Plasmapheresis combined with prednisone and azathioprine therapy produced striking clinical improvement in five patients with myasthenia gravis who still had moderate to severe disability despite thymectomy, high-dose prednisone therapy and optimal doses of cholinesterase inhibitors. Serial determinations of titers of serum antibody toward the acetylcholine receptor demonstrated a fall to 21 +/- 5 per cent (mean +/- S.D.) of the original levels concurrently with the patients' increasing strength. Clinically improved patients maintained lowered titers, whereas clinical relapses were associated with a rebound in titer. Our results suggest that plasmapheresis will find a place in the management of patients with myasthenia gravis, and they implicate antibodies to acetylcholine receptor as a pathogenic factor in this disease.

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.

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Plasmapheresis in the treatment of myasthenia gravis has led to disparate results when applied by different investigators because of considerable differences in the volume, number, and tempo of plasmaphereses and in the type and amount of concomitant immunosuppressive drug therapy. Used as short-term crisis intervention, plasmapheresis produces temporary clinical improvement and reduction in titer of antibody to acetylcholine receptor, even without accompanying drug therapy. When applied as long-term primary therapy under optimal conditions, plasmapheresis is capable of generating stable improvement in most patients. This response appears to result from a synergistic action with immunosuppressive drugs, since it is characterized by a sustained reduction in titer of antibody to acetylcholine receptor. Where clinical circumstances warrant cytotoxic immunosuppression in patients with myasthenia gravis, consideration should be given to the simultaneous employment of plasmapheresis, in order to maximize benefit to the patient from a given exposure to drug therapy.

Five patients with Eaton-Lambert syndrome (ELS) without associated malignancy were first treated by plasmapheresis alone, and subsequently by plasmapheresis combined with prednisone and azathioprine therapy. Three of the five were also treated by the immunosuppressive drugs alone. Although all three therapeutic regimens resulted in some clinical and electromyographic (EMG) improvement, the greatest improvement was seen during plasmapheresis combined with prednisone and azathioprine. The initial evoked compound muscle action potential (CMAP) increased during treatment in all patients, while facilitation of the initial CMAP by tetanic stimulation decreased. Overall, the EMG decrement elicited at 2 Hz lessened in four of the five patients. Serious complications probably attributable to guanidine toxicity developed in three patients: two had renal failure and one had gastrointestinal and urinary tract bleeding. Our results suggest that immunosuppressive therapy may have a place in the management of ELS and that circulating factors such as autoantibody may participate in its pathogenesis.

In seven of eight patients with progressive multiple sclerosis subjected to long-term plasmapheresis in combination with azathioprine and pulsed prednisone therapy, we found modest improvement of neurologic function. There was no change in auditory and visual evoked responses or serum demyelinating activity. In six of seven patients, cerebrospinal fluid IgG content decreased. Three additional patients in acute, severe exacerbation refractory to prednisone therapy made a substantial recovery, which commenced with plasmapheresis therapy. In two of them, the onset of clinical improvement after plasmapheresis was corroborated by decreased latency or increased amplitude of somatosensory evoked potentials. These results suggest that blood-borne factors, possibly autoantibodies, may play a role in the pathogenesis of the disease. The lesions may be at least partially reversible with plasmapheresis therapy, but a controlled trial is necessary to confirm these preliminary findings.

Evidence for accelerated specific antibody (Ab) rebound or overshoot after single or multiple therapeutic plasmapheresis (TP) is fragmentary but suggested by both clinical and experimental evidence. In vitro studies showing increased peripheral blood lymphocyte turnover and total immunoglobulin production after a series of TP without immunosuppression may signify a generalized immunostimulation through removal of regulatory molecules by TP. It is known that IgG class Ab can down regulate B cells by cross linkage of their Ag and Fc receptors. Cyclophosphamide and other cytotoxic immunosuppressive agents effectively delete proliferating lymphocytes. TP could particularly foster deletion of lymphocytes actively mediating autoimmunity, since they would be more readily stimulated to proliferation by removal of Ab or other inhibitory factors than the generally resting normal immune system. This is supported by a relatively greater reduction of autoantibody levels than total immunoglobulin after treatment with TP and cytotoxic immunosuppressives.

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