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Multiple sclerosis: why ?
Biomed. & Pharmacother., 43 (1989) 327333 Q Elsevier, Paris
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ultiple sclerosis
:
why ?
G.W. ELLISON UCLA Multiple Sclerosis Research and Treatment Center, Departmet of Neurology, School of Medicine University of California, 710 Westwood Plaza, Los Angeles, CA 90024-I 749, USA {Received 20 March 1989; accepted 24 March 1989)
Summary -
Multiple sclerosis is a chronic inflammatory demyelinating condition of the nervous system. Its etiology is obscure. Something in the environment strikes a susceptible host. Somehow the immune system produces central nervous system lesions. Magnetic resonance imaging scans show far greater “lesion” formation in the brain than was expected from clinical exacerbations. White blood cell changes suggest the disease is not entirely localized to the CNS. Some immunomodulatory treatments temporarily slow the rate of deterioration. multiple sclerosis / etiology / immunomodulatory treatment / deterioration rate
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SC~&OS~ multiple : une mise P jour. h sclerose multiple correspond h un processus inflnmmatoire chronique dPmyPIinisant du systeme nerveux. Son Ptiologie reste obscure. On peut penser que le malade est sensible ci un facteur d’agression environnemental. Par un mecanisme quelconque, le systeme immunitaire produit des lesions du systeme nerveux central. La resonance magnetique nucleaire montre dans l’encephale des lesions bien plus &ndues que ce qu’on attendrait en fonctin des acces cliniques de la maladie. les anomalies leucocytaires constatees suggtknt que cette maladie ne se localise pas exclusivement au systeme nerveux central. I1 est possible, grrice d certains traitements immuno-modulants, de ralentir la d&+ioration. s&rose multipk /&tiologie/ tmitements immunommiutants/d&Giomtion
It seems likely that multiple sclerosis (MS) is a disease with a multifactorial etiology. Something in the environment, perhaps a virus, induces disease in a genetically susceptible host [12]. Reddy et al. detected human retrovirus lymphotrophic virus type 1 (HTLV-1) nucleic acid in the white blood mononuclear cells of subjects with MS [54]. The investigators had detected antibodies against HTLV-1 earlier [33],but others had difficulty in confirming the findings 1391.Reddy et al. used the polymerasc chain reaction and forced cloning of amplified DNA to look for the HTLV-1 sequences. They found sequences in all 6 patients’ adherent cells (monocytes and macrophages) and in 1 of the 20 normal individuals. Only 2 of the patients’ sera had antibodies. After amplification and cloning, nonadherent MS lymphocytes had low levels of hybridizable cellular
DNA, but none of the 13 control subjects demonstrated such sequences. The investigators claim an association between the HTLV-1 sequences and MS. However, if the virus caused MS, we would expect to find autonomously proliferating spinal fluid lymphocytes in MS patients. Bimbaum et al. could find none [2]. Thus, we must await confirmation from other laboratories and larger studies on patients whith other neurological diseases before concluding that HTLV-1 causes MS (see also Hauser et al., who could not find any viral sequences with the less sensitive in situ hybridization or antibodies by ELISA [24]). One method to clarify the genetic component in the etiology of MS is to study twins. Kinnunen et al. have shown a genetic relationship in 15815 twins in the Finnish National Twin Registry. Two
of 7 affected monozygotic twins were concordant S. Six of 6 dixygotic twins were discordant. The authors expect more associations, since many of the twins are under age SO and are expected to show more MS as time passes. In 1988 Sadovnik and Baird found increased risk for MS within the families of those afflicted. Earlier studies had not corrected for age. Sadovnik and Baird made the age correction and found that children and siblings of patients were 30-50 times more likely than the general popu!ation to have MS. However, the risk factor is still small
WI.
Elevated cerehrospinal fluid oligoclonal immunoglob~ins and in~ammato~ parenchymal infiltrations support the view that plaques are caused by the immune system [47, 37,41,65,42]. However, there are many inconsistencies. It appears that macrophages carry out the actual demyelina~on [52, 423. We do not know what activates the macrophages. For example, Hayashi er al, found few activated thymus-derived T-cells in plaques in the brains from 9 patients [ZS].One of the inconsistencies with an autoaggressive immune attrack is the presence in the brain pa~n~hyma of mainly suppressor/c~otoxi~ Tcells (CD2, 3, 8f cells) which do not have activation antigens such as the IL2 receptors (Ta, Tll-3, or 2-N markers). There is increasing evidence that astrocytes could be the “antigen-presenting cells” for the lymphocytes. But Hayashi et af, found no expression of major histo~ompatibility complex (MHC) II markers in their specimens. Endothelial cells, on the other hand, had both MHC I and II and the 4B marker, indica~ng they were activated. Thus, not only do we not know what attracts lymphocytes into the white matter (the antigen), but we are also ignorant of what the cells do when they arrive in the brain 15, 221. Traugott and Lebon have discovered astrocytes with interferon gamma and Ia on their surfaces in MS plaques [64]. This discovery implicates the local produ~ion of inte~eron gamma in plaques, Interestingly, they found interferon alpha and interferon beta on macrophages, suggesting that these molecules are locally immunosuppressive via macrophages. Thus, rather than being purely destructive cytotoxic effector cells, the maerophages could be immunoreg~lato~ for cytotoxic lymphocytes ! Tke are changes in the peripheml blood immune cells in MS [l, 17, 221. Chof~on et al., using autoiogous mixed lymphocyte reactions
(AMLR) to generate suppressor cells for pokeweed mitogen-stimulated immunoglobulin G synthesis, found less suppression in progressive type MS [8]. They also found a correlation with a decrease in circulating CD4f 2W4+ subset of circulating T-cells. Rose ef al. found a decrease in CD45 + CD4 + (suppressor inducer T-cells) within 1 month of new symptoms in patients with exacerbatingremitting (E-R) type MS studied at monthly intervals. Seven of 9 patients had 4 major exacerbations and 3 minor subjective changes. In all 7 patients, the ratio of %CD4 + CD45R- / %CD4 +CD45R+ increased. This was secondary to an absolute increase in the number of CD4 + CD4SR- cells and a decrease in CD4+ CD45R+. Gallo et al. found increased amounts of interIeukin 2 (IL2) in serum or CSF of only 20 % of MS patients. This discovery suggests that only a small number of T-lymphocytes are activated (28 % of exacerbating-remitting type MS). Surprisingly, none of the chronic progressive patients had elevated IL2. These patients are those with the greatest frequency of new MRI lesions. ~aimone et al. found that bone marrow derived B-cells responded normallly when stimulated with endogenous B-cell specific growth factor (BCGF}. It was known that pokeweed mitogen induced immunoglobulin secretion by peripheral blood cells is increased in MS. The increase could be secondary to altered regulatory T-cell functions or intrinsic B-cell function. Their work favors increased secretion under the direction of T-cells. This is in contrast to the elonal expansion of B-cells, which are seen in the central nervous system in MS [40]. It is clear there are more magnetic resonance imaging scan (MRI) “lesions’* than clinical exacerbations [50]. Oget et al. found large MRI lesions correlated with decreased natural killer cell function, decreased immunoglobulin G secretion after pokeweed mitogen stimulation, and concanavalin A induced suppression. There was no parallel change in the lymphocyte phenotypic markers. There was no correlation between changes in immune function and clinical attacks. These findings probably explain the marked disparities in clinical-laboratory correlations in the past [l, 421. The detection of high signal intensity “lesions” on T2 weighted MRI scans has revolutionized the diagnosis of MS [49]. Diagnostic dilemmas arise in patients over the age of 40 who may have areas
Mdtiple sclerosis : why ? of high signal intensity which are similar to MS [18, 31.Fazekas et al. found the specificity for MS was increased if the lesion was equal to or larger than 6 mm diameter, abutted a ventricular body, or was located infratentorially. These is little correlation between changes in clinical scores and total lesion load in square millimeters [32]. However, patients with chronic progressive MS have a greater lesion load than those with benign MS, a greater number of infratentorial lesions, and lesions associated with an expected clinical expression, e.g. paralysis [32]. There is a greater appreciation for cognitive impairment with or without “hard” neurological signs [16]. Litvan et al. detected slow information processing in MS [38]. In 16 patients they found long-term verbal memory impairment, but shortterm memory and memory scanning was spared. Also, when high rates of presentation in the auditory serial audition test were used information processing was slowed down. There is a correlation between MRI lesions and cognitive defects or neuropsychological tests [15, 55, 53). Reischier er al. found small periventricular MR1 lesions to correlate with depression. Massive periventricular and frontal white matter lesions correlated with euphoria and disorders of judgment [55]. Although there is a good correlation between MRI lesions and pathology [58, 571, new MR1 lesion formation correlates poorly with clinical manifestations of MS in E-R type patients [27]. Willoughby et al. found 3.2 enlarged MR1 lesions per patient per year in a serial study of E-R patients. There were only 0.53 clinical relapses per patient per year. The MR1 lesions expanded over a 4-week period, then gradually shrank to leave a small residual abnormality that is indistinguishable from chronic MR1 lesions. Such studies show that MS is a much more active process than has been suspected clinically. They also suggest that MRI lesion-laboratory test correlations will be necessary in future studies t671. Kappos et al. found MR1 lesion localization to be more important for correlations with cerebral spinal tluid IgG levels and visual evoked response abnormalities than total lesion volume I29J. Those involved in MS clinical trials have relied upon changes in ncurologic functions as the primary outcome measures. There is a search for more quantitative outcome variables. John Kurtzke’s Expanded Disability Status Scale (EDSS) score is a ranking scale rather than a measure-
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ment, where intervals between each value are equidistant [34, ‘59, 351. Recently, serial MRI scans have been recommended [4g]. According to Kappos et af., treatment with high dose cortical steroids, cyclophosphamide, cyclosporine A or azathioprine decreased the number and intensity of new lesions [63]. On the other hand, Kappos et al. found 40 % of 194 patients treated with either cyclosporine A or azathioprine had an increase in the number and volume of MRI lesions after 24-32 months of treatment despite clinical stabilization [63]. Although we have used corticotropin (ACTH) since the 1950s as a treatment for MS, the role of the adrenal corticosteroids has not been certain [51]. The situation has changed since the advent of high dose “pulse” methylprednisolone. Milligan et al. treated 13 patients with chronic progressive MS with 500 mg of methylprednisolone intravenously for 5 days. At 4 weeks after treatment the methylprednisolone treated patients’ EDSS improved significantly compared to the placebo treated group. An additional 22 patients in relapse phase had a “significant” effect in favor of methylprednisolone treatment [43]. Our group at the University of California, Los Angeles, conducted a trial of methylprednisolone with azathioprine versus placebo methylprednisolone and real azathioprine and double placebo in 97 patients in progression phase. Although there was little deterioration in all 3 groups, those receiving methylprednisolone did the best [46, 141.There are theoretical reasons for considering ACTH treatments [lo]. Because of fewer adverse effects, it is possible that some variation of pulse methylprednisolone treatment will become the standard of care. Azathioprine has been used to treat MS since the late 1960s [13]. Since most trials were anecdotal (i.e., they used non randomized controls, did not use placebos, or did not mask the patients or investigators), we have not been able to determine the true usefulness of azathioprine. The British and Dutch Multiple Sclerosis Azathioprine Trial Group has shown only slight benefit from fixed dose azathioprine 141.Their randomized, placebo-controlled, double-masked trial of azachioprine (2.5 mg per kg per day for 3-4 yr) showed slight differences with Student’s t-test on outcome measures such as Kmtzke’s Disability Status Scale score or the Ambulation Index. One hundred and sixty-one patients received azathioprine; 171 were treated with placebo. There were trends in favor of the azathioprine
G. W. Ellison
treatment but no statistically significant differences (pc0.01) were demonstrated. The authors conclude, and agree that the slight benefit was outweighed by the inconvenience of the treatment and the possible increase in malignancy. Our UCLA group has used axathioprine for treating the chronic progression phase in a randomixed placebo-controlled double-masked trial (Neur&w; in press). Although the exacerbation rate was decreased in this study, (from 0.48 in the placebo-treated to 0.24 in the axathioprine recipients) we found no difference in the primary measures of progression. The proponents of axathioprine suggest that we have used the drug COOlate in the course of the disease and for too short a time. However, I consider that the British and Dutch Axathioprine Trial Group results militate against any role for axathioprine when
used alone. Cyclosporin A was tested in a randomized, masked, placebo-controlled, multicenter clinical trial [60].Two hundred and seventy-three patients in chronic progression phase received cyclosporin A (274 placebo) for 2 years. Outcome measures were Kurtzke’s EDSS, Ambulation Index (AI), Quantitative Examination of Neurologic Function, and an Incapacity Status Scale. The patients received 6 mg per kg of cyclosporin A. There was a slight delay in the time to becoming wheelchair-bound and a delay in the time to loss of independence as measured by the upper extremity functions in those receiving the cydosporin A. There was no difference in the time to sustained progression (an increase of 0.5 units in the collapsed EDSS or a 1.0 increase in the AI over 2 consecutive visits). There was 44 % attrition in the cyclosporin A group and 33 % in the placebotreated group. Eight cyclosporin A recipients discontinued the treatment due to hypertension, and 13 because of nephrotoxicity. There was a greater than 25 % incidence of hirsutism, headache, edema, nausea, and gingival hyperplasia in the cyclosporin recipients [61]. Kappos et al. stabilized the course of patients with MS with either azathioprine or cyclosporine 1291.They concluded that the toxicity of cyclosporine outweighed the benefit. Cyclophosphamide by itself administered either intravenously or orally appears to induce a 2-year remission in patients with MS [19, 211. Myers et al. treated 14 patients in progression phase with ascending doses of cyclophosphamide WI. Although there was stabilization or improvement in many of the patients, the toxicity level
was unacceptable. Similar problems were encountered by Goodkin et al. [20]. In a randomized, single masked (physician) trial, Likosky et al. treated 44 patients in progression phase with folic acid or intravenous cyclophosphamide [36]. With Kurtzke’s Functional Systems Scores, EDSS, AI, Incapacity and Environmental Status Scores collected beforehand, 12, 18 and 24 months after therapy; they found no differences between the groups. These results can be contrasted with those of treatment with the combination of adrenal cortical steroids and cyclophosphamide. Hommes et al. have treated patients in progression phase since 1971 [26]. Their work demonstrating improvement in 32/47 patients after 7- 11 yr follow-up is complemented by the trial of Hauser et al. with ACTH substituted for the prednisone 1223:.In open studies, Carter et al. also found improve-
ment with the combination of cyclophosphamide and ACTH in 154 patients [6]. Unfortunately, progression reoccurs approximately 2 yr after the initial treatment. Current investigations will ascertain the effects of repeated treatments. Although Khatri et al. [30] demonstrate that plasmapheresis is useful for chronic progressive MS, others do not find much benefit [62]. Further work is under way to determine the efficacy and risk benefit ratio of plasmapheresis. Immunosuppression with total lymphoid irradiation (TLI) appears to stabilize the course with patients with chronic progressive phase of MS [9]. A relationship exists between lymphopenia and improvement [l l]; there is concern that the beneficial effects will fade and further treatment will become difficult [45]. Interferon alpha and beta have been given to patients with MS both as an antiviral and as an immunoregulatory therapy [3I]. Although exacerbations are decreased in frequency, we are not certain of long-term benefit. Clinical trials are under way of subcutaneous beta interferon. We do know, however that interferon gamma is an unsuitable treatment for MS [28]. Contrary to expectations, exacerbations were increased in frequency rather than decreased. There is hope that changes might be brought about in the immune system with monoclonal antibodies against specific receptors on thymusderived cells [66]. Currently, antimouse antibodies develop in most patients treated with mouse monoclonal antibody [7]. If we can delete the appropriate T-cell subset, we may impair the primary immune response and the treatment
Multiple sclerosis : why ? would be repeatable. Mouse-human chime& ~tibodies might be less immunogenic. In conclusion, progress has been made in understanding the etiology and pathogenesis of MS, although the identity of the environmentai agent which provokes the disease in the genetically susceptible host has not been dete~ined. The immune response seems important for central nervous system demyelination and piaqle formation. Treatments with immunosuppressive regimens, particularly total lymphoid irradiation and the combination of adrenal steroids with alkylating agents appear to slow the rate of deterioration but not to halt it. Because progression of the disease reoccurs, we must devise treatments for MS which can be repeated safely.
This work was papacy supported by the Pacific Multiple Sclerosis Research Foundation, The Conrad Hilton Foundation, The Joe Gheen Fund and the Gustafson Endowment. I am grateful to Mr. Richard Burger for his assistance.
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ultiple sclerosis
:
why ?
G.W. ELLISON UCLA Multiple Sclerosis Research and Treatment Center, Departmet of Neurology, School of Medicine University of California, 710 Westwood Plaza, Los Angeles, CA 90024-I 749, USA {Received 20 March 1989; accepted 24 March 1989)
Summary -
Multiple sclerosis is a chronic inflammatory demyelinating condition of the nervous system. Its etiology is obscure. Something in the environment strikes a susceptible host. Somehow the immune system produces central nervous system lesions. Magnetic resonance imaging scans show far greater “lesion” formation in the brain than was expected from clinical exacerbations. White blood cell changes suggest the disease is not entirely localized to the CNS. Some immunomodulatory treatments temporarily slow the rate of deterioration. multiple sclerosis / etiology / immunomodulatory treatment / deterioration rate
R&urn& -
SC~&OS~ multiple : une mise P jour. h sclerose multiple correspond h un processus inflnmmatoire chronique dPmyPIinisant du systeme nerveux. Son Ptiologie reste obscure. On peut penser que le malade est sensible ci un facteur d’agression environnemental. Par un mecanisme quelconque, le systeme immunitaire produit des lesions du systeme nerveux central. La resonance magnetique nucleaire montre dans l’encephale des lesions bien plus &ndues que ce qu’on attendrait en fonctin des acces cliniques de la maladie. les anomalies leucocytaires constatees suggtknt que cette maladie ne se localise pas exclusivement au systeme nerveux central. I1 est possible, grrice d certains traitements immuno-modulants, de ralentir la d&+ioration. s&rose multipk /&tiologie/ tmitements immunommiutants/d&Giomtion
It seems likely that multiple sclerosis (MS) is a disease with a multifactorial etiology. Something in the environment, perhaps a virus, induces disease in a genetically susceptible host [12]. Reddy et al. detected human retrovirus lymphotrophic virus type 1 (HTLV-1) nucleic acid in the white blood mononuclear cells of subjects with MS [54]. The investigators had detected antibodies against HTLV-1 earlier [33],but others had difficulty in confirming the findings 1391.Reddy et al. used the polymerasc chain reaction and forced cloning of amplified DNA to look for the HTLV-1 sequences. They found sequences in all 6 patients’ adherent cells (monocytes and macrophages) and in 1 of the 20 normal individuals. Only 2 of the patients’ sera had antibodies. After amplification and cloning, nonadherent MS lymphocytes had low levels of hybridizable cellular
DNA, but none of the 13 control subjects demonstrated such sequences. The investigators claim an association between the HTLV-1 sequences and MS. However, if the virus caused MS, we would expect to find autonomously proliferating spinal fluid lymphocytes in MS patients. Bimbaum et al. could find none [2]. Thus, we must await confirmation from other laboratories and larger studies on patients whith other neurological diseases before concluding that HTLV-1 causes MS (see also Hauser et al., who could not find any viral sequences with the less sensitive in situ hybridization or antibodies by ELISA [24]). One method to clarify the genetic component in the etiology of MS is to study twins. Kinnunen et al. have shown a genetic relationship in 15815 twins in the Finnish National Twin Registry. Two
of 7 affected monozygotic twins were concordant S. Six of 6 dixygotic twins were discordant. The authors expect more associations, since many of the twins are under age SO and are expected to show more MS as time passes. In 1988 Sadovnik and Baird found increased risk for MS within the families of those afflicted. Earlier studies had not corrected for age. Sadovnik and Baird made the age correction and found that children and siblings of patients were 30-50 times more likely than the general popu!ation to have MS. However, the risk factor is still small
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Elevated cerehrospinal fluid oligoclonal immunoglob~ins and in~ammato~ parenchymal infiltrations support the view that plaques are caused by the immune system [47, 37,41,65,42]. However, there are many inconsistencies. It appears that macrophages carry out the actual demyelina~on [52, 423. We do not know what activates the macrophages. For example, Hayashi er al, found few activated thymus-derived T-cells in plaques in the brains from 9 patients [ZS].One of the inconsistencies with an autoaggressive immune attrack is the presence in the brain pa~n~hyma of mainly suppressor/c~otoxi~ Tcells (CD2, 3, 8f cells) which do not have activation antigens such as the IL2 receptors (Ta, Tll-3, or 2-N markers). There is increasing evidence that astrocytes could be the “antigen-presenting cells” for the lymphocytes. But Hayashi et af, found no expression of major histo~ompatibility complex (MHC) II markers in their specimens. Endothelial cells, on the other hand, had both MHC I and II and the 4B marker, indica~ng they were activated. Thus, not only do we not know what attracts lymphocytes into the white matter (the antigen), but we are also ignorant of what the cells do when they arrive in the brain 15, 221. Traugott and Lebon have discovered astrocytes with interferon gamma and Ia on their surfaces in MS plaques [64]. This discovery implicates the local produ~ion of inte~eron gamma in plaques, Interestingly, they found interferon alpha and interferon beta on macrophages, suggesting that these molecules are locally immunosuppressive via macrophages. Thus, rather than being purely destructive cytotoxic effector cells, the maerophages could be immunoreg~lato~ for cytotoxic lymphocytes ! Tke are changes in the peripheml blood immune cells in MS [l, 17, 221. Chof~on et al., using autoiogous mixed lymphocyte reactions
(AMLR) to generate suppressor cells for pokeweed mitogen-stimulated immunoglobulin G synthesis, found less suppression in progressive type MS [8]. They also found a correlation with a decrease in circulating CD4f 2W4+ subset of circulating T-cells. Rose ef al. found a decrease in CD45 + CD4 + (suppressor inducer T-cells) within 1 month of new symptoms in patients with exacerbatingremitting (E-R) type MS studied at monthly intervals. Seven of 9 patients had 4 major exacerbations and 3 minor subjective changes. In all 7 patients, the ratio of %CD4 + CD45R- / %CD4 +CD45R+ increased. This was secondary to an absolute increase in the number of CD4 + CD4SR- cells and a decrease in CD4+ CD45R+. Gallo et al. found increased amounts of interIeukin 2 (IL2) in serum or CSF of only 20 % of MS patients. This discovery suggests that only a small number of T-lymphocytes are activated (28 % of exacerbating-remitting type MS). Surprisingly, none of the chronic progressive patients had elevated IL2. These patients are those with the greatest frequency of new MRI lesions. ~aimone et al. found that bone marrow derived B-cells responded normallly when stimulated with endogenous B-cell specific growth factor (BCGF}. It was known that pokeweed mitogen induced immunoglobulin secretion by peripheral blood cells is increased in MS. The increase could be secondary to altered regulatory T-cell functions or intrinsic B-cell function. Their work favors increased secretion under the direction of T-cells. This is in contrast to the elonal expansion of B-cells, which are seen in the central nervous system in MS [40]. It is clear there are more magnetic resonance imaging scan (MRI) “lesions’* than clinical exacerbations [50]. Oget et al. found large MRI lesions correlated with decreased natural killer cell function, decreased immunoglobulin G secretion after pokeweed mitogen stimulation, and concanavalin A induced suppression. There was no parallel change in the lymphocyte phenotypic markers. There was no correlation between changes in immune function and clinical attacks. These findings probably explain the marked disparities in clinical-laboratory correlations in the past [l, 421. The detection of high signal intensity “lesions” on T2 weighted MRI scans has revolutionized the diagnosis of MS [49]. Diagnostic dilemmas arise in patients over the age of 40 who may have areas
Mdtiple sclerosis : why ? of high signal intensity which are similar to MS [18, 31.Fazekas et al. found the specificity for MS was increased if the lesion was equal to or larger than 6 mm diameter, abutted a ventricular body, or was located infratentorially. These is little correlation between changes in clinical scores and total lesion load in square millimeters [32]. However, patients with chronic progressive MS have a greater lesion load than those with benign MS, a greater number of infratentorial lesions, and lesions associated with an expected clinical expression, e.g. paralysis [32]. There is a greater appreciation for cognitive impairment with or without “hard” neurological signs [16]. Litvan et al. detected slow information processing in MS [38]. In 16 patients they found long-term verbal memory impairment, but shortterm memory and memory scanning was spared. Also, when high rates of presentation in the auditory serial audition test were used information processing was slowed down. There is a correlation between MRI lesions and cognitive defects or neuropsychological tests [15, 55, 53). Reischier er al. found small periventricular MR1 lesions to correlate with depression. Massive periventricular and frontal white matter lesions correlated with euphoria and disorders of judgment [55]. Although there is a good correlation between MRI lesions and pathology [58, 571, new MR1 lesion formation correlates poorly with clinical manifestations of MS in E-R type patients [27]. Willoughby et al. found 3.2 enlarged MR1 lesions per patient per year in a serial study of E-R patients. There were only 0.53 clinical relapses per patient per year. The MR1 lesions expanded over a 4-week period, then gradually shrank to leave a small residual abnormality that is indistinguishable from chronic MR1 lesions. Such studies show that MS is a much more active process than has been suspected clinically. They also suggest that MRI lesion-laboratory test correlations will be necessary in future studies t671. Kappos et al. found MR1 lesion localization to be more important for correlations with cerebral spinal tluid IgG levels and visual evoked response abnormalities than total lesion volume I29J. Those involved in MS clinical trials have relied upon changes in ncurologic functions as the primary outcome measures. There is a search for more quantitative outcome variables. John Kurtzke’s Expanded Disability Status Scale (EDSS) score is a ranking scale rather than a measure-
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ment, where intervals between each value are equidistant [34, ‘59, 351. Recently, serial MRI scans have been recommended [4g]. According to Kappos et af., treatment with high dose cortical steroids, cyclophosphamide, cyclosporine A or azathioprine decreased the number and intensity of new lesions [63]. On the other hand, Kappos et al. found 40 % of 194 patients treated with either cyclosporine A or azathioprine had an increase in the number and volume of MRI lesions after 24-32 months of treatment despite clinical stabilization [63]. Although we have used corticotropin (ACTH) since the 1950s as a treatment for MS, the role of the adrenal corticosteroids has not been certain [51]. The situation has changed since the advent of high dose “pulse” methylprednisolone. Milligan et al. treated 13 patients with chronic progressive MS with 500 mg of methylprednisolone intravenously for 5 days. At 4 weeks after treatment the methylprednisolone treated patients’ EDSS improved significantly compared to the placebo treated group. An additional 22 patients in relapse phase had a “significant” effect in favor of methylprednisolone treatment [43]. Our group at the University of California, Los Angeles, conducted a trial of methylprednisolone with azathioprine versus placebo methylprednisolone and real azathioprine and double placebo in 97 patients in progression phase. Although there was little deterioration in all 3 groups, those receiving methylprednisolone did the best [46, 141.There are theoretical reasons for considering ACTH treatments [lo]. Because of fewer adverse effects, it is possible that some variation of pulse methylprednisolone treatment will become the standard of care. Azathioprine has been used to treat MS since the late 1960s [13]. Since most trials were anecdotal (i.e., they used non randomized controls, did not use placebos, or did not mask the patients or investigators), we have not been able to determine the true usefulness of azathioprine. The British and Dutch Multiple Sclerosis Azathioprine Trial Group has shown only slight benefit from fixed dose azathioprine 141.Their randomized, placebo-controlled, double-masked trial of azachioprine (2.5 mg per kg per day for 3-4 yr) showed slight differences with Student’s t-test on outcome measures such as Kmtzke’s Disability Status Scale score or the Ambulation Index. One hundred and sixty-one patients received azathioprine; 171 were treated with placebo. There were trends in favor of the azathioprine
G. W. Ellison
treatment but no statistically significant differences (pc0.01) were demonstrated. The authors conclude, and agree that the slight benefit was outweighed by the inconvenience of the treatment and the possible increase in malignancy. Our UCLA group has used axathioprine for treating the chronic progression phase in a randomixed placebo-controlled double-masked trial (Neur&w; in press). Although the exacerbation rate was decreased in this study, (from 0.48 in the placebo-treated to 0.24 in the axathioprine recipients) we found no difference in the primary measures of progression. The proponents of axathioprine suggest that we have used the drug COOlate in the course of the disease and for too short a time. However, I consider that the British and Dutch Axathioprine Trial Group results militate against any role for axathioprine when
used alone. Cyclosporin A was tested in a randomized, masked, placebo-controlled, multicenter clinical trial [60].Two hundred and seventy-three patients in chronic progression phase received cyclosporin A (274 placebo) for 2 years. Outcome measures were Kurtzke’s EDSS, Ambulation Index (AI), Quantitative Examination of Neurologic Function, and an Incapacity Status Scale. The patients received 6 mg per kg of cyclosporin A. There was a slight delay in the time to becoming wheelchair-bound and a delay in the time to loss of independence as measured by the upper extremity functions in those receiving the cydosporin A. There was no difference in the time to sustained progression (an increase of 0.5 units in the collapsed EDSS or a 1.0 increase in the AI over 2 consecutive visits). There was 44 % attrition in the cyclosporin A group and 33 % in the placebotreated group. Eight cyclosporin A recipients discontinued the treatment due to hypertension, and 13 because of nephrotoxicity. There was a greater than 25 % incidence of hirsutism, headache, edema, nausea, and gingival hyperplasia in the cyclosporin recipients [61]. Kappos et al. stabilized the course of patients with MS with either azathioprine or cyclosporine 1291.They concluded that the toxicity of cyclosporine outweighed the benefit. Cyclophosphamide by itself administered either intravenously or orally appears to induce a 2-year remission in patients with MS [19, 211. Myers et al. treated 14 patients in progression phase with ascending doses of cyclophosphamide WI. Although there was stabilization or improvement in many of the patients, the toxicity level
was unacceptable. Similar problems were encountered by Goodkin et al. [20]. In a randomized, single masked (physician) trial, Likosky et al. treated 44 patients in progression phase with folic acid or intravenous cyclophosphamide [36]. With Kurtzke’s Functional Systems Scores, EDSS, AI, Incapacity and Environmental Status Scores collected beforehand, 12, 18 and 24 months after therapy; they found no differences between the groups. These results can be contrasted with those of treatment with the combination of adrenal cortical steroids and cyclophosphamide. Hommes et al. have treated patients in progression phase since 1971 [26]. Their work demonstrating improvement in 32/47 patients after 7- 11 yr follow-up is complemented by the trial of Hauser et al. with ACTH substituted for the prednisone 1223:.In open studies, Carter et al. also found improve-
ment with the combination of cyclophosphamide and ACTH in 154 patients [6]. Unfortunately, progression reoccurs approximately 2 yr after the initial treatment. Current investigations will ascertain the effects of repeated treatments. Although Khatri et al. [30] demonstrate that plasmapheresis is useful for chronic progressive MS, others do not find much benefit [62]. Further work is under way to determine the efficacy and risk benefit ratio of plasmapheresis. Immunosuppression with total lymphoid irradiation (TLI) appears to stabilize the course with patients with chronic progressive phase of MS [9]. A relationship exists between lymphopenia and improvement [l l]; there is concern that the beneficial effects will fade and further treatment will become difficult [45]. Interferon alpha and beta have been given to patients with MS both as an antiviral and as an immunoregulatory therapy [3I]. Although exacerbations are decreased in frequency, we are not certain of long-term benefit. Clinical trials are under way of subcutaneous beta interferon. We do know, however that interferon gamma is an unsuitable treatment for MS [28]. Contrary to expectations, exacerbations were increased in frequency rather than decreased. There is hope that changes might be brought about in the immune system with monoclonal antibodies against specific receptors on thymusderived cells [66]. Currently, antimouse antibodies develop in most patients treated with mouse monoclonal antibody [7]. If we can delete the appropriate T-cell subset, we may impair the primary immune response and the treatment
Multiple sclerosis : why ? would be repeatable. Mouse-human chime& ~tibodies might be less immunogenic. In conclusion, progress has been made in understanding the etiology and pathogenesis of MS, although the identity of the environmentai agent which provokes the disease in the genetically susceptible host has not been dete~ined. The immune response seems important for central nervous system demyelination and piaqle formation. Treatments with immunosuppressive regimens, particularly total lymphoid irradiation and the combination of adrenal steroids with alkylating agents appear to slow the rate of deterioration but not to halt it. Because progression of the disease reoccurs, we must devise treatments for MS which can be repeated safely.
This work was papacy supported by the Pacific Multiple Sclerosis Research Foundation, The Conrad Hilton Foundation, The Joe Gheen Fund and the Gustafson Endowment. I am grateful to Mr. Richard Burger for his assistance.
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