Disease modifying therapies in multiple sclerosis.
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Biomedical subjects
Publications and source records attributed to B O Khatri.
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Although the cause of multiple sclerosis (MS) remains unknown, the recent advances in research and the use of immunomodulating therapies have revolutionalized the way this disease is now approached. Apheresis is but one of the various immunomodulating therapies successfully used in MS. Pilot and double-blind randomized controlled studies, long-term follow-up studies, and the possible mechanism of action of therapeutic apheresis in MS are discussed. Based on our current knowledge, as well as on the available published data, it is concluded that apheresis is an effective therapy in severely progressive MS (both acute and chronic) when conventional therapies have failed.
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In patients with multiple sclerosis (MS), the apparently uninvolved cerebral white matter between demyelinated plaques may have biochemical abnormalities. To what degree the changes in the white matter contribute to symptomatology in MS is unknown. In 39 patients with multiple sclerosis, and in 39 age-matched nondiseased volunteers, T1 and T2 were calculated from spin-echo images in four regions of apparently uninvolved white matter. In three of four white matter areas, the average T1 and T2 were significantly longer in the patients than in the controls. The T1 correlated with the disability, measured by the Kurtzke Extended Disability Status Scale, although the correlation was marginally significant. The results suggest that in patients with MS, white matter disease that is not visualized in MR as distinct foci of abnormal signal intensity may contribute to disease burden and disability.
Three hundred twelve patients were entered into a long-term study of effects of hyperbaric oxygen on multiple sclerosis. The protocol called for an initial 20 treatments in either the monoplace or multiplace chamber on a daily basis followed by monthly booster treatments for 2 years. One hundred seventy neurologists and 22 institutions provided data for this study. There was no control group, but the study was based on Schumacher's postulation that a scientifically valid study to test the efficacy of a new therapy was possible by choosing patients who were definitively diagnosed with multiple sclerosis and following them up for 2 years after the imposed treatment. If the overwhelming majority of the subjects failed to get worse over the 2-year observation period, the efficacy of the treatment would be manifest. The expanded Kurtzke Disability Status Scale (EDSS) was used to assess the severity of the disease state. The dropout rate was high with only 76% (237 of 312 patients) finishing the initial 20 treatments. Twenty-two percent (69 of 312) finished 1 year of booster therapy, and 9% (28 of 312) completed 2 years of monthly boosters. The mean deterioration on the Kurtzke EDSS score was 0.93 or almost a full step from the beginning of treatment until the last evaluation. There was no difference in outcome between those who had the shortest and longest periods of time between onset of symptoms and hyperbaric oxygen treatment. Treatment pressure made no difference in outcome. Changes in the Kurtzke EDSS score bore no relationship to the use of booster treatment. Patients who were reasonably well off at the onset of treatment with initial Kurtzke EDSS scores of 1 or 2 (n = 21) deteriorated by an average of 1.7 Kurtzke points. Those patients whose initial Kurtzke EDSS scores were greater than 2 (n = 164) deteriorated on an average of 0.82 points. Of interest was that 19.5% (39 of 200) of the patients reported a temporary improvement in bladder function, but improvement was maintained in only 11 patients (5.5%) at 2-year follow-up. Fifteen patients (7.5%) indicated long-term worsening. There was no significant change in the working status of the patients following hyperbaric oxygen treatment. Although this study treated the patients in accordance with protocols reported to produce a benefit in multiple sclerosis, we were unable to substantiate any useful long-term effect of hyperbaric oxygen therapy.
Plasma exchange (PE) was shown in a previous double-blind randomized controlled study to confer significant additional benefit at 1 year upon patients with chronic progressive multiple sclerosis (CPMS) treated with immunosuppressive drug therapy (ISDT). Efficacy over an extended term, indications for retreatment, and long-term toxicity are dealt with in this analysis of a larger number of patients. During the past 7 years, 200 patients with CPMS have been treated with PE and low-dose ISDT at this center. Improvement on the Kurtzke Disability Status Scale by one or more steps post-therapy and at 3-year follow-up is significant by comparison with pre-PE disability status. Clinical improvement was maintained in the majority of patients, reaching as far as a 6-year follow-up. Major life-threatening complications attributable to this combined therapy were not observed.
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We enrolled 116 patients in a multicenter, randomized, double-blind controlled trial of an 8-week course of 11 plasma exchange (PE) treatments in exacerbations of MS. The control group received sham PE, and both groups received identical treatment with IM ACTH and oral cyclophosphamide. Serum IgG decreased in the PE and sham treatment groups by 76% versus 22% by treatment 5, and by 64% versus 14% by treatment 11. PE also produced significant reductions in IgA, IgM, C3, and fibrinogen. PE patients had moderately enhanced improvement at 2 weeks relative to the sham group. PE patients with relapsing/remitting disease had significantly enhanced improvement at 4 weeks and there was also an increased improvement at 12 months, although this latter effect disappeared when we analyzed relapsing/remitting patients as a separate subgroup. Life table analysis showed the median time to recover preattack disability status was shorter in PE- than in sham-treated relapsing/remitting patients (4 vs. 13 weeks), a result confirmed by raw disability status scores in which there was recovery to their average preattack disability score by 3 months. PE given with ACTH plus cyclophosphamide enhances recovery from an exacerbation of disease in relapsing/remitting patients, although we observed no clear long-term benefits.
To study the incidence of deep venous thrombophlebitis (DVT) and pulmonary embolism (PE) in patients with multiple sclerosis (MS), charts of 228 subjects with multiple sclerosis who constituted 1986 hospital admissions to the Milwaukee Regional Medical Center were reviewed, covering a 3 1/2-year period. The records were investigated for any other hospitalization for deep venous thrombophlebitis and pulmonary embolism. No case of pulmonary embolism or deep venous thrombophlebitis was found. There were over 57,416 non-MS-related admissions during the same interval. Among these patients there were 175 with PE and 258 with DVT. The presence of lower extremity spastic disease may have prevented clotting. This statistically low incidence of thromboembolic events in MS is less than expected, and further studies are warranted.
Based on the assumptions that multiple sclerosis (MS) is an autoimmune disorder and that plasmapheresis (PP) is an effective means of removing antibodies and other proteins from the circulation, several uncontrolled studies were undertaken to ascertain the role of PP in MS. Since MS is a chronic and persistent rather than monophasic illness, PP has been used in MS in conjunction with a variety of immunosuppressive drug regimens, theoretically to prevent the rebound reformation of the offending protein being removed. Careful analysis of the uncontrolled studies shows wide variance in the types of patients treated; the extent, duration and activity of their disease; and the methodology of PP and the adjunctive immunosuppressive treatment. Nevertheless, the conclusion we reached from this analysis was that prolonged treatment with PP, in conjunction with corticosteroid and other immunosuppressive drug treatment, may have a major clinical effect in patients severely disabled with chronic progressive MS. This in itself is a remarkable conclusion, since it is drawn from data about a form of MS which, by definition, rarely if ever improves spontaneously: more than one-half of the patients reported improvement.
Forty-seven patients with chronic progressive multiple sclerosis were examined to assess the possible relationship between cerebral atrophy (by computed tomography [CT] ) and performance on neuropsychological tests of memory and verbal intelligence. Nineteen patients were found to have mildly dilated ventricles and another nine patients had moderate to severe ventricular enlargement. Performance on memory and intelligence testing was related to the degree of ventriculomegaly. Three linear CT measurements were also recorded. Using this method, the width of the third ventricle proved to be the best indicator of intellectual and memory dysfunction. Measures of cognition and ventricular size did not correlate with length of illness or overall disability as rated by the Kurtzke Disability Status Score.
Fifty-four patients with chronic progressive multiple sclerosis received prednisone plus oral low-dose cyclophosphamide and either true plasmapheresis (PP) or "sham" PP weekly for 20 weeks in a double-blind controlled study. Immunosuppressive drug therapy alone (sham PP group, n = 29) was associated with improvement (greater than or equal to one step in Kurtzke Disability Status Scale [DSS]; mean change of 1.5) in 8 and stabilization of MS in 18 patients, with this status sustained in 23 patients at follow-up, 11 months after entry. In contrast, 14 of 26 patients who received "true" PP improved (greater than or equal to one step in DSS; mean change of 2.6), and 11 more were stable, with these changes sustained in 23 of 26 patients at follow-up. These differences, overall, between the PP and sham PP groups were significant at p less than 0.007.
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In light of encouraging preliminary data, 45 patients with severely progressive multiple sclerosis underwent long-term plasmapheresis in conjunction with low-dose cyclophosphamide and prednisone therapy. The disease progression was monitored by the Kurtzke disability status scale (DSS) and functional systems scale, neuro-ophthalmologic evaluations, evoked potentials, computed tomographic scans, and suppressor cell function assays. The conditions of 28 of the 45 patients improved significantly, the conditions of 14 patients showed limited improvement, and the conditions of three patients neither improved nor worsened. Improvement in other parameters correlated with the clinical results. Significant improvement in suppressor cell function was noted in those patients whose conditions had improved by one or more steps on the DSS.
High-resolution computed tomography (CT) of the lumbar spine in 80 consecutive patients with lower back pain was correlated with electromyography (EMG) and with the clinical outcome at one-year follow-up. Forty-two patients had abnormal EMG findings that could be explained on the basis of anatomical defect(s) seen on CT. Nine had normal CT scans but abnormal EMGs, and five patients had normal EMGs but abnormal CT scans. Thirteen of the 80 patients were further investigated with myelography, 22 patients underwent surgical exploration, and the remainder received conservative therapy. In the majority of cases, surgery confirmed the abnormal CT and EMG findings; in some instances, however, myelography and/or surgery confirmed the abnormality only at the level demonstrated on EMG. The CT and EMG often agree. However, an abnormal EMG seems to correlate better with the demonstrated course of radiculopathy than CT.
Forty-four patients with chronic progressive multiple sclerosis (MS) were compared with age- and education-matched control groups on a battery of clinical and experimental memory measures. Patients with MS performed substantially below the control groups on both immediate learning and delayed recall tasks, particularly in the retrieval of spatial information. The MS sample was subdivided into three groups using a cluster analytic procedure. One group (N = 9) performed well below expectations on memory tasks, exhibited signs of global cognitive disturbance, and had an atypical personality adjustment, characterized by irritability, social withdrawal, and apathy. A second group (N = 19) showed mild memory disturbance, associated with a greater use of psychotropic medications and a higher incidence of reactive depression. A third group (N = 16) performed normally on memory measures. The three groups of patients with MS did not differ in length or overall severity of illness.