Hillel S. Panitch

Treatment of multiple sclerosis with gamma interferon: Exacerbations associated with activation of the immune system

We treated 18 clinically definite relapsing-remitting MS patients with recombinant gamma interferon in a pilot study designed to evaluate toxicity and dosage. Patients received low (1 μg), intermediate (30 μg), or high (1,000 μg) doses of interferon by intravenous infusion twice a week for 4 weeks. Serum levels of gamma interferon were proportional to dose and no interferon was detected in CSF. Seven of the 18 patients had exacerbations during treatment, a significant increase compared with the prestudy exacerbation rate (p < 0.01). Exacerbations occurred in all three dosage groups and were not precipitated by fever or other dose-dependent side effects. There were significant increases in circulating monocytes bearing class II (HLA-DR) surface antigen, in the proliferative responses of peripheral blood leukocytes, and in natural killer cell activity. These results show that systemic administration of gamma interferon has pronounced effects on cellular immunity in MS and on disease activity within the CNS, suggesting that the attacks induced during treatment were immunologically mediated. Gamma interferon is unsuitable for use as a therapeutic agent in MS. Agents that specifically inhibit gamma interferon production or counteract its effects on immune cells should be investigated as candidates for experimental therapy.

A neurologic rating scale (NRS) for use in multiple sclerosis

A neurologic rating scale (NRS) has been developed for clinical assessment of MS patients. The scale has been tested on 250 MS patients. Assignment of the NRS score is based on assessment of each component of the neurologic examination and accurately reflects overall neurologic function. Clinical exacerbations are evident as significant deviations from baseline scores. There was close interexaminer correlation, with the range of variability no greater than 2.6%. The NRS is a simple, reliable, and sensitive scale that can be used with other objective measurements of neurologic function, such as neurophysiologic studies, in the clinical assessment of MS patients.

Systemic alpha‐interferon therapy of multiple sclerosis

A randomized, double-blind, placebo-controlled crossover study tested the efficacy of natural alpha interferon in altering exacerbating-remitting MS. Twenty-four patients with frequent exacerbations were treated for 6-month periods, beginning with either 5 × l06 IU of interferon daily or placebo. A 6-month washout period followed each treatment. Exacerbation rates were reduced during interferon and placebo phases compared with pre-study rates; a greater reduction occurred on interferon, particularly following placebo, possibly reflecting a learning phenomenon. Fifteen patients with a strictly exacerbating-remitting course had fewer and milder exacerbations on interferon compared with those on placebo, whereas 9 patients with a progressive component continued to have active disease. These results suggest that interferon might reduce exacerbations in certain patients and indicate guidelines for future trials of interferon in MS.

Plasmapheresis in multiple sclerosis Preliminary findings

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.

Monoclonal gammopathy and neuropathy: Myelin‐associated glycoprotein reactivity and clinical characteristics

Immunoblot analysis was performed on the serum from 29 patients with polyneuropathy and monoclonal gammopathy. Nine patients had IgM spikes, and six of the nine had reactivity against myelin-associated glycoprotein (MAG) associated with a slowly progressive, predominantly sensory neuropathy. In contrast, 23 patients who lacked anti-MAG reactivity had more severe sensory motor neuropathy. Thus, IgM monoclonal gammopathy with reactivity against MAG may define a distinct clinical entity.

Relapsing transverse myelitis

Acute transverse myelitis is a monophasic disorder, the recurrence of which raises the question of multiple sclerosis (MS) or other multifocal CNS disease. We now report three patients with a previously undescribed syndrome of relapsing isolated acute transverse myelitis. Each had two to five attacks over periods of 3 to 8 years, characterized by ascending paresthesias, urinary retention, sensory loss with a thoracic or cervical level, paraparesis, hyperreflexia, and bilateral Babinski signs. MRI demonstrated areas of increased signal intensity on T2‐ and proton density‐weighted scans and decreased signal intensity on T1‐weighted scans of the cervical or thoracic spinal cord consistent with an inflammatory or demyelinating process. All patients had normal complete myelograms, oligoclonal IgG bands were consistently absent from the cerebrospinal fluid, cranial MRIs were normal, and there was no other clinical or laboratory evidence of MS, collagen‐vascular disease, or active viral infection. They were treated with high doses of intravenous corticosteroids, stabilized between episodes, and had partial or complete recovery. The recognition of these three patients at a single medical center in a 1‐year period suggests that relapses of acute transverse myelitis may not be rare. NEUROLOGY 1991;41:703‐706

Adoptive transfer of experimental allergic encephalomyelitis with activated spleen cells: Comparison of in vitro activation by concanavalin A and myelin basic protein☆

Abstract Adoptive transfer of experimental allergic encephalomyelitis (EAE) was carried out in Lewis rats using splenic lymphocytes incubated in vitro with either concanavalin A (Con A) or myelin basic protein (MBP). Requirements were established for sensitization of donors, culture conditions, numbers of transferred cells, and incubation period of EAE in recipients. These were strikingly similar whether Con A or MBP was used. In addition, cellular proliferation in vitro was not required in either system, but proliferation after transfer to the recipient was essential for the development of clinical signs and histological lesions. These methods have potential value for analyzing mechanisms of immune induction in this classic model of autoimmune disease.

Clinical correlations of serial somatosensory evoked potentials in multiple sclerosis

Serial median nerve somatosensory evoked potentials (SEPs) were recorded in 12 patients with definite MS. On the initial tests, there was no clear association between the severity of clinical disease activity and SEP findings. The cervical response was most frequently affected and, when present, was often abnormal in configuration, suggesting absence or delay in the far field P14 component with preservation of cervical N11 and N13 components. Clinical motor and sensory findings in the corresponding limb frequently correlated with abnormalities of the cervical response. When new motor and sensory findings developed in the arms during the study, the SEP deteriorated in some patients but improved in others. Most SEP changes were not accompanied by clinical changes. Overall disability sometimes increased during the study despite improvements in the SEP.

MYELOPATHIC NEUROSARCOIDOSIS : DIAGNOSTIC VALUE OF ENHANCED MRI

Neurosarcoidosis is an underdiagnosed variant of the systemic disease. We report a case of myelopathic neurosarcoidosis, noting the contribution made by MRI in establishing the diagnosis, and we discuss the possibility that the disease is differentially responsive to various steroid formulations.

Adoptive transfer of experimental allergic encephalomyelitis: requirement for macrophages in activation of spleen cells in vitro by concanavalin A or myelin basic protein.

Abstract Adoptive transfer of experimental allergic encephalomyelitis (EAE) in Lewis rats is markedly enhanced when sensitized spleen cells are incubated in vitro with either concanavalin A (Con A) or myelin basic protein (MBP). This phenomenon permits more detailed analysis of the inductive phase of EAE than has heretofore been possible. We have now demonstrated that macrophages are essential for the process to occur, and that they probably act by different means depending on whether activation is carried out with the mitogen or the specific antigen. Depletion of macrophages by passage through G-10 Sephadex columns prevented activation of spleen cells by either Con A or MBP. The effect of Con A could be partially restored with 2-mercaptoethanol, while activation by MBP could not. Reconstitution of macrophage-depleted cultures with peritoneal exudate cells from either immune or normal rats fully restored activation by both Con A and MBP. Supernatants taken from spleen cell cultures were unable to restore the transfer activity of macrophage-depleted cells, indicating that activation probably is not mediated by a soluble factor released by macrophages. Depletion of macrophages after incubation with Con A slightly reduced transfer activity, but depletion after incubation with MBP abolished it. Thus the mechanisms of activation appear to differ in the two systems, and in the case of MBP the macrophage-mediated portion of the process may be incomplete prior to adoptive transfer.