Methodology for analyzing clinical neurological data: ACTH in multiple sclerosis.

From 1965 to 1968 a multicenter (USA) clinical trial was conducted to compare ACTH with placebo for the treatment of multiple sclerosis patients in a stage of acute exacerbation. Of seven evaluation systems which were used, one was a quantitative neurological examination. In this report, the quantitative neurological data have been re-evaluated using a transformation of the data which express patient scores in terms of a percentage of age- and sex-matched normal function followed by a reduction of the data into composite neurological functions vs time. The results support the positive findings of previous reports. In addition, the methodology helps to simplify the therapists' task of interpreting results by enabling him to determine how near normal function the patient came following the treatment trial.

Critical frequency of photic driving in the diagnosis of multiple sclerosis. A comparison to pattern evoked responses.

Patients with known or suspected multiple sclerosis (MS) were tested for abnormalities in visual evoked potentials. We compared the critical frequency of photic driving (CFPD) with pattern reversal visual evoked potentials (PVER). We found the CFPD to be somewhat more sensitive than PVER for detecting abnormalities in the visual pathways of patients with MS. When used together, the two were complementary, each fining abnormalities that the other missed. When evaluating patients with MS with evoked potentials, both PVER and CFPD should be tested.

Increased ratio of carbidopa to levodopa in treatment of Parkinson's disease.

A randomized, double-blind clinical trial was designed to compare two ratios of carbidopa to levodopa (10 mg of carbidopa to 100 mg of levodopa [Sinemet 10/100] and 20 mg of carbidopa to 100 mg of levodopa [Sinemet 20/100]) with levodopa (100 mg) alone. Twenty-nine male patients (46 to 78 years of age) with clinically definite idiopathic Parkinson's disease of mild to moderate severity were selected and hospitalized for the three-week period of the study. Medications being taken at time of entry were phased out during week 1. Fixed daily increments of medications were given during week 2, and adjusted during week 3 to achieve best clinical response with fewest side effects. Qualitative and quantitative examinations of neurologic function showed that upper extremity measurements of resting tremor, rigidity, and finger-tapping speed, and lower extremity measurements of foot coordination and tandem gait (both types of speed tests) showed significantly more improvement in patients receiving the 20:100 combination than in those receiving the 10:100 combination or levodopa alone. Adverse effects were similar and minimal in each of the three groups. Results indicate that increasing the amount of carbidopa from 10 to 20 mg per 100-mg dose of levodopa gives a greater therapeutic response in Parkinson's disease than does a 10:100 carbidopa-levodopa ratio or levodopa alone.

Multimodality evoked potentials and neurophysiological tests in multiple sclerosis. Effects of hyperthermia on test results.

Data on critical frequency of photic driving (CFPD), frequency following response (FFR), and visual, somatosensory (peroneal nerve), and brain-stem auditory evoked potentials (EPs) were obtained from 20 patients who had clinically definite multiple sclerosis and ten healthy normal subjects in a controlled, balanced study under normothermic and hyperthermic (+1 degrees C) conditions with a test-retest interval of one week. Normal subjects' test results showed no changes during hyperthermia. Patients' EP and CFPD data correlated well with history, clinical signs, and symptoms during both normothermia and hyperthermia. The FFR test data were equivocal and not fully analyzed. Data from the four other tests showed additional patient abnormalities during hyperthermia. Multimodality testing increased the number of patient abnormalities compared with single tests, and the number increased further during hyperthermia. Test-retest reproducibility was higher during hyperthermia.

Multiple sclerosis de novo CNS IgG synthesis. Effect of CNS irradiation.

Megavoltage CNS irradiation was given to 20 patients with clinically definite multiple sclerosis (MS) to determine if de novo CNS IgG synthesis could be eradicated. In all five patients given 1,200 rads, a transient reduction in the de novo CNS IgG synthesis rate was noted. In ten patients given 1,800 rads, the following occurred: a reduction in synthesis rate in three patients, a reduction followed by enhancement in two, only enhancement in four, and no change in one. In all five additional patients, a therapy of adrenocorticotropic hormone (ACTH) followed by prednisone in combination with 1,800 rads produced greater and more persistent decreases in CNS IgG synthesis, but did not block the enhancement effect. Only two of 19 patients who had abnormal CNS IgG synthesis rates had reductions to normal; no patients showed changes in the number or pattern CSF IgG oligoclones. Hence, no treatment eradicated de novo CNS IgG synthesis. A persistent decrease in CSF leukocytes occurred in all 20 patients due to the reduction of small lymphocytes (not dose related). The blood-brain-barrier to albumin concentration was transiently damaged in 11 of 15 patients given irradiation, but when patients were premedicated with ACTH/prednisone therapy, no damage was found. None of the patients demonstrated neurological improvement, change in the activity of their disease, or persistent adverse effects.

Intra-blood-brain barrier measles virus antibody synthesis in multiple sclerosis patients.

Antibodies to nine viruses were measured in serum and CSF of MS patients, patients with other neurologic diseases (OND), and healthy controls. The extent of antibody production inside the blood-brain barrier (BBB) was determined by making a new correction for BBB permeability. Compared with OND and healthy controls, MS patients as a group had significantly higher corrected CSF:serum antibody ratios for measles virus but not to the other eight viruses studied. The incidence of significantly high CSF:serum ratios for measles antibody in MS patients was 50%, and in the other two control groups it was 0 to 12%. The incidence of corrected antibody ratios to the other eight viruses was not significantly different among the three groups.

Multiple sclerosis: measurement and validation of central nervous system IgG synthesis rate.

An empirical formula has been developed to calculate the de novo rate of synthesis of IgG in the central nervous system (CNS), based on physiologic principles that govern the passage of albumin and IgG across the blood-brain barrier (BBB). To validate the formula, radiolabeled IgG and albumin from pooled normal sera were followed from the blood to the cerebrospinal fluid (CSF) over 21 days in nine patients with definite multiple sclerosis (MS). IgG synthesis rates were calculated by the isotope exchange method and compared to values obtained with the empirical formula. There was excellent concordance, from a low rate of synthesis of 5 mg per day to a high rate of 120 mg per day. A double radiolabeled IgG experiment in two patients showed that the MS BBB processed normal serum IgG in the same way as IgG derived from autologous MS serum. Accordingly, the empirical formula, which requires only one sample of CSF and matched serum, can reliably and validly estimate the de novo rate of IgG synthesis in CNS of patients with MS.

Multiple sclerosis de novo CNS IgG synthesis: effect of ACTH and corticosteroids.

ACTH gel and corticosteroids were given to 28 clinically definite multiple sclerosis (MS) patients to determine whether de novo central nervous system (CNS) IgG synthesis (rate and cerebrospinal fluid [CSF] IgG oligoclonal bands) could be eradicated. The most effective treatments were ACTH gel and ACTH gel followed by prednisone, all 11 patients had a significant reduction in rate (p < 0.05), which became normal in eight patients (< 3.3 mg per day). In order of effectiveness, the other drugs used were: dexamethasone or prednisone given orally, and hydrocortisone administered intrathecally. For most treatments, reduction of the rate of CNS IgG synthesis occurred within days and persisted for months after cessation of treatment. The MS CNS immune reaction was not eradicated when IgG synthesis rate became normal, because CSF IgG oligoclonal bands persisted. None of the chronic progressive, severely disabled patients demonstrated significant change in neurologic function or persistent adverse effects.

Human neurologic function and the aging process.

Sixty-one normal men whose ages ranged from 20 to 80 years were evaluated on two occasions by means of a comprehensive series of 128 instrumented tests of neurologic function. The tests measured cognition, vision, strength, steadiness, reactions, speed, coordination, fatigue, gait, station, sensations, and tasks of daily living. The reliability of each test measured was determined, and any measure found unreliable (r less than or equal to 0.41) was not further analyzed. Significant age-related linear decreases were found for almost all neurologic functions. The declines over the age span varied from less than 10 percent to more than 90 percent for different functions. For the upper extremities, the largest declines (greater than 50 percent) were in hand-force steadiness, speed of hand-arm movements, and vibration sense; for the lower extremities, the largest declines were in one-legged balance with eyes closed and in vibration sense. For 13 of 14 tests in which significant dominant body-side effects were found, larger re-testing 7-10 days later, the subjects improved their scores by more than 5 percent on only 17 tests, 9 of which concerned the activities of daily living. No significant differential learning effects were found across age groups. The results point to the importance of developing a data bank on age-based neurologic function so that therapeutic effects can be evaluated in terms of age- and sex-matched normal functioning.

Parkinson's disease: Cogentin with Sinemet, a better response.

1. A randomized, placebo controlled, double-blind cross-over study was conducted to evaluate the clinical efficacy of the anticholinergic agent, benztropine mesylate (CogentinR) in 29 patients with mild to moderate, idiopathic Parkinson disease. 2. Patients were maintained on a stable, therapeutically optimal dosage and schedule of levadopa-carbidopa (Sinemet) throughout the study. 3. Both the neurologist's and the patient's global assessments of treatment efficacy indicated that Sinemet plus benztropine mesylate resulted in significantly greater improvement than Sinemet plus placebo. 4. Qualitative and quantitative evaluations of relevant neurologic functions showed small, but statistically significant improvements for rigidity, finger tapping speed and activities of daily living in patients during the Sinemet plus benztropine mesylate treatment period. 5. At the completion of the study 16 patients chose to continue taking benztropine mesylate as an adjuvant to Sinemet. 6. No important adverse side effects occurred during the study.

Motion sickness and otolith sensitivity: a pilot study of habituation to linear acceleration.

Astronauts, particularly in Skylab flights, experienced varying degrees of motion sickness lasting 3-5 d. One possible mechanism for this motion sickness adaptation is believed to be a reduction in otolith sensitivity with an attendant reduction in sensory conflict. In an attempt to determine if this hypothesis is valid, a ground-based pilot study was conducted on a vertical linear accelerator. The extent of habituation to accelerations which initially produced motion sickness was evaluated, along with the possible value of habituation training to minimize the space motion sickness problem. Results showed that habituation occurred for 6 of the 8 subjects tested. However, in tests designed to measure dynamic and static otolith function, no significant differences between pre- and post-habituation tests were observed. Cross habituation effects to a standard Coriolis acceleration test were not significant. It is unlikely that ground-based pre-habituation to linear accelerations of the type examined would alter susceptibility to space motion sickness.