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Demyelination in the brain as a paraneoplastic disorder

We read with interest the report of Butteriss et al [1] describing a 40-year-old man with a 15 year history of multiple sclerosis (MS) who developed a large right frontal lobe lesion, which initially exhibited imaging characteristics potentially consistent with either tumefactive MS plaque or a primary glioma. The authors utilized serial proton magnetic resonance spectroscopy which allowed them to correctly suspect that the lesion was sufficiently unlikely to be a manifestation of MS to justify a brain biopsy, which revealed the lesion to be an oligodendroglioma.

We agree with the authors that the development of a new brain lesion during the course of MS presents a variety of problems in diagnosis. Some recent reports have suggested a paraneoplastic aetiology for brain demyelination associated with malignancy [2]. These reports have described both neurological and non-neurological malignancies associated with brain demyelination in a variety of patterns including acute disseminated encephalomyelitis, MS and large focal tumour-like demyelinating lesions [3, 4]. The authors' case [1] is similar to cases of paraneoplastic aetiology caused by the oligodendroglioma notwithstanding the 15 year lapse between discovery of each disease process.

Another recent report identified an immune marker which linked a variety of non-neurologic malignancies with the development of specific paraneoplastic neuro-ophthalmological manifestations in 16 patients [5]. Collapsin response-mediator protein-5 immunoglobin (CRMP-5 IgG) was present in the serum and/or cerebrospinal fluid (CSF) of these cancer patients who developed both optic neuritis and retinitis. Optic neuritis is a frequent manifestation of MS and is caused by demyelination of the optic nerve, a component of the central nervous system (CNS). Retinitis as well has been associated directly with MS [6]. Although the report did not mention a possible relationship between CRMP-5 IgG and brain demyelination, some of the patients described had been considered to have MS, especially Devic's syndrome. Other patients had brain imaging which suggested white matter disease of the CNS and/or oligoclonal banding in CSF.

In previous reports of paraneoplastic brain demyelination [2–4], none of the patients described underwent testing for CRMP-5 IgG, which is now available commercially (Athena Diagnostics, Worcester, MA). However, the possibility that these antibodies may have been present in some cases is further supported by a report suggesting that immunoreactive CRMP-5 phosphoprotein may be expressed normally in oligodendrocytes, most prominently in the brainstem and spinal cord [7]. Damage to oligodendroglial cells by an immune reaction between CRMP-5 IgG and CRMP-5 phosphoprotein could potentially cause paraneoplastic CNS demyelination.

We speculate that paraneoplastic brain demyelination is immune mediated and that accompanying immune markers will eventually be discovered. In cases similar to that described by the authors [1], testing serum and CSF for immune markers may one day be an additional tool in evaluating new brain lesions in patients with MS, and CRMP-5 IgG may eventually prove to be such a marker. Until future research confirms the identity and applicability of such immune markers, techniques such as that described by the authors [1] will be among our best tools in evaluating new brain lesions in patients with MS.

Yours etc.,

J H Jaster and T W Smith

¹ London Corporation, 570 Bridle Path 1117 Grand Prairie, TX 75050 USA ² Department of Pathology (Neuropathology) University of Massachusetts Medical Center Worcester, MA 01655 USA

Received for publication January 29, 2004. Revision received May 24, 2004. Accepted for publication June 16, 2004.

References

1. Butteriss DJA, Ismail A, Ellison DW, Birchall D. Use of serial proton magnetic resonance spectroscopy to differentiate low grade glioma from tumefactive plaque in a patient with multiple sclerosis. Br J Radiol 2003;76:662–5.[Abstract/Free Full Text]
2. Jaster JH, Dohan FC Jr, O'Brien TF. Demyelination in the brain as a paraneoplastic disorder: candidates include some cases of seminoma and central nervous system lymphoma. J Neurol Neurosurg Psychiatry 2002;73:352.[Free Full Text]
3. Jaster JH, Bertorini TE, Dohan FC Jr, O'Brien TF, Wang H, Becske T, et al. Solitary focal demyelination in the brain as a paraneoplastic disorder. Med Pediatr Oncol 1996;26:111–5.[Medline]
4. Jaster JH, Niell HB, Dohan FC Jr, Smith TW. Demyelination in the brain as a paraneoplastic disorder: candidates include some cases of leukemia and non-Hodgkin's lymphoma. Ann Hematol 2003;82:714–5.[Medline]
5. Cross SA, Salomao DR, Parisi JE, Kryzer TJ, Bradley EA, Mines JA, et al. Paraneoplastic autoimmune optic neuritis with retinitis defined by CRMP-5-IgG. Ann Neurol 2003;54:38–50.[CrossRef][Medline]
6. Lucarelli MJ, Pepose JS, Arnold AC, Foos RY. Immunopathologic features of retinal lesions in multiple sclerosis. Ophthalmology 1991;98:1652–6.[Medline]
7. Ricard D, Rogemond V, Charrier E, Aguera M, Bagnard D, Belin MF, et al. Isolation and expression pattern of human Unc-33-like phosphoprotein 6/collapsin response mediator protein 5 (Ulip6/CRMP5): coexistence with Ulip2/CRMP2 in Sema3a- sensitive oligodendrocytes. J Neurosci 2001;21:7203–14.[Abstract/Free Full Text]

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