EFFECT OF TOTAL LYMPHOID IRRADIATION IN CHRONIC PROGRESSIVE MULTIPLE SCLEROSIS

1405

EFFECT OF TOTAL LYMPHOID

IRRADIATION IN CHRONIC PROGRESSIVE MULTIPLE SCLEROSIS

STUART D. COOK

CORINNE DEVEREUX MARINOS P. HAFSTEIN ENRIQUE HERNANDEZ ROBERT VIDAVER* PETER C. DOWLING

RAYMOND TROIANO GEORGE ZITO MARVIN LAVENHAR

University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark; Veterans Administration Medical Center, East Orange; and Clara Maass Medical Center, Belleville; New Jersey, USA

Summary

Total lymphoid irradiation (TLI; 1980

cGy) or sham irradiation was given to 40 patients with chronic progressive multiple sclerosis (MS) in a prospective, randomised, double-blind study. During mean follow-up of 21 months, MS patients treated with TLI had less functional decline than shamirradiated MS patients (p<0·01). A significant relation was noted between absolute blood lymphocyte counts in the first year after TLI and subsequent course, patients with higher lymphocyte counts generally having a worse TLI was well tolerated and prognosis (p<0·01). associated with only mild short-term, and to date, long-term side-effects. Introduction

TOTAL lymphoid irradiation (TLI) is generally considered a safe method for producing sustained TLI prolongs organ transplant survival and can induce long-term remissions in both natural and experimental autoimmune disorders. 1-5 TLI treatment has led to improvement, lasting for up to several years, in patients with severe rheumatoid arthritis refractory to steroids, azathioprine, and other drugs.3-s Unlike cytotoxic drugs, the other main way of producing prolonged immunosuppression, TLI has not been associated with a high risk of haematological neoplasia in long-term follow-up of patients with Hodgkin’s disease.s

immunosuppression.1-s

*Present address: East Virginia Medical School, Norfolk, Virginia

23501, USA.

3. Williamson R, Gilliam C, Blaxter M, Scambler P, Robbins T, Davies KE. Gene cloning—a tool to find the basic defect in cystic fibrosis. In: Lawson D, ed. Cystic fibrosis: horizons. Chichester: John Wiley and Sons, 1984: 139-51. 4. Wainwright BJ, Scambler PJ, Schmidtke J, et al. Localization of cystic fibrosis locus to human chromosome 7 cen-q22. Nature 1985; 318: 384-85. 5. Scambler PJ, Wainwright BJ, Farrall M, et al. Linkage of COL1A2 collagen gene to cystic fibrosis, and its clinical implications. Lancet 1985; ii: 1241-42. 6. White R, Woodward S, Leppert M, et al. A closely linked genetic marker for cystic fibrosis. Nature 1985; 318: 382-84. 7. Tsui L.-C, Buchwald M, Barker D, et al. Cystic fibrosis locus defined by a genetically linked polymorphic DNA marker. Science 1985, 230: 1054-57. 8. Knowlton RG, Cohen-Haguenauer O, Van Cong N, et al. A polymorphic DNA marker linked to cystic fibrosis is located on chromosome 7. Nature 1985; 318: 380-82. 9. Rodeck CH, Morsman JM, Nicolaides KH, McKenzie C, Gosden CM, Gosden JR. A single-operator technique for first-trimester chorion biopsy Lancet 1983; ii: 1340-41. 10. Williamson R, Eskdale J, Coleman DV, Niazi M, Loeffler FE, Modell BM. Direct gene analysis of chorionic villi: a possible technique for first-trimester antenatal diagnosis of haemoglobinopathies. Lancet 1981; ii: 1125-27. 1 1. Lathrop GM, Lalouel JM. Easy calculations of Lod scores and genetic risks on small computers. Am J Hum Genet 1984; 36: 460-65. 12. Chakravarti A, Buetow KH. A strategy for using multiple linked markers for genetic counseling. Am J Hum Genet 1985; 37: 984-97. 13. Super M. Prenatal diagnosis of cystic fibrosis. Lancet 1986, i: 510.

long-term effectiveness and relative immunosuppressive therapy, we decided to investigate its effect in patients with multiple sclerosis (MS).6 We now report the results of a prospective, randomised, double-blind, controlled study to determine whether TLI can modify disease course in chronic progressive MS. In view of the

safety of TLI

as an

Patients and Methods

study planned to compare the effects of TLI in 20 patients with those of sham TLI in another 20 patients. 40 patients with clinically definite MS7 entered the trial between April, 1982, and February, 1985, and were followed-up for at least 6 months after completion of therapy. Patients were considered for the study if they were aged 20-60 years; had had MS for at least 3 years; had had progressive neurological disability (as documented by a neurologist, or confirmed by the patient and a family member) for at least the previous year; had a score of 4-8 on a disability scale modified from the Kurtzke disability status scale (table I); and would remain available for at least 2 years of follow-up. Most patients had previously received steroids or corticotropin. Reasons for exclusion were: severe psychiatric or psychoneurotic disease; intellectual impairment sufficient to interfere with understanding and participating in the study; chronic bacterial infections (decubiti or urinary tract infections); serious medical illness; previous neoplasm or tuberculosis; leucopenia (white-cell count thrombo<4-5x 10/1); anaemia (haematocrit <25°o); cytopenia (platelet count < z/1); previous use of immunosuppressive drugs; pregnancy or a desire to become pregnant subsequently. 1 patient had a urinary catheter at entry into the study, but we subsequently excluded patients with catheters. During an initial interview, the trial protocol and potential risks and benefits were explained in detail to the patient and at least one family member. Patients were admitted to University Hospital, Newark, or the Veterans Administration Medical Center, East Orange, where comprehensive medical, neurological, and, when necessary, psychiatric evaluations were carried out. In addition to routine laboratory tests, lumbar puncture, evoked potential studies, and computed tomography scan were carried out on most patients. Renal and spleen scans were done to locate normal tissues during the simulation of radiation fields. On the final day in hospital just before he or she received therapy, the patient signed informed consent under the guidelines of the research committee of the University of Medicine and Dentistry of New Jersey. A sealed envelope prepared by our statistician was then drawn to determine whether the patient was randomised to the TLI or sham group. Only the patient coordinators (M. H. and E. H.) and radiotherapist (C. D.) were aware of the patient’s therapy, although a sealed copy of the code was available to one of us (S. C.) for possible emergency use; it was not required. TLI or sham TLI was administered over 29-56 days (mean 39 days) on an outpatient basis to all patients at Clara Maass Medical Center. Patients were treated on a Phillips SL 75-10 linear accelerator with an 8 MeV photon beam using two pairs The

was

TABLE I-MODIFIED DISABILITY SCALE

*In the

opinion of the

examiner.

1406 of treatment fields. A modified mantle was used that extended from the top of the thyroid cartilage superiorly to the bottom of the first lumbar vertebra, including the spleen inferiorly. The patient was placed with the arms extended fully above the head. This position raises the infraclavicular nodes and allows more of the lungs to be shielded while including these nodes in the treatment field. Custom-made blocks of ’Cerrobend’, equivalent to six half-value layers, were designed to shield the lungs anteriorly and posteriorly. A thyroid block was placed anteriorly over the thyroid cartilage and a mid-line spine block

placed posteriorly from the beginning of treatment to keep the dose to the spine below 10 Gy. The patients were treated using anteroposterior and posteroanterior fields to a total dose of 1980 cGy, in eleven fractions of 180 cGy. Both anterior and posterior fields were treated 5 days a week. After completion of the mantle an inverted Y field was treated. Treatment of the inverted Y usually began on day 12, although there was an occasional delay of 2-3 days when simulation could not be scheduled optimally. The inverted Y was also treated with 180 cGy daily fractions to a total dose of 1980 cGy. A 2cm spine block was used at the superior portion of the posterior field to ensure that no excessive radiation was given at the matchline to the spinal cord. Sham irradiation was given by an identical protocol including simulation, use of blocks, and drawing of skin marks. Patients were evaluated by one or two neurologists before treatment to establish a baseline. The same neurologists, who were unaware of the treatment given, assessed the patients’ neurological status monthly for 6 months after therapy, and then every 3 months. Patients and these neurologists were instructed not to discuss side-effects of treatment. The patients were seen in mid-to-late morning in an attempt to avoid diurnal fluctuations of neurological status. 6 months after therapy, the patients were readmitted to hospital, and lumbar puncture, evoked potential studies, and computer tomography scan were repeated. At each visit, a detailed self-evaluation questionnaire was completed, a comprehensive neurological examination carried out, and the disability score determined. In addition, the patient was graded on a practical functional scale of 1-12 (developed by R. T.) by the examining neurologist (table 11). Physiotherapy, steroids, and other drugs (excluding immunosuppressants) were prescribed to patients at the discretion of the blinded neurologists. Progression was determined by measuring time from completion of therapy to first sustained progression (as defined by a deterioration on the functional scale of at least one grade confirmed, at least, at two consecutive follow-up visits or present at the completion of the study); assessing for decline on individual disability or functional scale by one or more grades 12, 18, 24, 30, and 36 months after therapy; and comparing was

muscle strength at the initial and final visits. Treatment failure was defined as exclusion of the patient from the study by the blinded neurologist after completion of therapy because of progressive deterioration in neurological status to a severe degree. If there was no further follow-up, the disability or function scale score at the time of treatment failure was assumed to be unchanged (though it was likely to be worse) at subsequent times when results were assessed. Patients who left the study for reasons other than progressive neurological deterioration, who were unavailable for evaluation thereafter, were assessed only up to the time of leaving the study since their subsequent course would not necessarily be static. Blood samples were taken at each clinic visit. The absolute lymphocyte count was calculated from the total leucocyte count based on the percentage of lymphocytes. The characteristics of the patients in the sham-treated and TLI groups were compared by the Wilcoxon rank sum test or Fisher’s exact test. Variables differing before and after treatment (paired comparisons) were tested for statistical significance by the Wilcoxon signed rank test. Estimated probability of no progression in each group at various times after treatment was determined by calculating Kaplan-Meier survival curves, with deterioration in functional scale score at two consecutive follow-up visits, or at the last visit, as the end point. Gehan’s generalised Wilcoxon test was used to compare the progression-free distribution times in the two treatment groups. Differences in the mean lymphocyte count by treatment group and by post-treatment time were analysed by a repeated measures analysis of variance design. Differences in group means were tested by Duncan’s multiple comparisons procedures. Unless otherwise noted, two-tailed tests of significance were used.

Results The two patient groups did not differ significantly at entry in sex, age, duration of MS, or mean scores on the functional and disability scales (table III). However, there was a slight disparity in the distribution of patients by functional scores, the TLI group had more patients with a functional score > 9 (table IV). The TLI patients fared significantly better than the sham patients by several criteria. Time to first sustained progression was longer in the TLI than the sham group (see figure). The estimated probability of no progression up to 6 months after treatment was 0-9±0’07 (95% confidence limits 0-76-1.00) in the TLI group compared with 0-49 ±0-11 (0-27-0-71) in the sham-treated group. At 18 months, the estimated probabilities of no

TABLE II-FUNCTIONAL SCALE

1407 TABLE III-PATIENTS’ CHARACTERISTICS AT START OF STUDY

TABLE V-FUNCTIONAL AND DISABILITY SCORES BY TIME OF

FOLLOW-UP

TABLE IV-FUNCTIONAL SCALE SCORE AT

12

ENTRY AND

MONTHS AFTER THERAPY

Even when the 5 TLI patients with entry functional of 10 were excluded, on the premise that they were so functionally disabled that disease progression could not be adequately detected, significant differences were still noted between TLI and sham-treated patients at 12 months (p=0-02) and in time to first sustained progression (p < 0-05). 3 patients were dropped from the study (12, 6, and 10 mo after therapy) by the blinded scores

Numbers in 12

parentheses

represent

patients

who had deteriorated

at

mo.

comparison of entry and tPaired comparison of entry and *Paired

12 mo not significant. 12 mo; p < 01.

neurologists because of such severe deterioration that they thought t unethical not to break the code and offer alternative treatment: 1 of these subsequently died; 1 was lost to follow-up; and 1 continued to deteriorate. All were in the sham group. 2 patients, 1 TLI and 1 sham-treated, left the study against medical advice 6 months after

treatment.

They had not

shown sustained

progression. No difference was noted in the number of patients receiving steroids in the month before the study between the two groups. After completion of therapy, -fifteen courses of steroids were prescribed in 8 sham-treated patients, compared with seven courses in 6 TLI patients. No significant differences were noted between the two groups in the number of patients receiving physiotherapy, the estimated number of hours received, or the number receiving treatment with antidepressants. An effort was made to ascertain whether patients knew which treatment they had received. Shortly after

Kaplan-Meier curves of estimated probability of no progression over

time.

progression were 0-72 ±0-11 CO’52-D’93) vs 0-29 ±0-11 (0-07-0-51) and at 24 months 0 44±0-13 (0-18-0-69) vs 0 19 ±0-11 (0-0-40). Significantly more patients in the sham-treated group had progressed at specified time points as measured by functional scale and, to a lesser extent, by disability scale (tables IV and v). At the final visit a decrease in muscle strength (MRC scale) of two grades or more from the original reading (to which the examiners referred) was seen in the proximal or distal limb of 5 of 20 TLI patients, whereas 11 of 20 sham-treated patients showed similar changes (not significant by two-tailed test; p < 0-05 - by one-tailed test).

treatment, 15 TLI and 10 sham patients thought they had received TLI, and there was no significant difference between the two groups. However, on their last follow-up visit, 19 of 20 TLI patients believed they had received TLI, compared with only 5 sham-treated patients (p < 0 001). All 5 patients who thought they had received TLI but later changed their minds were in the sham group, and all had progressed as determined by the blinded neurologist. In contrast, all 3 patients who originally believed they had not received TLI but later thought they had, were in the TLI group, and none had progressed. These findings suggest that the patients were initially quite well blinded, and that changes in opinion were based on disease course. Adverse effects occurred in similar frequency in both groups; they were generally mild and abated shortly after completion of therapy. Nausea was more common in the TLI group (9 patients vs 1 sham patient; p < 0-01) and 2 TLI patients became menopausal. Transient hair loss at the nape of the neck, axillary regions,

1408 and mid-chest (in hirsute men) was seen in 6 TLI patients but no sham-treated patients (p < 005). Thrombocytopenia and leucopenia occurred commonly during TLI but were transient in all patients. During mean follow-up of 21 months, no neoplasms were detected in either group. The, incidence of upper respiratory infections was similar in the two groups, but more urinary tract infections were noted in sham-treated patients, probably associated with their greater neurological deterioration. 1 sham-treated patient died from complications of MS. Absolute lymphocytopenia (< 1 X 109/1) was noted during therapy in all 20 TLI patients but in no sham-treated patient. It was significant and persisted in the TLI group for at least 2 years although a gradual return towards normal of the absolute lymphocyte count was detected. The subgroup of TLI patients who deteriorated on the disability scale had significantly higher mean lymphocyte counts 1, 3, 6, and 12 months after treatment than those who did not deteriorate In all 3 TLI patients with absolute (p < 001). lymphocyte counts > 1 x 109/1 3 months after TLI, the functional score at 18 months had decreased (mean 1 of 13 with -3-67 grades), compared with only

lymphocyte counts < 1 x 109/1 (mean+0-23 grades, 4 patients did not have lymphocyte counts p<001); done at 3 months. Further, the patient who deteriorated most had the highest post-treatment lymphocyte count; his TLI had been interrupted and extended to 8 weeks instead of the usual 5 weeks. Thus, the absolute lymphocyte count appeared to be a crude indicator of therapeutic efficacy. Discussion On the premise that the immune response may play a role in causing the demyelination of MS,8 we initiated a prospective, randomised, double-blind study of the effects of TLI in patients with chronic progressive MS, for whom no accepted long-term therapy is available and who are likely to continue to deteriorate. 9,10 We added a posterior spinal block to the irradiation regimen3 to help prevent possible untoward damage to a spinal cord already compromised by MS. Our decision to set a low limit (10 Gy) for spinal cord irradiation was based on the following considerations: CNS irradiation may cause damage to vascular endothelium and the blood-brain barrier, making it more permeable;l1-13 CNS irradiation can produce spinal cord damage; 14 transfer of lymphnode cells from Lewis rats with experimental allergic

encephalomyelitis to normal rats predisposed to paralysis in those which had had prior irradiation of the spinal cord;15 cellular infiltrates of experimental allergic encephalomyelitis are more pronounced in the irradiated region of the neuraxis;15 and transient damage to the blood-brain barrier occurred in patients with chronic progressive MS who received 12-18 Gy to the CNS.’3 We found significantly less decline in functional status in the TLI group than in the sham-treated patients, especially in patients who showed sustained lymphocytopenia. These findings suggest that TLI causes changes in lymphoid tissue which result in amelioration of disease activity; they accord with other indirect evidence that MS has an immune-mediated pathogenesis. Our initial experience suggests that TLI in MS is well tolerated and associated with only mild

short-term and, to date, long-term side-effects. A slight imbalance in entry functional score had no effect on our conclusions, since omission of the TLI patients with the most severe initial impairment did not change the significant benefit of TLI treatment. Since transient hair loss and amenorrhoea occurred only in the TLI group, it could be argued that the study was not effectively blinded or that a stronger placebo effect existed in these patients than in controls. However, the areas of hair loss were not readily apparent and not inspected by the examining neurologists, and the patients and blinded neurologists did not discuss sideeffects of treatment with each other. It is also unlikely that a placebo effect would last for up to 3 years of follow-up. Most importantly, there was no significant difference immediately after therapy between the two groups in the proportions who thought they had received TLI or sham therapy. Few TLI patients improved, the remainder stabilising or progressing at a less rapid rate than the sham-treated patients. The limitations of TLI alone as therapy in chronic progressive MS are shown by the fact that about half of patients so treated have progressed by 36 months. Thus TLI, as administered here, is not curative therapy for MS but appears to be palliative in some patients. We did not expect more patients treated with TLI to improve, since they were patients with long-standing progressive disease. A stronger beneficial effect might be obtained if patients were treated before potentially irreversible CNS changes had occurred, or if TLI were combined with other immunomodulating treatment.

A relation similar to that we noted between lymphocyte and prognosis was seen in studies of TLI in rheumatoid arthritis. Trentham et al’ observed a temporal correlation between the initial subsidence of joint inflammation and decline in lymphocyte count after TLI. However, in that study, which used three fields, 30 Gy total dose, and a course of several months, mean absolute lymphocyte counts rose rapidly to 1-27 x 109/1 6 months and 3-16 x 109/1 12 months after TLI, and all patients had shown partial recrudescence of disease within a year of therapy. In contrast, in the study by Kotzin et al,3,5 who used a similar TLI regimen to ours, all patients had a lymphocytopenia that persisted for at least 2 years and was associated with persistent clinical improvement for 13-28 months of follow-up.3°s Thus, an absolute lymphocytopenia may be an important indicator of effective immunosuppression and may be clinically useful in monitoring therapy regardless of the immunosuppressive regimen used. Unfortunately, in our study the absolute lymphocyte count tended to increase with time, and even in Hodgkin’s disease patients treated with 40 Gy TLI lymphocyte counts returned to pretreatment levels in less than 2 years. 16 There may therefore be relapses in MS patients given TLI alone, as their lymphocyte counts return to normal and it may prove necessary to combine TLI with other lymphocytopenic treatments in order to sustain clinical remission. Many immunosuppressive treatments, mostly studied in uncontrolled settings, have been used to treat MS patients. Short-term therapy with corticotropin or high-dose pulse steroids speeds up recovery after acute exacerbations of My,17 20 but it is not clear whether long-term, high-dose steroids are effective in changing count

1409 of Combinations and steroids may cyclophosphamide, plasmapheresis, also have short-term beneficial effects in MS.1O.21

the

course

of

the

disease.

Unfortunately immunosuppressive drugs, particularly alkylating agents, have a close therapeutic/toxic ratio and a wide range of side-effects.22 Although long-term risks of malignant disorders in patients with nonneoplastic disease treated with immunosuppressive drugs are not precisely defined, alkylating agents such as cyclophosphamide have been associated with a higher than expected incidence of malignant disorders of the blood.19 Even less is known about long-term risks of immunosuppressive drugs in MS. However, in one MS study, a 2.5-fold increased risk of cancer was found in 131 patients treated with azathioprine for a mean of 6 years and malignant disorders occurred in almost 10% of the subgroup of MS patients followed 5 years or longer.23 TLI seems not to be associated with a high risk of neoplasia and generally produces few serious sideeffects in long-term follow-up.s>6 TLI and immunosuppressive drugs in MS each have another theoretical advantage and disadvantage. By sparing the brain, TLI cannot damage its oligodendrogliocytes, thereby allowing the possibility of remyelination, whereas immunosuppressive drugs which cross a normal or damaged blood-brain barrier might injure the oligodendrogliocytes and inhibit remyelination. On the other hand, TLI does not eliminate immunocompetent cells in the brain; if MS is an autoimmune disease, these cells could continue to cause immune-mediated tissue injury for their lifetime in the CNS. TLI therefore appears to be a promising new therapy for the treatment of patients with chronic progressive MS. However, amplification of our results is needed before the overall efficacy of TLI in MS can be judged and the subgroups of patients who might most benefit identified. In the mean time, TLI should be considered an experimental therapy in MS patients and its use in this disorder restricted to MS study groups.

Addendum to Subsequent completion of this study, 1 severely disabled MS patient, 3 years after TLI, died from a flu-like syndrome complicated by staphylococcal pneumonia, obstruction of her endotracheal tube, and

cardiorespiratory

arrest.

This work was supported Veterans Administration.

by

the Medical Research Service of the

Correspondence should be addressed to S. D. C., VA Medical Center, Neurology Service (127), East Orange, New Jersey 07019, USA. REFERENCES 1. Slavin

S, Strober S, Fuks Z, Kaplan HS. Induction of specific tissue transplantation tolerance using fractionated total lymphoid irradiation in adult mice: long-term survival of allogeneic bone marrow and skin grafts. J Exp Med 1977; 146: 34-48. 2. Kotzin BL, Strober S. Reversal of NZB/NZW disease with total lymphoid irradiation. J Exp Med 1979; 150: 371-78. 3. Kotzin BL, Stober S, Engleman EG, et al. Treatment of intractable rheumatoid arthritis with total lymphoid irradiation. N Engl J Med 1981; 305: 969-76 4. Trentham DE, Belli JA, Anderson RJ, et al. Clinical and immunologic effects of fractionated total lymphoid irradiation in refractory rheumatoid arthritis. N Engl J Med 1981; 305: 976-82. 5. Field EH, Strober S, Hoppe RT, et al. Sustained improvement of intractable rheumatoid arthritis after total lymphoid irradiation. Arthritis Rheum 1983;

EVIDENCE FOR DOWN-REGULATION OF BETA-2-ADRENOCEPTORS IN CIRRHOTIC PATIENTS WITH SEVERE ASCITES ALEXANDER L. GERBES DIETER JÜNGST

GUSTAV PAUMGARTNER

Department of Medicine II, Klinikum Grosshadern, and Walther Straub Institute of Pharmacology, University of Munich, Federal Republic of Germany

density and affinity of beta-2adrenoceptors on mononuclear cells from peripheral blood were studied in fifteen patients with cirrhosis of different severity and in thirteen controls. There was no significant difference between cirrhotic patients and controls in density or affinity of beta-2 binding sites. Within the cirrhotic group, however, the number of binding sites per cell was significantly lower in patients with severe ascites than in patients with mild to moderate or no ascites. This down-regulation of beta-adrenoceptors could influence the haemodynamic response to beta-blockers.

Summary

The

Introduction LEBREC and colleagues1.2 found that the non-selective beta-adrenoceptor blocker propranolol reduced the frequency of gastrointestinal rebleeding in patients with cirrhosis and oesophageal varices, but this finding was not confirmed by Burroughs et awl. This discrepancy might be due to differences in the severity of cirrhosis in the selected patients, since the stage of liver disease influences the haemodynamic effects of propranolol.4

8. Cook

SD, Dowling PC. Multiple sclerosis and viruses: an overview. Neurology 1980; 30: 80-91. 9. Bauer HJ, Firnhaber W, Winkler W. Porgnostic critèria in multiple sclerosis. Ann NY Acad Sci 1965; 122: 542-51. 10. Hauser SL, Dawson DM, Lehrich JR, et al. Intensive immunosuppression in progressive multiple sclerosis. A randomized, three-arm study of high-dose intravenous cyclophosphamide, plasma exchange, and ACTH. N Engl J Med 1983; 308: 173-80. L, Shealy NC. Experimental selective alteration of the blood-brainbarrier by x-irradiation. J Neurosurg 1970; 32: 89-94. 12. Oldendorf WH, Cornford EM. A comparison of total body and local spinal cord 11. Schettler

irradiation in experimental allergic encephalomyelitis. J Neuropathol Exp Neurol 1977; 36: 50-61. 13. Tourtellotte WW, Potvin AR, Baumhefner RW, et al. Multiple sclerosis de novo CNS IgG synthesis. Effect of CNS irradiation Arch Neurol 1980; 37: 620-24. 14. Mastaglia FL, McDonald WI, Watson JV, Yogendran K. Effects of X-radiation on the spinal cord: an experimental study of the morphological changes in central nerve fibers Brain 1976; 99: 101-22. 15. Paterson PY, Richardson WP, Drobish DG. Cellular transfer of experimental allergic encephalomyelitis: altered disease pattern in irradiated recipient Lewis rats. Cell Immunol 1975; 16: 48-59. 16. Fuks Z, Strober S, Bobrove AM, Sasazuki T, McMichael A, Kaplan HS. Long-term effects of radiation on T and B lymphocytes in peripheral blood of patients with Hodgkin’s disease. J Clin Invest 1976; 58: 803-14. 17. Rose AS, Kuzma JW, Kurtzke JF, Namerow NS, Sibley WA, Tourtellotte WW. Cooperative study in the evaluation of therapy in multiple sclerosis: ACTH vs placebo: final report. Neurology 1970; 20: 1-59. 18. Dowling PC, Bosch VV, Cook SD. Possible beneficial effect of high dose intravenous steroid therapy in acute demyelinating disease and transverse

myelitis. Neurology 1980; 30: 33-36. R, Hafstein M, Ruderman M, Dowling P, Cook SD. Effect of high-dose intravenous steroid administration on contrast-enhancing computed tomographic scan lesions in multiple sclerosis. Ann Neurol 1984; 15: 257-63. 20. Sowa K, Hamaguchi K, Ohno R, Tanaka H. High dose intravenous corticosteroids treatment in multiple sclerosis. J Neurol 1985; 232 (suppl): 19. Troiano

123.

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 1985;

21. Khatri

26: 937-46. 6. Hafstein MP, Devereux

C, Troiano R, et al. Total lymphoid irradiation in chronic progressive multiple sclerosis: a preliminary report. Ann NY Acad Sci 1984; 436: 397-409. 7. Poser CM, Paty DW, Scheinberg L, et al New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983; 13: 227-31.

JÖRG REMIEN TILMAN SAUERBRUCH

35. 312-19. N Engl J Med 1983; 289: 952-54. 23. Lhermitte F, Marteau R, Roullet E. Not so benign long-term immunosuppression in multiple sclerosis. Lancet 1984; i- 276-77.

22.

Kaplan SR, Calabresi P. Drug therapy. Immunosuppressive agents.