduction delay ( 1). Cerebrospinal fluid examination in PON usually shows lymphocyte- predominant reactive pleocytosis with white cell counts in the range of 20 to 50 ( range of 0- 122 has been reported), elevated total protein ( usually 50- 120 mg%), and oligoclonal immunoglobulin bands on electrophoresis ( 1). Cerebrospinal fluid cytology shows no evidence of direct meningeal infiltration. Examination of the pathologic optic nerves in a few cases ( 5,6) has shown findings of perivascular inflammation and associated demyelination. Similar findings have been seen in many other central nervous system areas, including medial temporal lobe, cerebellum ( with Purkinje cell loss), brainstem, and spinal cord ( 1,5,6). Peripheral nerve structures may also be involved ( 1). Examination of the serum has shown IgG antibodies directed against an antigen expressed in neural tissues and associated tumors. Although a number of apparently different antigen specificities have been reported, they have all been shown to be Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland. Address correspondence to Preston C. Calvert, MD, Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD; E- mail: pcalver( t amail. com J Neuro- Ophthalmol, Vol. 26, No. 3, 2006 165 J Neuro- Ophthalmol, Vol. 26, No. 3, 2006 Editorial indistinguishable from the 62 kDa collapsin response-mediator protein- 5 ( CRMP- 5) ( 7- 9). The CRMP- 5 antigen is expressed in many central and peripheral tissues by neurons and supporting cells. It is also regularly expressed in small cell lung carcinoma cytoplasm, providing an explanation for the crossreactivity of the antitumoral immune response with host neural tissues. The widespread expression of CRMP- 5 in central and peripheral nervous system cells presumably accounts for the wide range of neurologic impairments in patients with PON. There are cases of PON that do not show CRMP- 5 reactivity, presumably related to other antigens shared by optic nerve and tumor cells. Continued laboratory serum screening may yield additional target antigens. In this issue of the Journal of Neuro- Ophthalmology, Sheorajpanday et al ( 10) report a case of PON as an isolated presenting manifestation of CRMP- 5- mediated autoimmunity. Discovery of the antibody led to the diagnosis of small cell lung carcinoma. Isolated PON as the presenting feature has been reported only rarely ( 1,11). Neuropathologic examination of the optic nerves showed features typical of those reported previously in PON; regrettably, pathologic examination of the rest of the brain in their case did not occur. The visual prognosis of patients with PON is reported to be quite variable. Some patients progress to severe visual loss despite treatment of the underlying tumor and efforts at immunosuppression ( 1). This was unfortunately true in the case of Sheorajpanday et al ( 10). Other patients have an apparent beneficial effect on their visual function after effective treatment of the underlying tumor ( 1,12). Such improvement can occasionally be dramatic ( 12). The potential responsiveness of PON to tumor treatment emphasizes the importance of early recognition of this entity so that the underlying tumor can be quickly identified and treated. Although there usually will be other neurologic manifestations such as progressive ataxia, myelopathy, or dementia associated with optic neuropathy to suggest a paraneoplastic syndrome, the case of Sheorajpanday et al ( 10) highlights the need to think of PON even when subacute or acute optic neuropathy is isolated. In their case, small cell lung carcinoma was apparent on routine chest radiography, but if such a study is negative in a patient with suspected PON, a chest CT should be considered as well as fluoro-deoxyglucose positron emission tomography because small cell lung tumors can be difficult to detect ( 1). If no evidence of a lung tumor is found, one should consider other sites such as the thyroid gland, nasopharynx, kidney, and possibly thymus gland. A serum assay for anti- CRMP- 5 antibody should be obtained immediately when the diagnosis is entertained. The CRMP- 5 antibody assay, developed at the Mayo Clinic, is available for clinical testing through the Mayo Clinic Laboratories by submitting a standard serum specimen ( 9,13). Situations that should suggest this diagnosis when isolated optic nerve disease is present include acute or subacute onset and progressive course of unilateral or bilateral optic neuropathy that remains unexplained after detailed history, examination, and initial ancillary evaluation. The presence of posterior vitreous cells with optic disc swelling in the absence of other apparent causes of inflammatory optic neuropathy such as sarcoidosis, infectious meningitis, or known systemic infection or autoimmune disorder should also raise the question of PON. Treatment of PON with corticosteroids has produced variable results ( 1,12,14). As noted previously, many patients experience no improvement or progressive decline in vision despite all treatment efforts. However, visual improvement has been reported after use of different corticosteroid regimens, including oral prednisone in doses of 60 mg per day ( 14) and 1,000 mg intravenous methyl-prednisolone per day for 5 days ( 12). One patient with PON was reported to have shown dramatic visual improvement after being treated with intravenous immunoglobulin ( IVIg), although another patient in the same report showed no change in visual acuity with the same regimen ( 2). The limited reported anecdotal experience does not permit firm recommendations about treatment of PON beyond the need to identify the underlying tumor rapidly and, if possible, treat it. Given the frequency of devastating permanent visual loss in PON, one should consider a trial of corticosteroid treatment possibly initiated by intravenous high-dose methylprednisolone and followed by a course of IVIg. The degree of permanent axonal loss that has occurred by the time of diagnosis and initiation of treatment probably influences the outcome. REFERENCES 1. Cross SA, Salamao DR, Parisi JE, et al. Paraneoplastic autoimmune optic neuritis with retinitis defined by CRMP- 5- IgG. Ann Neurol 2003; 54: 38- 50. 2. Guy J, Aptsiauri N. Treatment of paraneoplastic visual loss with intravenous immunoglobulin: report of 3 cases. Arch Ophthalmol 1999; 117: 471- 7. 3. Matsui Y, Mehta MC, Katsumi O, et al. Electrophysiological findings in paraneoplastic retinopathy. Graefes Arch Clin Exp Ophthalmol 1992; 230: 324- 8. 4. Alexander KR, Fishman GA, Peachey NS, et al. ' On' response defect in paraneoplastic night blindness with cutaneous malignant melanoma. Invest Ophthalmol Vis Sci 1992; 33: 477- 83. 5. Pillay N, Gilbert JJ, Ebers GC, et al. Internuclear ophthalmoplegia and ' optic neuritis': paraneoplastic effects of bronchial carcinoma. Neurology 1984; 34: 788- 91. 6. Boghen D, Sebag M, Michaud J. Paraneoplastic optic neuritis and encephalomyelitis. Report of a case. Arch Neurol 1988; 45: 353- 6. 7. Malik S, Furlan AJ, Sweeney PJ, et al. Optic neuropathy: a rare paraneoplastic syndrome. J Clin Neuroophthalmol 1992; 12: 137^ 1. 8. 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- 8. 166 © 2006 Lippincott Williams & Wilkins Editorial J Neuro- Ophthalmol, Vol. 26, No. 3, 2006 9. Yu Z, Kryzer TJ, Griesmann GE, et al. CRMP- 5 neuronal autoantibody: marker of lung cancer and thymoma related autoimmunity. Ann Neurol 2001; 49: 146- 54. 10. 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 Neuro-ophthalmol 2006; 26: 168- 172. 11. Asproudis IC, Nikas AN, Psilas KG. Paraneoplastic optic neuropathy in a patient with a non- small cell lung carcinoma: a case report. Eur J Ophthalmol 2005; 15: 420- 3. 12. Luiz JE, Lee AG, Keltner JL, et al. Paraneoplastic optic neuropathy and autoantibody production in small- cell carcinoma of the lung. J Neuroophthalmol 1998; 18: 178- 81. 13. Paraneoplastic autoantibody evaluation, serum. Mayo Medical Laboratories Test Catalog, [ database on the Internet]. Rochester, MN: Mayo Foundation, Mayo Medical Laboratories; 2000- 2001. Available at: http:// 216.245.161.151/ TestView. aspx? testID= 9722. Accessed June 5, 2006. 14. Waterston JA, Gilligan BS. Paraneoplastic optic neuritis and external ophthalmoplegia. Aust N Z J Med 1986; 16: 703^ k 167 |
