Systemic alpha-interferon in multiple sclerosis. Long-term patient follow-up.

Twelve patients with relapsing multiple sclerosis who had participated in a clinical trial of systemic (subcutaneous) natural alpha-interferon were interviewed and reexamined 4.3 years after beginning interferon treatment and 2.3 years after completion of the study. There was a progressive reduction in exacerbation rate from 1.33 per year to 0.47 per year. Overall neurologic function and disability did not change significantly. Six patients stabilized or improved, and were able to carry on normal daily activities. There were no long-term deleterious side effects. These results are similar to those described for patients treated with intrathecal beta-interferon. The mechanism of the prolonged beneficial effect is unknown, but is unlikely to represent antiviral activity in the central nervous system, and more probably involves systemic immunoregulatory functions. The systemic route of administration of interferon may be as effective as the intrathecal route in multiple sclerosis, and is potentially less hazardous.

Serial evoked potential studies in patients with definite multiple sclerosis. Clinical relevance.

Twelve patients with clinically definite multiple sclerosis were examined both clinically and electrophysiologically at repeated intervals over one year to determine the clinical relevance of data obtained by serial multimodality evoked potential studies. We frequently found a disparity between the clinical and electrophysiologic changes, and also an excessive variability between test sessions of the responses to stimulation of a clinically involved afferent pathway even when the clinical deficit was stable. Our findings indicate that though evoked potential studies may provide information of diagnostic relevance, their role in monitoring disease progression has not been established.

CSF antibody to myelin basic protein. Measurement in patients with multiple sclerosis and subacute sclerosing panencephalitis.

A solid phase radioimmunoassay was used to detect antibodies to myelin basic protein (MBP) in the CSF of patients with multiple sclerosis (MS) and subacute sclerosing panencephalitis (SSPE). F(ab')2 fragments prepared from SSPE IgG retained their activity, which showed that the assay measures a true antigen-antibody reaction rather than nonspecific adherence to IgG to MBP. Samples of CSF from 48 patients with MS and 30 patients with SSPE were tested and, in both conditions, antibody activity was significantly greater than in controls, when tested at identical IgG concentrations. In MS, levels of antibody were highest in patients with acute exacerbations and lower in patients in remission, which supported the hypothesis that autoimmunity to a myelin antigen may play a role in the pathogenesis of the disease. The reaction with MBP was consistently more pronounced in SSPE than in MS. In view of the association of SSPE with measles virus and the presence of high titers of measles antibody in the CSF, antibodies to measles and to MBP may be directed against similar antigenic determinants.

Reflex epilepsy evoked by decision making.

A patient had seizures while playing chess or cards or when filling out complex forms, doing complex mathematical problems, and during certain parts of the neuropsychological testing. Seizures were myoclonic and accompanied and electroencephalographic dysrhythmia of the atypical spike and wave type. Evoked seizures were not related to visual, tactile, or auditory stimuli or clues. In chess, seizures occurred when he was on the defense and threatened. Simple decision making or physiologic stress did not evoke seizures nor did nonsequential decision making under verbal pressure. Evoking factors were complex decision making in a sequential fashion and with an element of stress or concern regarding the outcome of the decision making. Stimulus was usually nonverbal. Three major factors--decision complexity, sequential factor, and related stress or concern--may have some reciprocal relationships.

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.

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.

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 microgram), intermediate (30 micrograms), or high (1,000 micrograms) 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 less than 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.

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-weighed 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.

Increased cathepsin B activity in peripheral blood mononuclear cells of multiple sclerosis patients.

Proteinase levels are increased in multiple sclerosis (MS) lesions and are implicated in demyelination. The cellular origins of the activity are not known, but inflammatory cells of hematogenous origin are one possibility. We studied the levels of two lysosomal proteinases implicated in the proteolysis of myelin basic protein, cathepsin B (CB) and cathepsin D (CD), in peripheral blood mononuclear cells (PBMCs) of 20 stable relapsing-remitting MS patients. We prepared and assayed cell lysates of PBMCs from the MS patients, 10 patients with other neurologic diseases (OND), and 12 normal controls (NC). Mean CB activity expressed as milliunits of activity per million cells was significantly increased in MS patients (7.86 +/- 0.54) compared with OND (6.80 +/- 0.74) and NC (5.94 +/- 0.28) cells (p < 0.05). CD levels were not significantly increased. To determine whether the increase was generalized or limited to a subset of cells, PBMCs were fractionated by plate adherence. CB levels in the adherent fraction (AD) of the 20 MS patients were higher than in the nonadherent fraction (NA), and the AD:NA ratio of CB in MS was higher than that in controls. This would be consistent with an increase in CB levels in monocytes and macrophages, cells known to be activated in the peripheral blood of MS patients and implicated as effectors of demyelination.

Concurrence of multiple sclerosis and brain tumor: clinical considerations.

We report a patient with multiple sclerosis (MS) who developed an oligodendroglioma 8 years after the initial diagnosis of MS. This is the first description of a neoplasm, suspected initially on brain MRI and subsequently confirmed by brain biopsy, in an MS patient. Our case emphasizes the need to evaluate atypical brain MRI lesions carefully, even in well-established MS patients, as well as to obtain a tissue diagnosis of such lesions whenever possible in order to determine their precise etiology.

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.

Gamma-interferon induction in patients with chronic progressive MS.

Although gamma interferon (gamma-IFN) may be involved in the pathogenesis of exacerbations of multiple sclerosis (MS), whether it plays a role in chronic progressive MS is not known. To investigate this, we retrospectively analyzed serum samples from nine chronic progressive MS patients who were treated with monthly intravenous infusions of the interferon inducer polyinosinic acid polycytidylic acid polylysine in carboxymethylcellulose (poly ICLC). Using a bioassay we found that the mean peak total interferon level was 177 U/ml 12 hours after infusion, and using a radioimmunoassay we found that the mean peak gamma-IFN level was 15.9 U/ml 12 hours after infusion, so that gamma-IFN made up approximately 10% of the total. Greater gamma-IFN induction did not correlate with clinical worsening; induced gamma-IFN levels were not higher in two patients who worsened on treatment, and the highest levels were found in a patient who remained stable. Either chronic progressive MS is not sensitive to gamma-IFN or the effects of gamma-IFN are masked by other mediators induced by poly ICLC.

Subacute sclerosing panencephalitis: remission after treatment with intraventricular interferon.

Three children with stage II-III subacute sclerosing panencephalitis (SSPE) were treated with intraventricular human leukocyte interferon for 6 months. All three improved to varying degrees and for different lengths of time. Clinical remissions were associated with decreased titers of antibody to measles virus in CSF and with reduced rates of intrathecal IgG synthesis. There were no serious complications or side effects. Intraventricular interferon deserves further study as a potential therapeutic agent in SSPE.

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.

Interferon beta-1b serum levels in multiple sclerosis patients following subcutaneous administration.

Recombinant interferon beta-1b (rIFNbeta) reduces the frequency of exacerbations in relapsing-remitting MS when administered subcutaneously on alternate days. However, the pharmacokinetics of rIFNbeta are not well understood and there are scant data on the detectability of rIFNbeta in the serum of MS patients following subcutaneous administration. Moreover, existing assays for detecting IFNbeta are biologic, time-consuming, and require handling of infectious agents. We developed and standardized an ELISA specific for measuring rIFNbeta with a detection range of 40 to 1,000 IU/ml. The specificity of our ELISA was confirmed by the lack of cross-reactivity with other cytokines, including IFNalpha, IFNgamma, IFN Consensus-1, and TNFalpha. We screened serum from 34 MS patients drawn within 12-36 hours of treatment: 15 patients taking 8 MIU, four patients taking 1.6 MIU, and 15 patients taking placebo. Eleven of the 15 patients in the 8-MIU treatment group had measurable rIFNbeta serum levels ranging from 120 to 475 MIU/ml. Two of four patients in the 1.6-MIU treatment group, but none of the placebo group, had detectable serum rIFNbeta levels. A small prospective time-course study was carried out in four MS patients receiving rIFNbeta. Serial blood samples were obtained prior to and 4, 8, 24, and 48 hours after rIFNbeta injection. A peak serum rIFNbeta level was observed between 8 and 24 hours after rIFNbeta injection and tended to decline to near preinjection levels at 48 hours postinjection. These results are consistent with the rationale of alternate-day, subcutaneous administration of rIFN beta. In addition, the ELISA described might be a useful tool to study the pharmacokinetics and the relationship of rIFN beta serum levels to clinical efficacy.

The effects of 4-aminopyridine in multiple sclerosis patients: results of a randomized, placebo-controlled, double-blind, concentration-controlled, crossover trial.

Because 4-aminopyridine (AP) improves residual deficits in some multiple sclerosis (MS) patients but has a narrow toxic-to-therapeutic margin, we compared the safety and efficacy of two target peak serum concentration ranges (low: 30 to 59 ng/ml and high: 60 to 100 ng/ml). We enrolled eight MS patients with temperature-sensitive visual and motor deficits in a randomized, placebo-controlled, double-blind, crossover trial of short-term oral AP treatment. We randomized patients to a sequence of three treatments on three separate days: placebo, low serum concentration, and high serum concentration. We determined dosing to achieve the desired steady-state peak serum concentration ranges from a test dose and population pharmacokinetic parameters using bayesian estimation. Contrast sensitivity, standard neurologic examination, ratings of videotaped neurologic examinations, and quantitative strength assessment all improved with treatment, but flicker fusion frequency, visual evoked response latencies, and Expanded Disability Status Scale scores did not. All patients experienced side effects during the high-serum-concentration arm. A grand mal seizure occurred at a serum AP level of 104 ng/ml, and an acute confusional episode occurred at 114 ng/ml. AP treatment produced improvements in residual deficits in MS patients, but the occurrence of significant toxicity suggests that AP serum levels should be monitored and peak levels above 100 ng/ml should be avoided. Concentration-control methodology may be useful in testing putative treatments for other neurologic diseases.

Demyelinating disease after neurologically complicated primary Epstein-Barr virus infection.

This report describes five patients who, following a neurologically complicated primary Epstein-Barr virus infection, developed progressive or relapsing neurologic deficits. The sequelae in four patients followed 4 to 12 years led to the diagnosis of multiple sclerosis (MS). The fifth patient presented with acute disseminated sclerosis and exhibits diffuse neurologic deficits that have persisted for 2 years. We suggest that the diagnosis of an unexplained acute neurologic or psychiatric syndrome should raise the question of a primary EBV etiology. A precisely timed serologic and hematologic study of the blood is imperative to capture the essential evidence. The data presented represent a clinical association between a neurologically complicated primary EBV infection and both chronic and acute demyelinating disease. The evidence does not justify a conclusion that EBV virus causes MS.

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 X 10(6) 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.

Treatment with oral 3,4 diaminopyridine improves leg strength in multiple sclerosis patients: results of a randomized, double-blind, placebo-controlled, crossover trial.

To examine the efficacy and toxicity of oral 3,4 diaminopyridine (DAP) in dosages up to 100 mg/day, 36 patients with multiple sclerosis (MS) enrolled in a randomized, double-blind, placebo-controlled, crossover trial. The primary outcome measure was improvement of a prospectively defined neurologic deficit, which was leg weakness in 34 patients. Secondary outcome measures included the patient's subjective response, scored manual motor testing (MMT) of leg strength, scored leg strength from videotaped motor testing (VMT), quadriceps and hamstrings strength (QMT) measured by isometric dynamometry, neuropsychological testing (NPT), ambulation index (AI), and Expanded Disability Status Scale (EDSS) score. Paresthesias and abdominal pain were common and were dose limiting in eight patients. Three patients had episodes of confusion, and one patient had a seizure while on DAP. Eight patients withdrew from the study, leaving 28 evaluable patients for the efficacy analysis. The prospectively defined neurologic deficit improved in 24 patients-22 on DAP and 2 on placebo (p = 0.0005). All improvements were in leg weakness. Subjective response and measures of leg strength and function (MMT, VMT, QMT, and AI) improved on DAP compared with placebo. Neither NPT nor EDSS scores improved. DAP treatment can induce improvements in leg strength in MS patients, but toxicity is limiting in many patients.

Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group.

We studied copolymer 1 (Copaxone) in a multicenter (11-university) phase III trial of patients with relapsing-remitting multiple sclerosis (MS). Two hundred fifty-one patients were randomized to receive copolymer 1 (n = 125) or placebo (n = 126) at a dosage of 20 mg by daily subcutaneous injection for 2 years. The primary end point was a difference in the MS relapse rate. The final 2-year relapse rate was 1.19 +/- 0.13 for patients receiving copolymer 1 and 1.68 +/- 0.13 for those receiving placebo, a 29% reduction in favor of copolymer 1 (p = 0.007) (annualized rates = 0.59 for copolymer 1 and 0.84 for placebo). Trends in the proportion of relapse-free patients and median time to first relapse favored copolymer 1. Disability was measured by the Expanded Disability Status Scale (EDSS), using a two-neurologist (examining and treating) protocol. When the proportion of patients who improved, were unchanged, or worsened by > or = 1 EDSS step from baseline to conclusion (2 years) was evaluated, significantly more patients receiving copolymer 1 were found to have improved and more receiving placebo worsened (p = 0.037). Patient withdrawals were 19 (15.2%) from the copolymer 1 group and 17 (13.5%) from the placebo group at approximately the same intervals. The treatment was well tolerated. The most common adverse experience was an injection-site reaction. Rarely, a transient self-limited systemic reaction followed the injection in 15.2% of those receiving copolymer 1 and 3.2% of those receiving placebo.(ABSTRACT TRUNCATED AT 250 WORDS)