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To find out whether treatment with 4-aminopyridine is beneficial in multiple sclerosis (MS), 70 patients with definite MS entered into a randomized, double-blind, placebo-controlled, cross-over trial in which they were treated with 4-aminopyridine and placebo for 12 weeks each (maximum dose, 0.5 mg/kg of body weight). The estimated effect of the treatment as measured with the Kurtzke expanded disability status scale, which was the main evaluation parameter, was 0.28 point (p = 0.001). A significant decrease in the scale score (1.0 point or more) was encountered in 10 patients (16.4%) during oral treatment with 4-aminopyridine whereas it was not seen during placebo treatment (p less than 0.05). A significant subjective improvement (defined as an improvement that significantly affected the activities of normal daily life) was indicated by 18 patients (29.5%) during 4-aminopyridine treatment and by 1 patient (1.6%) during placebo treatment (p less than 0.05). Significant improvements related to 4-aminopyridine occurred in a number of neurophysiological parameters. No serious side effects were encountered. However, subjective side effects such as paresthesias, dizziness, and light-headedness were frequently reported during 4-aminopyridine treatment. Analysis of subgroups revealed that there was no difference in efficacy between those patients randomized to receive 4-aminopyridine and then placebo and those randomized to receive placebo and then 4-aminopyridine or between patients with and those without subjective side effects. Especially patients with temperature-sensitive symptoms and patients characterized by having a longer duration of the disease and being in a progressive phase of the disease were likely to show clear clinical benefit.

In 22 patients with clinically definite multiple sclerosis (MS) who were without visual symptoms and had a visual acuity of at least 1.0 in both eyes at the time of measurement, the following tests were performed to detect subclinical lesions in the visual system: visual evoked potential (VEP), contrast sensitivity test (CS), flight of colours test (FOC), colour vision test (Ishihara plates) (CV) and the pupillary light reflex (PLR). VEP was abnormal in 81.8%, CS in 72.7%, FOC in 36.4%, CV in 31.8%, and PLR in 52.3% of the patients. VEP and CS together were most sensitive: combining these techniques subclinical lesions of the visual system were detected in 90.9% (20/22) of these asymptomatic patients.

In a group of eight patients suffering from clinically definite multiple sclerosis, we studied the effects of treatment with cyclophosphamide on the immune reactivity in vitro and in vivo. The results are compared with those obtained in a control group consisting of eight patients who received no drug therapy and who were matched with the former group for age, sex and severity of disease. The results indicate that therapy with cyclophosphamide at a mean dose of 100 mg/day induces a profound lymphocytopenia in peripheral blood involving both T and B cells. Serum levels of immunoglobulins as well as primary and secondary antibody responses were depressed. In tests with standardized cell numbers, proliferative responses of lymphocytes in vitro and cytotoxic T cell function remained normal, whereas K and NK cell activities were diminished. Secondary cellular immune responses in vivo remained intact; however, the primary cellular immune response in vivo was markedly depressed. From these data, it is concluded that therapy with cyclophosphamide in man mainly affects humoral immune functions, but also cellular immunity, although to a lesser extent.

Antibodies to acetylcholine receptors (AChR) are probably directly responsible for the pathogenesis of myasthenia gravis (MG). Methods for the demonstration of these antibodies are complicated. The present study shows that the antibodies can also be revealed by the use of the simple indirect immunofluorescence technique with rat diaphragm as substrate. Antibodies were demonstrated with FITC-labelled anti-human Ig. The location on the motor endplates was confirmed by using a TRITC-labelled anti-alpha-bungarotoxin system. Antibodies to motor endplates were only demonstrated in MG and not in either twenty-two patients with neuromuscular disorders or fifty normal subjects. Antibodies to motor endplates were found in only twelve out of fifty-seven MG patients. In fifteen of the other forty-five patients, antibodies were found of the classical anti-skeletal muscle type, 'overluminating' the anti-motor endplate antibodies.

Immunoglobulin D (IgD) was measured by radioimmunoassay in paired cerebrospinal fluid and serum samples from patients with various neurological diseases. The IgD index was calculated for every patient and compared with the IgG index. An increased IgD index was found in 18 out of 41 patients suffering from multiple sclerosis and in 52 out of all 122 patients investigated. An increased IgD index did not always coincide with an increased IgG index. An increased IgD index suggests an abnormal intrathecal synthesis of this immunoglobulin within the central nervous system. We conclude that the determination of IgD in the cerebrospinal fluid yields additional information on immunological reactions within the central nervous system.

Characterization of T cells present in the cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS) may contribute to an understanding of the immunopathologic role of these cells. To analyze the T cells in the CSF of MS patients, 30 cloned T cell lines from each of two MS patients were surveyed for their patterns of T cell receptor (TcR) beta-chain gene rearrangement. DNA from the (CSF-derived) T cell clones was digested with a number of restriction endonucleases and the gene rearrangement patterns were analyzed with a T cell receptor beta-chain probe. Southern blot analysis of the DNA of these T cell clones indicated that all had rearrangements of the TcR beta-chain genes, but none of the rearrangements were identical. These results suggest that, if a few clones of specific T cells are involved, they must form a tiny minority in comparison to the total number of T cells in the CSF of MS patients.

In a 2 year double blind controlled trial of cyclosporin against placebo in multiple sclerosis conducted at two centres there was a beneficial effect of the therapy upon the progression of the disease, relapse rate and relapse severity at one of the centres where the patients received a mean dose of 7.2 mg/kg/day. This beneficial effect was not seen in the other centre where a lower dose (mean 5 mg/kg/day) was given. Reduction in clinical progression was accompanied by decreased IgG synthesis in the central nervous system. Side effects included hypertension, renal insufficiency and anaemia and were of such severity to preclude the use of cyclosporin in a high enough dose to alter the course of the disease.

Twelve antisera were prepared, each specific for idiotype(s) of IgG from the cerebrospinal fluid (CSF) of an individual patient with multiple sclerosis (MS). Idiotype-positive (Id(+)) IgG represented 24 to 33% of the CSF-IgG. Radioautographic analysis showed that Id(+)IgG in CSF and in serum had a restricted electrophoretic mobility. From serum of three patients, at least two different noncross-reacting Id(+)IgG fractions were isolated. The anti-Id antisera, which detect IgG considered to be of importance in MS, were used to measure Id(+)IgG in CSF and in serum. Relative to the total IgG, Id(+)IgG was always enriched in CSF, which suggests intrathecal synthesis of such IgG. However, in all patients the absolute concentration of Id(+)IgG was higher in serum than in CSF. Studies attempting to demonstrate cross-reactivity between the IgG of different patients were negative.

Two radioimmunoassay (RIA) procedures were used to measure human myelin basic protein (HBP) in cerebrospinal fluid (CSF): (1) an inhibition RIA, with the use of TNP-conjugated anti-BP IgG, 125I-labelled HBP, and anti-TNP-coated polystyrene beads, and (2) a non-competitive two-site RIA, with the use of Sepharose-coupled anti-BP antibodies and 125I-labeled anti-BP IgG. The two-site RIA detects less HBP in CSF than the inhibition RIA, partly due to the presence of HBP fragments in CSF that are detected by the inhibition assay, but less by the two-site RIA. The correlation was improved when in the two-site RIA Sepharose-coupled anti-BP antibodies were changed. Because certain substances (such as autoantibodies to HBP) may give false-positive results in the competitive RIA but not in the two-site RIA, we conclude that a combination of the (more sensitive) inhibition RIA with the (more specific) two-site assay provides a more reliable HBP assay than either assay alone.

Having determined immunoglobulin G (IgG) and albumin concentrations in 1100 cerebrospinal fluid and serum samples, we calculated the IgG index. Likelihood ratios for multiple sclerosis were calculated by using a training set consisting of 100 patients with definite multiple sclerosis and one consisting of 97 patients suffering from diseases from which multiple sclerosis must be differentiated. Predictive values for multiple sclerosis, given different values for the IgG index, are given in a graphical representation of Bayes' theorem. We conclude that this approach increases the diagnostic usefulness of the IgG index for the diagnosis of multiple sclerosis.