simultaneous comparison of sphenoidal, nasopharyngeal, and ear electrodes. Epilepsia 1986;27:8 1-86 4. Silverman D. The anterior temporal electrode and the ten-twenty system. Electroencephalogr Clin Neurophysiol 1960;12:735 5. Homan RW, Jones MC, Rawat S. Anterior temporal electrodes in complex partial seizures. Electroencephalogr Clin Neurophysiol 1988;70:105-109 6. Goodin DS, Aminoff MJ, Laxer KD. Detection of epileptiform activity by different noninvasive EEG methods in complex partial epilepsy. Ann Neurol 1990;27:330-334
CvclosDorine and Mdtipie Sclerosis M. P. Pender, MD, PhD, FRACP
I read with interest the paper by The Multiple Sclerosis Study Group reporting that cyclosporine delayed the progression of multiple sclerosis rl]. As stated in the introduction, the rationale for undertaking the study was partly based on the ability of cyclosporine to suppress the development of experimental allergic encephalomyelitis (EAE), a T-cell-mediated autoimmune disease that serves as a possible model of multiple sclerosis [2, 31. Recent studies have shown, however, that the administration of low-dose cyclosporine can convert acute EAE, a self-limited monophasic disease, into chronic relapsing EAE 14, 53 with large plaques of spinal cord demyelination [ S ] . Low-dose cyclosporine also converts acute experimental allergic neuritis (EAN), another autoimmune Tcell-mediated disorder, into chronic relapsing EAN 161. The mechanism by which cyclosporine facilitates the development of chronic relapsing EAE or EAN is unclear, but it is likely that it interferes with immunoregulation as demonstrated by its ability to induce syngeneic graft-versus-host disease I71 and, when administered neonatally, autoimmune disease {S]. In view of these recent observations, the possibility that cyclosporine may aggravate multiple sclerosis in some patients should be borne in mind. This may be more likely to occur in patients on a low dose of cyclosporine.
4. Polman CH, Matthaei I, de Groot CJA, et al. Low-dose cyclosporin A induces relapsing remitting experimental allergic encephalomyelitis in the Lewis rat. J Neuroimmunol 1988;17: 209-2 16 5. Pender MP, Stanley GP, Yoong G, Nguyen KB. The neuropathology of chronic relapsing experimental allergic encephalomyelitis induced in the Lewis rat by inoculation with whole spinal cord and treatment with cyclosporin A. Acta Neuropathol 1990;80:172-183 6. McCombe PA, van der Kreek SA, Pender MP. The effects of prophylactic cyclosporin A on experimental allergic neuritis (EAN) in the Lewis rat. Induction of relapsing EAN using low dose cyclosporin A. J Neuroimmunol 1990;28:131-140 7. Fischer AC, Beschorncr WE, Hcss AD. Requirements for the induction and adoptive transfer of cyclosporine-induced syngeneic graft-versus-host disease. J Exp Med 1989;169:1031-1041 8. Sakaguchi S, Sakaguchi N. Organ-specific autoimmune disease induced in mice by elimination of T cell subsets. V. Neonatal administration of cyclosporin A causes autoimmune disease. J Immunul 1989;142:471-480
Reply
Jerry S. Wolinsky, M D D r Pender makes an extremely important point. It is well accepted that the dose, timing, route of administration, duration of therapy, method of disease induction, and host are all critical and interdependent variables that affect the clinical and pathological manifestations of experimental allergic encephalomyelitis. This dictum is very well illustrated by the observations of Pender and others using several cyclosporines, a variety of animal species, and several induction and treatment paradigms. I t is an equally valid maxim when other immunosuppressive agents are used. However, n o detrimental effect on clinical disease progression was observed when cyclosporine was administered to multiple sclerosis patients over the course of our [l] o r several other clinical trials [2, 31. Notwithstanding, one should a f t m y be concerned that treatment of multiple sclerosis patients with any immunosuppressant may be accompanied by unwelcome deterioration or unanticipated effects, especially if one deviates from carefully studied protocols. Perhaps it is surprising that cyclosporine and other immunosuppressants seem t o have such a modest effect, for better or ill, on the clinical course of multiple sclerosis.
Department of Medicine University of Queensland Department of Neurology Royal Brisbane Hospital B risbane, Australia
Department of Neurology University of Texas Health Sciences Center at Houston Houston, T X
Refwences
RefeerenreJ
1. The Multiple Sclerosis Study Group. Efficacy and toxicity of cyclosporine in chronic progressive multiple sclerosis: a randomized, double-blinded, placebo-controlled clinical trial. Ann Neurol 1990;27:591-60> 2. Bolton C, Bore1 JF, Cuzner ML, et al. Immunosuppression by cyclosporin A of experimental allergic encephalomyelitis. J Neurol Sci 1982;56:147-153 3. Hinrichs DJ, Wegmann KW, Peters BA. The influence of cyclosporin A on the development of actively induced and passively transferred experimental allergic encephalomyelitis. Cell Immunol 1983;77:202-209
1. Multiple Sclerosis Study Group. Efficacy and toxicity of cy-
226 Annals of Neurology
Vol 29
No 2 February 1991
closporine in chronic progressive multiple sclerosis: a randomized, double-blinded, placebo-controlled clinical trial. Ann Neurol 1990;27:591-605 2. Kappos L, Patzold U, Dommasch D, et al. Cyclosporine versus azarhioprine in the long-term treatment of multiple sclerosis: results of the German multicenter study. Ann Neurol 1988;23: 56-63 3. Rudge P, Koetsier JC, Mertin J, et al. Randomised double blind controlled trial of cyclosporin in multiple sclerosis.J Neurol Neurosurg Psychiatry 1989;52:559-565
CvclosDorine and Mdtipie Sclerosis M. P. Pender, MD, PhD, FRACP
I read with interest the paper by The Multiple Sclerosis Study Group reporting that cyclosporine delayed the progression of multiple sclerosis rl]. As stated in the introduction, the rationale for undertaking the study was partly based on the ability of cyclosporine to suppress the development of experimental allergic encephalomyelitis (EAE), a T-cell-mediated autoimmune disease that serves as a possible model of multiple sclerosis [2, 31. Recent studies have shown, however, that the administration of low-dose cyclosporine can convert acute EAE, a self-limited monophasic disease, into chronic relapsing EAE 14, 53 with large plaques of spinal cord demyelination [ S ] . Low-dose cyclosporine also converts acute experimental allergic neuritis (EAN), another autoimmune Tcell-mediated disorder, into chronic relapsing EAN 161. The mechanism by which cyclosporine facilitates the development of chronic relapsing EAE or EAN is unclear, but it is likely that it interferes with immunoregulation as demonstrated by its ability to induce syngeneic graft-versus-host disease I71 and, when administered neonatally, autoimmune disease {S]. In view of these recent observations, the possibility that cyclosporine may aggravate multiple sclerosis in some patients should be borne in mind. This may be more likely to occur in patients on a low dose of cyclosporine.
4. Polman CH, Matthaei I, de Groot CJA, et al. Low-dose cyclosporin A induces relapsing remitting experimental allergic encephalomyelitis in the Lewis rat. J Neuroimmunol 1988;17: 209-2 16 5. Pender MP, Stanley GP, Yoong G, Nguyen KB. The neuropathology of chronic relapsing experimental allergic encephalomyelitis induced in the Lewis rat by inoculation with whole spinal cord and treatment with cyclosporin A. Acta Neuropathol 1990;80:172-183 6. McCombe PA, van der Kreek SA, Pender MP. The effects of prophylactic cyclosporin A on experimental allergic neuritis (EAN) in the Lewis rat. Induction of relapsing EAN using low dose cyclosporin A. J Neuroimmunol 1990;28:131-140 7. Fischer AC, Beschorncr WE, Hcss AD. Requirements for the induction and adoptive transfer of cyclosporine-induced syngeneic graft-versus-host disease. J Exp Med 1989;169:1031-1041 8. Sakaguchi S, Sakaguchi N. Organ-specific autoimmune disease induced in mice by elimination of T cell subsets. V. Neonatal administration of cyclosporin A causes autoimmune disease. J Immunul 1989;142:471-480
Reply
Jerry S. Wolinsky, M D D r Pender makes an extremely important point. It is well accepted that the dose, timing, route of administration, duration of therapy, method of disease induction, and host are all critical and interdependent variables that affect the clinical and pathological manifestations of experimental allergic encephalomyelitis. This dictum is very well illustrated by the observations of Pender and others using several cyclosporines, a variety of animal species, and several induction and treatment paradigms. I t is an equally valid maxim when other immunosuppressive agents are used. However, n o detrimental effect on clinical disease progression was observed when cyclosporine was administered to multiple sclerosis patients over the course of our [l] o r several other clinical trials [2, 31. Notwithstanding, one should a f t m y be concerned that treatment of multiple sclerosis patients with any immunosuppressant may be accompanied by unwelcome deterioration or unanticipated effects, especially if one deviates from carefully studied protocols. Perhaps it is surprising that cyclosporine and other immunosuppressants seem t o have such a modest effect, for better or ill, on the clinical course of multiple sclerosis.
Department of Medicine University of Queensland Department of Neurology Royal Brisbane Hospital B risbane, Australia
Department of Neurology University of Texas Health Sciences Center at Houston Houston, T X
Refwences
RefeerenreJ
1. The Multiple Sclerosis Study Group. Efficacy and toxicity of cyclosporine in chronic progressive multiple sclerosis: a randomized, double-blinded, placebo-controlled clinical trial. Ann Neurol 1990;27:591-60> 2. Bolton C, Bore1 JF, Cuzner ML, et al. Immunosuppression by cyclosporin A of experimental allergic encephalomyelitis. J Neurol Sci 1982;56:147-153 3. Hinrichs DJ, Wegmann KW, Peters BA. The influence of cyclosporin A on the development of actively induced and passively transferred experimental allergic encephalomyelitis. Cell Immunol 1983;77:202-209
1. Multiple Sclerosis Study Group. Efficacy and toxicity of cy-
226 Annals of Neurology
Vol 29
No 2 February 1991
closporine in chronic progressive multiple sclerosis: a randomized, double-blinded, placebo-controlled clinical trial. Ann Neurol 1990;27:591-605 2. Kappos L, Patzold U, Dommasch D, et al. Cyclosporine versus azarhioprine in the long-term treatment of multiple sclerosis: results of the German multicenter study. Ann Neurol 1988;23: 56-63 3. Rudge P, Koetsier JC, Mertin J, et al. Randomised double blind controlled trial of cyclosporin in multiple sclerosis.J Neurol Neurosurg Psychiatry 1989;52:559-565
