Intensity of leg and arm training after primary middle-cerebral-artery stroke: a randomised trial.

BACKGROUND: We investigated the effects of different intensities of arm and leg rehabilitation training on the functional recovery of activities of daily living (ADL), walking ability, and dexterity of the paretic arm, in a single-blind randomised controlled trial. METHODS: Within 14 days after stroke onset, 101 severely disabled patients with a primary middle-cerebral-artery stroke were randomly assigned to: a rehabilitation programme with emphasis on arm training; a rehabilitation programme with emphasis on leg training; or a control programme in which the arm and leg were immobilised with an inflatable pressure splint. Each treatment regimen was applied for 30 min, 5 days a week during the first 20 weeks after stroke. In addition, all patients underwent a basic rehabilitation programme. The main outcome measures were ability in ADL (Barthel index), walking ability (functional ambulation categories), and dexterity of the paretic arm (Action Research arm test) at 6, 12, 20, and 26 weeks. Analyses were by intention to treat. FINDINGS: At week 20, the leg-training group (n=31) had higher scores than the control group (n=37) for ADL ability (median 19 [IQR 16-20] vs 16 [10-19], p<0.05), walking ability (4 [3-5] vs 3 [1-4], p<0.05), and dexterity (2 [0-56] vs 0 [0-2], p<0.01). The arm-training group (n=33) differed significantly from the control group only in dexterity (9 [0-39] vs 0 [0-2], p<0.01). There were no significant differences in these endpoints at 20 weeks between the arm-training and leg-training groups. INTERPRETATION: Greater intensity of leg rehabilitation improves functional recovery and health-related functional status, whereas greater intensity of arm rehabilitation results in small improvements in dexterity, providing further evidence that exercise therapy primarily induces treatment effects on the abilities at which training is specifically aimed.

Effects of intensity of rehabilitation after stroke. A research synthesis.

BACKGROUND AND PURPOSE: A research synthesis was performed to (1) critically review controlled studies evaluating effects of different intensities of stroke rehabilitation in terms of disabilities and impairments and (2) quantify patterns by calculating summary effect sizes. The influences of organizational setting of rehabilitation management, blind recording, and amount of rehabilitation on the summary effect sizes were calculated. METHODS: A Medline literature search was performed for a critical review of the literature. The internal and external validity of the studies was evaluated. In addition, a meta-analysis was performed by applying the fixed (Hedges's g) effects model. RESULTS: The effects of different intensities of rehabilitation were studied in nine controlled studies involving 1051 patients. Analysis of the methodological quality revealed scores varying from 14% to 47% of the maximum feasible score. Meta-analysis demonstrated a statistically significant summary effect size for activities of daily living (0.28 +/- 0.12). Lower summary effect sizes (0.19 +/- 0.17) were found for studies in which experimental and control groups were treated in the same setting compared with studies in which the two groups of patients were treated in different settings (0.40 +/- 0.19). Variables defined on a neuromuscular level (0.37 +/- 0.24) showed larger summary effect sizes than variables defined on a functional level (0.10 +/- 0.21). Weighting individual effect sizes for the difference in amount of rehabilitation between experimental and control groups resulted in larger summary effect sizes for activities of daily living and functional outcome parameters for studies that were not confounded by organizational setting. CONCLUSIONS: A small but statistically significant intensity-effect relationship in the rehabilitation of stroke patients was found. Insufficient contrast in the amount of rehabilitation between experimental and control conditions, organizational setting of rehabilitation management, lack of blinding procedures, and heterogeneity of patient characteristics were major confounding factors.

4-Aminopyridine is superior to 3,4-diaminopyridine in the treatment of patients with multiple sclerosis.

OBJECTIVE: To compare the efficacy and toxicity of 4-aminopyridine and 3,4-diaminopyridine in patients with multiple sclerosis. DESIGN: Intervention study with a before-after design and a randomized, double-blind, crossover design. SETTING: University referral center. PATIENTS: Twenty-four patients with definite multiple sclerosis who had been treated in a previous clinical trial with 4-aminopyridine. INTERVENTIONS: Nonresponders to treatment with 4-aminopyridine (14 patients) were treated with 3,4-diaminopyridine in a 4-week, open-label trial with doses up to 1.0 mg/kg of body weight (before-after design). Responders to treatment with 4-aminopyridine (10 patients) participated in a comparative study of 6 weeks' duration with 4-aminopyridine and 3,4-diaminopyridine according to a randomized, double-blind, double-crossover design. MAIN OUTCOME MEASURES: Neurophysiologic variables for nonresponders, neurologic functions and symptoms on a visual analogue scale for responders, and side effects for both groups. RESULTS: Toxicity profiles of 4-aminopyridine and 3,4-diaminopyridine were different, and systemic tolerability was reduced for 3,4-diaminopyridine. 4-Aminopyridine was more effective than 3,4-diaminopyridine, especially for ambulation, fatigue, and overall daily functioning. CONCLUSION: Our data suggest that, concerning both efficacy and side effects, 4-aminopyridine is superior to 3,4-diaminopyridine in the treatment of patients with multiple sclerosis.

4-aminopyridine in the treatment of patients with multiple sclerosis. Long-term efficacy and safety.

OBJECTIVE: To study the long-term efficacy and safety of 4-aminopyridine in patients with multiple sclerosis. DESIGN: Case series, follow-up varying from 6 to 32 months. SETTING: University referral center. PATIENTS: Thirty-one patients with definite MS, 23 of them being exposed to long-term administration (6 to 32 months) of 4-aminopyridine, since they showed a favorable initial response to the drug. INTERVENTIONS: Long-term oral treatment with 4-aminopyridine in daily doses of up to 0.5 mg/kg of body weight. MAIN OUTCOME MEASURES: Neurologic functions and symptoms as reported by the patients; side effects. RESULTS: Twenty of 23 patients who showed a favorable initial response benefited from long-term administration. Ambulation and fatigue (each in 13 patients) and visual function (in five patients) were most frequently reported to be improved. Three major side effects did occur during a follow-up of 406 patient months: a generalized epileptic seizure in two patients and hepatitis in one. CONCLUSIONS: Although a substantial proportion of patients with multiple sclerosis seem to benefit from long-term administration of 4-aminopyridine, additional studies are needed to clarify the exact value of the drug.

4-Aminopyridine induces functional improvement in multiple sclerosis patients: a neurophysiological study.

This study reports on the neurophysiological measurements that were performed in the context of a randomized, double-blind, placebo-controlled, cross-over study with intravenously administered 4-aminopyridine (4-AP) in 70 patients with definite multiple sclerosis (MS). A beneficial effect of 4-AP was found for both visual evoked response and eye movement registration parameters. This study extends the experimental data obtained on animal nerve fibers, showing that 4-AP can improve impulse conduction in demyelinated nerve, to clinical data which indicate that 4-AP induces an objective improvement in the central nervous system function in MS-patients. It thereby also provides a theoretical basis for clinical efficacy of 4-AP in MS.

4-Aminopyridine in patients with multiple sclerosis: dosage and serum level related to efficacy and safety.

In a recent randomized, double-blind, placebo-controlled crossover trial, we demonstrated efficacy of 4-aminopyridine (4-AP) in improving disability of patients with multiple sclerosis (MS). Here we describe the relationship between dosage, serum level, efficacy, and safety of intravenously and orally administered 4-AP in the same group of 70 MS patients. After both intravenous and oral administration there was a significant relationship between serum levels and 4-AP doses used (p < 0.001 and p < 0.01, respectively). The use of 4-AP in oral doses three times a day showed a large variation and fluctuation in serum levels. After 12 weeks of oral treatment (maximum daily dosage 0.5 mg/kg body weight), a statistically significant improvement was found for the smooth pursuit gain of the eye movements (estimated effect 0.14, 95% confidence interval 0.06-0.23, p < 0.001). The amount of improvement was significantly related to 4-AP serum levels (p = 0.0013). Side effects after intravenous 4-AP occurred frequently and were very troublesome (pain in infusion arm, dizziness). Side effects during oral treatment (dizziness, paresthesias) were very mild and occurred 30-45 min after intake of the medication and could be related to high serum levels.

The effect of 4-aminopyridine on clinical signs in multiple sclerosis: a randomized, placebo-controlled, double-blind, cross-over study.

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.

Evaluation of the visual system in multiple sclerosis: a comparative study of diagnostic tests.

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.

Making a diagnosis in patients with an isolated spinal cord syndrome.

In this study, a retrospective comparison was made between 40 patients with an isolated spinal cord syndrome in whom an ultimate diagnosis of multiple sclerosis was made and 40 patients with a spinal cord syndrome due to other diseases. The results of the study indicate which anamnestic items and laboratory findings at the time of presentation can provide additional support for making a diagnosis in the individual patient with myelopathy without clinical evidence of supraspinal lesions.

Magnetic resonance imaging studies in multiple sclerosis twins.

Magnetic resonance (MR) imaging examinations were performed on a series of seven sets of twins (four monozygotic and three dizygotic) and one set of triplets who were clinically discordant for multiple sclerosis (MS). MR abnormalities were detected in some of the unaffected monozygotic pairs of twins.

Observer agreement in the assessment of clinical signs in experimental allergic encephalomyelitis.

Rats suffering from experimental allergic encephalomyelitis (EAE) were examined by a number of investigators whose assessments were compared. Considerable consensus of opinion was reached, especially when a standard, easily interpretable, scoring classification was used. More discrepancies occurred when a more expanded scale, differentiating between more clinical grades, was used. It is demonstrated that part of these discrepancies can be overcome by having the examinations done by the same investigator. Possible consequences of these findings for the assessment of clinical signs in EAE are discussed.

Randomised double blind controlled trial of cyclosporin in multiple sclerosis.

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.

Low-dose cyclosporin A induces relapsing remitting experimental allergic encephalomyelitis in the Lewis rat.

Experimental allergic encephalomyelitis (EAE) in Lewis rats is an acute monophasic autoimmune disease. It can be treated prophylactically and therapeutically with high doses of cyclosporin A (CsA). Here we demonstrate that low-dose CsA does not prevent a first attack of EAE, but, on the contrary, induces a chronic relapsing form of the disease in 100% of Lewis rats examined. Possible explanations for the high relapse rate after low-dose CsA treatment are discussed. Further studies will be needed to evaluate the immunological mechanisms responsible for these results.