Immunosuppressive Treatment of Multiple Sclerosis

Immunosuppressive Treatment of Multiple Sclerosis

JONATHAN L. CARTER, M.D.,* MOSES RODRIGUEZ, M.D., Department of Neurology

Multiple sclerosis is thought, by many investigators, to be an immunologie disease. Therefore, a rationale exists for treating this disease by immunosuppressive therapy. In exacerbatingremitting multiple sclerosis, corticosteroids and adrenocorticotropic hormone are the most widely used drugs; high doses of intravenously administered methylprednisolone have recently gained favor. Chronic progressive multiple sclerosis has been treated with a number of immunosuppressive regimens, several of which have shown promise to date. Cyclophosphamide and azathioprine have been used most often and are reviewed in this report, as are other agents currently under investigation. No firm guidelines for the treatment of chronic progressive multiple sclerosis can be offered, but an approach to immunosuppressive therapy is suggested in this review.

Multiple sclerosis (MS) is thought by many investigators to be an immunologically mediated illness. The experimental and clinical data supporting this hypothesis are extensive and are summarized elsewhere in this symposium (see page 573 in the May 1989 issue of the Proceedings). These findings suggest a role for immunosuppressive therapy in MS. The goals of immunosuppressive therapy in MS vary in accordance with the clinical stage of disease in each patient. In exacerbating-remitting disease, the goals of therapy include (1) improving recovery from each exacerbation, (2) decreasing the number of future exacerbations, (3) decreasing the accumulation of additional disability, and (4) preventing the development of chronic progressive disease. In chronic progressive disease, the major goal is to halt progression of the disease and thereby prevent additional disability.

*Mayo Clinic Scottsdale, Scottsdale, Arizona. Individual reprints of this article are not available. The entire Symposium on Multiple Sclerosis will be available for purchase as a bound booklet from the Proceedings Circulation Office in July. Mayo Clin Proc 64:664-669, 1989

EXACERBATING-REMITTING DISEASE The main therapy for acute exacerbations of MS has been adrenocorticotropic hormone (ACTH) or corticosteroids. In a double-blind trial of ACTH versus placebo, the National Cooperative ACTH Study 1 proved t h a t ACTH hastened recovery from an acute exacerbation. By 1 month after treatment, however, little difference was noted between the ACTH and placebo groups. The protocol used in t h a t trial is summarized in Table 1. Recently, several reports have described superior results with high-dose intravenously administered methylprednisolone therapy. Durelli and colleagues 2 found more rapid improvement within 3 to 6 days after the methylprednisolone therapy was begun than with placebo; at the same time, the cerebrospinal fluid (CSF) IgG synthesis rate became normal. Abbruzzese and associates 3 and Barnes and colleagues 4 found more rapid improvement with this methylprednisolone regimen than with ACTH in patients with relapses of MS. Corticosteroid or ACTH therapy produces a substantial decrease in the CSF IgG synthesis rate 2 · 5 7 (this rate characteristically is increased in MS). Intravenously administered methylprednisolone has been most effective in decreasing the CSF IgG synthesis rate, and the effect seems to be dose related. 7 In

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Table 1.—Protocol for T r e a t m e n t of Multiple Sclerosis in National Cooperative A d r e n o c o r t i c o t r o p i c H o r m o n e (ACTH) Study 1 Medication*

Dose (units)t

Interval

ACTH gel ACTH gel ACTH gel

40 20 20

Twice daily Twice daily Once daily

Duration (days)

*Administered in sequence listed. tlntramuscularly.

8 9

addition, Troiano and associates · found t h a t highdose intravenously administered methylprednisolone substantially decreased contrast enhancement of acute MS lesions within 8 hours after administration. A suggested protocol is outlined in Table 2. The rate of prednisone withdrawal may need to be individualized because in many patients with MS the symptoms worsen as the corticosteroid therapy is withdrawn. Isolated reports have described cardiac arrhythmias and sudden death in a small number of renal transplant patients who were receiving oral immunosuppressive therapy and concomitantly were given 1 g or more of methylprednisolone rapidly in intravenous boluses for renal allograft rejection. 1013 This outcome has not been reported in patients with MS, perhaps because of the slower rate of administration (over 2 to 3 hours) in the MS trials. Other side effects of short-term ACTH and corticosteroid therapy have been reviewed in detail elsewhere. Although corticosteroids hasten the recovery from acute exacerbations of MS, no convincing studies have provided evidence that they can help prevent future attacks or the development of additional disability or chronic progressive MS. Recently, potentially encouraging results have been reported from a randomized, double-blind controlled trial of a random polymer of L-alanine, L-glutamic acid, L-lysine, and Ltyrosine (copolymer 1 [Cop 1]) and placebo in exacerbating-remitting MS. 14 Cop 1 was prepared to simulate myelin basic protein; it suppresses experimental allergic encephalomyelitis in several species. This study demonstrated a statistically significant decrease in the number of exacerbations in patients treated with Cop 1 for a 2-year period. Patients with low initial disability (Kurtzke disability scores of 0 to 2) improved a mean of 0.5 Kurtzke unit during treatment with Cop 1; patients receiving placebo worsened by a mean of 1.2 Kurtzke units. Patients with greater initial disability (Kurtzke scores of 3 to 6) had similar rates of progression in both the Cop 1 and placebo

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Table 2.—Protocol for High-Dose I n t r a v e n o u s l y A d m i n i s t e r e d M e t h y l p r e d n i s o l o n e in T r e a t m e n t of Moderate to S e v e r e Multiple Sclerosis Drug* Methylprednisolonet Prednisonet Prednisone Prednisone Prednisone Prednisone Prednisone

Daily dose (mg) 1,000 60 50 40 30 20 10

Duration (days) 5 3 3 3 3 3 3

*Administered in sequence listed. tGiven intravenously over 3 hours, dissolved in 500 ml of 5% dextrose in water. φΑΙΙ prednisone doses are given orally.

treatment groups. The mechanism of action of Cop 1 in MS is unknown. These encouraging initial reports require confirmation by larger, multicenter clinical trials before this treatment can be recommended. CHRONIC PROGRESSIVE DISEASE The treatment of chronic progressive MS has involved considerable controversy. Therapeutic approaches currently under investigation include cyclophosphamide, azathioprine, plasmapheresis, interferon-ß, total lymphoid irradiation, cyclosporine A, and monoclonal antibodies. Cyclophosphamide has been used in an uncontrolled fashion in Europe for more than 20 years. 1 5 1 7 The first randomized, controlled trial with it in the United States was reported by Häuser and colleagues 18 in 1983. This was a three-arm study: ACTH alone; low-dose orally administered cyclophosphamide, ACTH, and plasma exchange; or ACTH and high-dose intravenously administered cyclophosphamide. Of the 20 patients treated with high-dose cyclophosphamide and ACTH, 16 (80%) had an improved or stable condition 1 year after treatment, in comparison with 20% of the group treated with ACTH alone. Of the 16 patients treated with high-dose cyclophosphamide and ACTH who had an improved or stable condition 1 year after treatment, 11 showed evidence of further progression of the disease in the second or third year after treatment. Carter and associates 19 recently reported on treatment of 164 patients with the same protocol used by Häuser and colleagues. 18 These patients received 500 mg of cyclophosphamide intravenously each day until their leukocyte count was less than 4,000 cells/mm 3 , after which the cyclophosphamide regimen was discontinued. Concurrently they received a tapering

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intravenous course of ACTH for 21 days. At 1 year after the initial treatment, the condition was improved in 24% of the patients, stabilized in 57%, and worse in 19%. Of those patients who initially responded to treatment, 69% showed evidence of further progression by 3 years after treatment (mean time to further progression, 17.6 months). Of the 58 patients treated a second time, at 1 year after this treatment the MS was improved in 15%, stable in 55%, and worse in 30%. Complications of treatment included alopecia (100%), nausea (27%), minor infections (26%), nausea and vomiting (20%), microscopic hematuria (6%), complications of ACTH (5%), macroscopic hematuria (5%), mucösitis (3%), major infections (1%), and febrile reactions (1%). Goodkin and colleagues20 found a statistically significant beneficial effect of cyclophosphamide and ACTH at 12,18, and 24 months after treatment in 27 patients in comparison with 24 patients in a nonrandomized control group. Myers and associates21 reported that 12 of 14 patients treated with monthly intravenous boluses of cyclophosphamide for 5 to 14 months were improved or stable at the end of the treatment period. They concluded that their veryhigh-dose cyclophosphamide regimen (1,200 to 2,000 mg/m2 of body surface area) was "too toxic for the longterm treatment of patients with MS" because of side effects of the therapy. Others have not found a significant beneficial effect of cyclophosphamide in chronic progressive MS.22·23 In the study by Likosky and colleagues,23 cyclophosphamide administered without ACTH yielded no benefit in a randomized, controlled, blind clinical trial, but the mean total dose of cyclophosphamide given was considerably less than in those regimens reported to be of benefit iri MS, and concurrent treatment with ACTH or corticosteroids was not used. The efficacy of cyclophosphamide in chronic progressive MS remains to be determined by additional randomized, controlled trials in comparison with placebo and with other immunosuppressive regimens used in MS. The reports on azathioprine in chronic progressive MS have been conflicting in regard to its efficacy. An open study24 and a controlled study25 found no benefit in exacerbating-remitting or chronic progressive disease. Patzold and associates26 found slower disease progression after azathioprine treatment only in patients with exacerbating-progressive disease. Patients with exacerbating-remitting disease or chronic progressive disease without relapses or remissions had no benefit. With azathioprine plus methylpredni-

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solone, azathioprine alone, or placebo in a study of chronic progressive MS, Nuwer and colleagues27 found a slower rate of worsening of visual evoked response and somatosensory evoked potential latencies and an improvement on the standard neurologic examination after 3 years of treatment with azathioprine and methylprednisolone. The Kurtzke disability status and illness severity scores were not significantly affected by treatment, however. Side effects of azathioprine therapy included hepatocellular damage, pulmonary infiltrates, anemia, increased risk of infections, and nausea and vomiting. An increased risk also exists for the occurrence of malignant lesions after long courses of treatment. Plasmapheresis has been used experimentally in several trials. In most of these trials, it has been combined with immunosuppressive therapy including corticosteroids, cyclophosphamide, or azathioprine. Thus, the possible therapeutic effects of plasmapheresis beyond the effects of immunosuppressive therapy alone are somewhat difficult to determine. Khatri and associates28 found a beneficial effect of plasma exchange, orally administered cyclophosphamide, and prednisone over "sham pheresis," orally administered cyclophosphamide, and prednisone during a 20-week treatment period. This effect was maintained at the 6-month follow-up. This study, however, has been criticized by other investigators.2930 Trouillas and colleagues31 found a highly significant difference (P<0.0001) between the disability scores before and after plasma exchange in 4 of 12 patients with chronic progressive MS. The improvement was greatest in pyramidal and cerebellar disorders; however, the improvement was transient and did not persist for more than 2 months. Other investigators found no benefit from plasmapheresis in comparison with azathioprine.32,33 Plasmapheresis may have a role in life-threatening exacerbations of MS when high-dose corticosteroid treatment is ineffective. Lymphocytapheresis has not been found to have a positive clinical effect in chronic progressive MS. The Therapeutic Plasmapheresis Consensus Conference concluded that plasmapheresis should be considered "an investigative procedure."34 Risks associated with plasma exchange include fatal anaphylaxis, pulmonary embolism, hepatitis, hemorrhage, sepsis, hypocalcemia, fluid and electrolyte imbalances, and iatrogenic infections. Additional drawbacks of plasma exchange include its expense and time requirements. Recently, interferons have been used in the treatment of MS. The results of these trials are helping to

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elucidate aspects of the pathogenesis of MS. A clinical trial of interferon-γ, a lymphokine that acts as an immune enhancer, exacerbated MS.35 In contrast, some investigators have suggested that systemic interferon-α therapy decreases exacerbations in certain patients, but the findings are inconclusive.36 A further study in which recombinant interferon-oc2 was used showed no clear therapeutic effect,37 and exacerbating MS evolved to progressive MS in more patients who received interferon than in those who received placebo. Intrathecal administration of human fibroblast interferon-ß seems to produce a decreased exacerbation rate of MS without change in clinical disability.38 Follow-up observations on such patients show persistent beneficial effects for 4 years.39 This result has been confirmed in a multicenter, double-blind trial.40 The mechanism of action of interferon-ß is unknown, but it may be interference with the viral infection that may predispose to exacerbations. A new multicenter, double-blind trial of subcutaneously administered interferon-ß in exacerbating-remitting MS is under way. Total lymphoid irradiation has been studied in a double-blind, randomized, prospective trial in comparison with "sham irradiation."41 Patients with chronic progressive MS who underwent this treatment had less neurologic progression. Of interest, patients with lymphocyte counts of less than 900/mm3 for prolonged periods after treatment had less rapid progression of MS during the ensuing 3 years of follow-up.42 This finding suggests that the absolute lymphocyte count may be valuable in monitoring the amount of immunosuppression needed to prevent progression. Although the results are encouraging, the use of total lymphoid irradiation in chronic progressive MS must be considered experimental until its efficacy has been confirmed by other groups and the long-term complications have been assessed. Cyclosporine A has been studied in a randomized, placebo-controlled, double-blind, multicenter clinical trial in the United States. Preliminary results of this trial43 suggest a possible effect of cyclosporine A in delaying the time to becoming wheelchair bound; however, significant toxicity was observed in the study. Cyclosporine A has been shown to alter T-cell function in patients with MS44 in comparison with control subjects, but whether this evidence predicts a clinical response to the drug is not yet known. A recently reported European study45 found no difference between patients treated with cyclosporine A at 15 mg/kg per day and those given azathioprine at 2.5

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mg/kg per day for a 2-year period in a double-blind controlled trial. In addition, significantly more patients treated with cyclosporine A had increased serum creatinine concentration and hypertension (36% and 39%, respectively, of all cyclosporine-treated patients). RECOMMENDATIONS Our approach to immunosuppressive treatment of MS can be summarized as follows. For moderate to severe exacerbations of MS, we recommend a 5-day course of high-dose methylprednisolone (1,000 mg intravenously per day by continuous infusion), followed by a tapering oral course of prednisone for a total of approximately 3 weeks of therapy (Table 2). In milder attacks, we recommend a 3-week oral course of prednisone (Table 3). For chronic progressive MS with rapid progression, no firm guidelines can be established. A 5-day intravenous course of methylprednisolone or a 3week oral course of corticosteroids as used in acute exacerbations may be tried in an attempt to halt the progression of the disease. This approach is justified by the relatively infrequent and mild side effects of short courses of corticosteroids. Extended oral courses of daily corticosteroid therapy, however, have had no long-term benefit in chronic progressive MS46,47 and have been associated with significant toxicity. Periodic booster doses of methylprednisolone given intravenously represent an attractive experimental approach to the treatment of chronic progressive MS, but this approach has not yet been evaluated in a controlled clinical trial. If short-term corticosteroid treatment is unsuccessful, a decision must be made about the use of cyclophosphamide or azathioprine. If possible, the patient should be referred to a medical center that is experienced in the use of immunosuppressive agents

Table 3.—Protocol for Orally Administered Prednisone in Treatment of Mild Multiple Sclerosis Daily dose (mg)*

Duration (days)

60 50 40 30 20 10 5

7 3 3 3 3 3 3

*Administered in sequence listed.

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in MS and involved in well-designed clinical trials with these agents. In this way, the maximal amount of useful data can be obtained from each patient treated. It is hoped that continued investigation by well-designed clinical trials will help determine which of the current immunosuppressive modalities, if any, are effective in chronic progressive MS. Research is continuing on specific immunosuppressive regimens that may replace the more global immunosuppressive agents, such as cyclophosphamide, azathioprine, and total lymphoid irradiation, currently available. A list of therapeutic agents that have such potential for MS and currently are under development is shown in Table 4. In addition to the promise of more effective and less toxic treatments for MS, these regimens also may provide clues about the pathogenesis of the disease.

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Table 4.—Agents U n d e r D e v e l o p m e n t for T r e a t m e n t of Multiple S c l e r o s i s Agent

Rationale for therapy

Anti-CD4 monoclonal antibody Anti-CD8 monoclonal antibody

Inhibition of helper T cells Inhibition of cytotoxic T-cell responses Interference with "immune response" gene products (DR2) Interference with migration of activated T cells into the central nervous system Inhibition of T cells t h a t have interleukin 2 receptors Antiviral or immunomodulatory properties Immunosuppression Interference with various arms of the immune response Induction of immune tolerance

Anti-la monoclonal antibody Low-dose heparin Monoclonal antibodies to activated T cells Interferons (α, β) Cyclosporine A Combination immunotherapy T-cell vaccination

REFERENCES 1.

2.

3. 4.

5. 6.

7.

8.

9. 10. 11.

Rose AS, Kuzma JW, Kurtzke J F , Namerow NS, Sibley WA, Tourtellotte WW: Cooperative study in the evaluation of therapy in multiple sclerosis: ACTH vs. placebo; final report. Neurology 20 (No. 5, Part 2): 1-59, 1970 Durelli L, Cocito D, Riccio A, Barile C, Bergamasco B, Baggio GF, Perla F, Delsedime M, Gusmaroli G, Bergamini L: High-dose intravenous methylprednisolone in the treatment of multiple sclerosis: clinical-immunologic correlations. Neurology 36:238-243, 1986 AbbruzzeseG, GandolfoC, LoebC: 'Bolus'methylprednisolone versus ACTH in the treatment of multiple sclerosis. Ital J Neurol Sei 4:169-172, 1983 Barnes MP, Bateman DE, Cleland PG, Dick DJ, Walls TJ, Newman PK, Saunders M, Tilley P J B : Intravenous methylprednisolone for multiple sclerosis in relapse. J Neurol Neurosurg Psychiatry 48:157-159, 1985 Trotter JL, Garvey WF: Prolonged effects of large-dose methylprednisolone infusion in multiple sclerosis. Neurology 30:702-708, 1980 Tourtellotte WW, Baumhefner RW, Potvin AR, Ma BI, Potvin J H , Mendez M, Syndulko K: Multiple sclerosis de novo CNS IgG synthesis: effect of ACTH and corticosteroids. Neurology 30:1155-1162, 1980 Warren KG, Catz I, Jeffrey VM, Carroll DJ: Effect of methylprednisolone on CSF IgG parameters, myelin basic protein and anti-myelin basic protein in multiple sclerosis exacerbations. Can J Neurol Sei 13:25-30, 1986 Troiano R, Hafstein M, Ruderman M, Dowling P, Cook S: Effect of high-dose intravenous steroid administration on contrast-enhancing computed tomographic scan lesions in multiple sclerosis. Ann Neurol 15:257-263, 1984 Troiano R, Cook SD, Dowling PC: Steroid therapy in multiple sclerosis: point of view. Arch Neurol 44:803-807, 1987 Wollheim FA: Acute and long-term complications of corticosteroid pulse therapy. Scand J Rheumatol [Suppl] 54:2732, 1984 McDougal BA, Whittier FC, Cross DE: Sudden death after bolus steroid therapy for acute rejection. Transplant Proc 8:493-496, 1976

12·

13. 14.

15. 16.

17-

18.

19.

20.

Stubbs SS, Morrell RM: Intravenous methylprednisolone sodium succinate: adverse reactions reported in association with immunosuppressive therapy. Transplant Proc 5:11451146, 1973 Warren DJ, Smith RS: High-dose prednisolone (letter to the editor). Lancet 1:594, 1983 Bornstein MB, Miller A, Slagle S, Weitzman M, Crystal H, Drexler E, Keilson M, Merriam A, Wassertheil-Smoller S, Spada V, Weiss W, Arnon R, Jacobsohn I, Teitelbaum D, Sela M: A pilot trial of Cop 1 in exacerbating-remitting multiple sclerosis. N Engl J Med 317:408-414, 1987 Hommes OR, Lamers KJB, Reekers P: Effect of intensive immunosuppression on the course of chronic progressive multiple sclerosis. J Neurol 223:177-190, 1980 Gonsette RE, Demonty L, Delmotte P: Intensive immunosuppression with cyclophosphamide in remittent forms of multiple sclerosis: a follow-up of 134 patients for 2-10 years. In Progress in Multiple Sclerosis Research. Edited by H J Bauer, S Poser, G Ritter. Berlin, Springer-Verlag, 1980, pp 401-406 Gonsette RE, Demonty L, Delmotte P: Intensive immunosuppression with cyclophosphamide in multiple sclerosis: follow up of 110 patients for 2-6 years. J Neurol 214:173181, 1977 Häuser SL, Dawson DM, Lehrich JR, Beal MF, Kevy SV, Propper RD, Mills JA, Weiner HL: Intensive immunosuppression in progressive multiple sclerosis: a randomized, three-arm study of high-dose intravenous cyclophosphamide, plasma exchange, and ACTH. N Engl J Med 308:173180, 1983 Carter JL, Hafler DA, Dawson DM, Orav J, Weiner HL: Immunosuppression with high-dose IV cyclophosphamide and ACTH in progressive multiple sclerosis: cumulative 6year experience in 164 patients. Neurology 38 (Suppl 2):914, 1988 Goodkin DE, Plencner S, Palmer-Saxerud J, Teetzen M, Hertsgaard D: Cyclophosphamide in chronic progressive multiple sclerosis: maintenance vs nonmaintenance therapy. Arch Neurol 44:823-827, 1987

Mayo Clin Proc, J u n e 1989, Vol 64

21.

22.

23.

24. 25. 26.

27. 28.

29. 30. 31.

32.

33.

34.

Myers LW, Fahey JL, Moody DJ, Mickey MR, Frane MV, Ellison GW: Cyclophosphamide 'pulses' in chronic progressive multiple sclerosis: a preliminary clinical trial. Arch Neurol 44:828-832, 1987 Theys P, Gosseye-Lissoir F, Ketelaer P, Carton H: Shortterm intensive cyclophosphamide treatment in multiple sclerosis: a retrospective controlled study. JNeurol 225:119133, 1981 LikoskyWH, Fireman B, Griffin C: Intensive cyclophosphamide immunosuppression in multiple sclerosis: a randomized blinded multicenter clinical trial (abstract). Neurology 37 (Suppl 1):108, 1987 Silberberg D, Lisak R, Zweiman B: Multiple sclerosis unaffected by azathioprine in pilot study. Arch Neurol 28:210-212, 1973 Swinburn WR, Liversedge LA: Long-term treatment of multiple sclerosis with azathioprine. J Neurol Neurosurg Psychiatry 36:124-126, 1973 Patzold U, Hecker H, Pocklington P: Azathioprine in treatment of multiple sclerosis: final results of a 4'/2-year controlled study of its effectiveness covering 115 patients. J Neurol Sei 54:377-394, 1982 Nuwer MR, Packwood JW, Myers LW, Ellison GW: Evoked potentials predict the clinical changes in a multiple sclerosis drug study. Neurology 37:1754-1761, 1987 Khatri BO, McQuillen MP, Harrington GJ, Schmoll D, Hoffmann RG: Chronic progressive multiple sclerosis: double-blind controlled study of plasmapheresis in patients taking immunosuppressive drugs. Neurology 35:312-319, 1985 Werner HL: An assessment of plasma exchange in progressive multiple sclerosis (editorial). Neurology 35:320-322, 1985 Tindall R: A closer look at plasmapheresis in multiple sclerosis: the cons. Neurology 38 (Suppl 2):53-56, 1988 Trouillas P, Neuschwander PH, Tremisi J P : Modification rapide par les echanges plasmatiques de la semiologie de formes progressives de la sclerose en plaques. Rev Neurol (Paris) 142:689-695, 1986 Tindall RSA, Walker J E , Ehle AL, Near L, Rollins J, Becker D: Plasmapheresis in multiple sclerosis: prospective trial of pheresis and immunosuppression versus immunosuppression alone. Neurology 32:739-743, 1982 Gordon PA, Carroll DJ, Etches WS, Jeffrey V, Marsh L, Morrice BL, Olmstead D, Warren KG: A double-blind controlled pilot study of plasma exchange versus sham apheresis in chronic progressive multiple sclerosis. Can J Neurol Sei 12:39-44, 1985 The utility of therapeutic plasmapheresis for neurological disorders (Consensus Conference). JAMA 256:1333-1337, 1986

IMMUNOSUPPRESSION IN MULTIPLE SCLEROSIS

35.

36.

37.

38. 39. 40.

41.

42.

43.

44.

45.

46. 47.

669

Panitch HS, Hirsch RL, Schindler J, Johnson KP: Treatment of multiple sclerosis with gamma interferon: exacerbations associated with activation of the immune system. Neurology 37:1097-1102, 1987 Knobler RL, Panitch HS, Braheny SL, Sipe JC, Rice GPA, Huddlestone JR, Francis GS, Hooper CJ, Kamin-Lewis RM, Johnson KP, Oldstone MBA, Merigan TC: Systemic alphainterferon therapy of multiple sclerosis. Neurology 34:12731279, 1984 Camenga DL, Johnson KP, Alter M, Engelhardt CD, Fishman PS, Greenstein JI, Haley AS, Hirsch RL, Kleiner J E , Kofie VY, Koski CL, Margulies SL, Panitch HS, Valero R: Systemic recombinant a-2 interferon therapy in relapsing multiple sclerosis. Arch Neurol 43:1239-1246, 1986 Jacobs L, O'Malley J, Freeman A, Ekes R: Intrathecal interferon reduces exacerbations of multiple sclerosis. Science 214:1026-1028, 1981 Jacobs L, O'Malley JA, Freeman A, Ekes R, Reese PA: Intrathecal interferon in the treatment of multiple sclerosis: patient follow-up. Arch Neurol 42:841-847, 1985 Jacobs L, Salazar AM, Herndon R, Reese PA, Freeman A, Jozefowicz R, Cuetter A, Husain F, Smith WA, Ekes R, O'Malley JA: Intrathecally administered natural human fibroblast interferon reduces exacerbations of multiple sclerosis: results of a multicenter, double-blinded study. Arch Neurol 44:589-595, 1987 Cook SD, Devereux C, Troiano R, Zito G, Hafstein M, Lavenhar M, Hernandez E, Dowling PC: Total lymphoid irradiation in multiple sclerosis: blood lymphocytes and clinical course. Ann Neurol 22:634-638, 1987 Cook SD, Devereux C, Troiano R, Hafstein MP, Zito G, Hernandez E, Lavenhar M, Vidaver R, Dowling PC: Effect of total lymphoid irradiation in chronic progressive multiple sclerosis. Lancet 1:1405-1409,1986 Multiple Sclerosis Study Group: The efficacy of cyclosporine immunosuppression in multiple sclerosis: a preliminary report of a randomized blinded, placebo-controlled clinical trial (abstract). Ann Neurol 24:169, 1988 Kerman RH, Wolinsky J S , Nath A, Sears ES Jr, Franklin GM, Nelson LM: Immune regulation in multiple sclerosis patients treated with cyclosporine (abstract). Ann Neurol 22:154, 1987 Kappos L, Patzold U, Dommasch D, Poser S, Haas J, Krauseneck P, Malin J-P, Fierz W, Graffenried BU, Gugerli US: Cyclosporine versus azathioprine in the long-term treatment of multiple sclerosis—results of the German multicenter study. Ann Neurol 23:56-63, 1988 Millar J H D , Vas CJ, Noronha MJ, Liversedge LA, Rawson MD: Long-term treatment of multiple sclerosis with corticotrophin. Lancet 2:429-431, 1967 FogT: The long-term treatment of multiple sclerosis with corticoids. Acta Neurol Scand [Suppl] 13:473-484, 1965

End of Symposium on Multiple Sclerosis, Part II. Part III will appear in the July issue.