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MEDICAL HYPOTHESIS: L. Bataller, D. F. Wade, F. Graus, H. D. Stacey, M. R. Rosenfeld, and J. Dalmau Antibodies to Zic4 in paraneoplastic neurologic disorders and small-cell lung cancer Neurology 2004; 62: 778-782 [Abstract] [Full text] [PDF]

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Antibodies to Zic4 in paraneoplastic neurologic disorders and small-cell lung cancer

J. Howard Jaster, MD   (21 April 2004)

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Josep Dalmau   (21 April 2004)

Antibodies to Zic4 in paraneoplastic neurologic disorders and small-cell lung cancer 21 April 2004
J. Howard Jaster, MD, London Corporation 570 Bridle Path 1117, Grand Prairie, TX 75050 Send Correspondence to journal: Re: Antibodies to Zic4 in paraneoplastic neurologic disorders and small-cell lung cancer harbert38104{at}yahoo.com J. Howard Jaster, MD	I read with interest the report of Bataller et al [1] which associated Zic4 antibodies with malignancy, neurologic symptoms, and other paraneoplastic antibodies including collapsin response mediator protein 5 (CRMP5). In their report, the authors summarize the clinical manifestations observed in their patients, and categorize them into several paraneoplastic neurologic syndromes. However, the authors do not present brain imaging or brain tissue examination of biopsy or autopsy material or other supporting evidence regarding the intermediate etiologic histopathology in the brain. Several recent reports [2] have postulated that some cases of demyelination in the brain may occur as a paraneoplastic disorder. These reports have described a large variety of neurologic symptoms associated with brain demyelination in a variety of patterns including acute disseminated encephalomyelitis, multiple sclerosis (MS), and large focal tumor- like demyelinating lesions. However, most of the cancer patients described were not tested for paraneoplastic antibodies, especially Zic4 and CRMP5 antibodies. Nonetheless, many of the neurologic symptoms associated with paraneoplastic brain demyelination were similar to those described by the authors [1] as associated with Zic4 antibodies, especially in some patients having multiple paraneoplastic antibodies including Zic4, and having "multifocal neurologic deficits characteristic of encephalomyelitis". [1] Another recent report [3] associated CRMP5 antibodies with various malignancies and paraneoplastic optic neuritis and retinitis. Optic neuritis is a frequent initial manifestation of MS and is caused by demyelination of the optic nerve, a component of the central nervous system. Retinitis as well has been associated directly with MS. [4] Many of the 16 patients discussed in this study [3] had imaging and other laboratory evidence consistent with demyelinating disease of the brain, especially MS or Devic's syndrome. Further supporting a possible association between CRMP5 and paraneoplastic brain demyelination is a report suggesting that immunoreactive CRMP5 phosphoprotein may be expressed normally in oligodendrocytes, most prominently in the brainstem and spinal cord. [5] I speculate that in some cases the neurologic manifestations observed in the patients of the authors [1] may have been caused by paraneoplastic demyelination in the brain. In such cases I speculate that paraneoplastic brain demyelination is immune mediated and that accompanying immune markers will eventually be discovered. I speculate that Zic4 antibodies, CRMP5 antibodies, or both, may eventually be discovered to play an etiologic role in paraneoplastic demyelination in the brain. References 1. Bataller L, Wade DF, Graus F, et al. Antibodies to Zic4 in paraneoplastic neurologic disorders and small-cell lung cancer. Neurology 2004;62:778-782. 2. 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 [letter]. Ann Hematol 2003;82:714-715. 3. 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. 4. Lucarelli MJ, Pepose JS, Arnold AC, Foos RY. Immunopathologic features of retinal lesions in multiple sclerosis. Ophthalmology 1991;98:1652-1656. 5. Ricard D, Rogemond V, Charrier E, 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;21:7203-7214.
Reply to Jaster 21 April 2004
Josep Dalmau, Department of Neurology, University of Pennsylvania 3400 Spruce Street, Philadelphia, PA 19104 Send Correspondence to journal: Re: Reply to Jaster jdalmau{at}mail.med.upenn.edu Josep Dalmau	Based on a few reported patients with leukemia, lymphoma and brain demyelination of unclear etiology,[2] Dr. Jaster speculates that Zic4 and/or CRMP5 antibodies play an etiologic role in paraneoplastic demyelination of the brain. None of our 61 patients with paraneoplastic immunity to Zic4 (with or without Hu or CRMP5 antibodies) had MRI findings supporting a primarily leukoencephalitic or demyelinating process. Three patients with Zic4 and Hu antibodies underwent autopsy, and in all three the findings were consistent with paraneoplastic encephalomyelitis (neuronal degeneration, perivascular and interstitial inflammatory infiltrates), without evidence of demyelination (data not shown). Furthermore, we did not find anti-Hu, anti-Zic4 or anti-CRMP5 antibodies in 20 patients with multiple sclerosis and 18 patients with retinitis/ optic neuropathy of unknown cause.[1] Because CRMP5 antibodies have been reported in association with a myriad of neurologic symptoms and deficits (including among others, Lambert-Eaton myasthenic syndrome, retinitis/ optic neuritis) the pathogenic role of this immunity in optic neuritis / retinitis is unclear.[6] In addition to the lack of MRI or pathological evidence of demyelination, the clinical features of the 61 patients with Zic4 antibodies differ in many ways from those of the patients discussed by Dr. Jaster.[2] The most important difference is that our patients harbored immune responses to onconeuronal antigens. Additionally, none of the Zic4 positive patients had leukemia, lymphoma, seminoma, bone marrow transplant (BMT), or were treated with post-BMT immunosuppressants (cyclosporine, tacrolimus) that may cause leukoencephalopathy.[7] These data do not support that the clinical features of our patients resulted from a paraneoplastic demyelinating process. References 6. Yu Z, Kryzer TJ, Griesmann GE, Kim K-K, Benarroch EE, Lennon VA. CRMP-5 neuronal autoantibody: marker of lung cancer and thymoma-related autoimmunity. Ann Neurol 2001;49:146-154. 7. Bartynski, WS, Zeigler Z, Spearmen MP, Lin L, Shadduck RK, Lister J. Etiology of cortical and white matter lesions in cyclosporin-A and FK- 506 neurotoxicity. Am J Neuroradiol 2001;22:1901-1914.