Alfred R. Potvin

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 t he 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 < 0.051, 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 oligoelonal bands persisted. None of the chronic progressive, severely disabled patients demonstrated significant change in neurologic function or persistent adverse effects.

A qualitative and quantitative evaluation of amantadine in the treatment of Parkinson's disease☆

Abstract A double-blind crossover trial of amantadine vs. placebo was carried out involving 42 patients with Parkinsons disease: 64 per cent of the patients on amantadine experienced subjective improvement compared to 21 per cent on placebo. A comprehensive battery of qualitative and quantitative tests was carried out on each patient on entry to the study, after previous standard treatment was discontinued or reduced to a minimal tolerable dose, while on placebo, and while on amantadine, at 3 week intervals. Almost all relevant symptoms and physical signs improved, and the neurologists judged amantadine superior to placebo in 74 per cent of the patients. Quantitative measurement revealed significant improvement in 10 of 19 tests of simulated activities of daily living, in several tests of strength and station, and in all tests of coordination and gait. When the amantadine scores were compared to the placebo scores, an average improvement of 29 per cent occurred in the simulated activities of daily living, 14 per cent in tests of coordination, 11 per cent for gait and 3 per cent for strength. Sensation and neuropsychologic performance were unaffected and side effects were minimal. Comparison of amantadine scores with entry scores obtained when the patients were on standard anti-Parkinsonian medications suggested that amantadine may also be superior to classical medications. The response to amantadine was not related to age, sex, or severity of disease, but those who responded were found to have a significantly longer duration of illness. Amantadine is a nontoxic, easily administered drug useful in the treatment of Parkinsons disease. It should be emphasized that the quantitative tests used in this study yielded interval data. This resulted in more valid comparisons with normal, particularly when expressed in terms of the percent of the age-matched normal function. Finally, this is the first report which describes a battery of quantitative tests designed to measure in part the effect of a drug on activities of daily living. It could be that these results were the most indicative of a significant effect in this experiment, since it is an improvement in the accomplishment of activities of daily living, not neurological tests, by which a patient with Parkinsonism bases his judgement of the effectiveness of a non-toxic treatment.

Amantadine and levodopa in the treatment of Parkinson's disease.

Twenty‐eight ambulatory patients with Parkinsons disease participated in successive double‐blind crossover trials of amantadine and levodopa. A comprehensive battery of tests was used to evaluate patient preference, neurologic symptoms and signs, quantitative neurologic performance, practical skills used in daily living, and neuropsychological performance. These permitted differential assessment of specific areas of function affected. Levodopa ameliorated functional disabilities, tremor, and loss of associated movements. It also improved grip strength, foot speed, foot coordination, gait, and several skilled activities more than did amantadine. The combination of levodopa and amantadine was more effective than levodopa alone in the management of total functional disability, tremor, and gait and in tests of grip strength, finger coordination, tracking, and tandem gait, as well as in the practiced skills of zipping, cutting, and opening a door. One neuropsychologic test‐picture completion‐was also better on the combination. The safety of the combination was affirmed and the relative efficacy quantitated.

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 to 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.

Isotachophoresis quantitation of subtractions of multiple sclerosis intra‐blood‐brain barrier IgG synthesis modulated by ACTH and/or steroids

We combined the IgG is otachophoresis (ITP) method and a formula to quantitate IgG synthesis rate inside the blood-brain barrier (intra-BBB) in multiple sclerosis (MS) patients. In MS, most IgG synthesized was cathodic, but synthesis occurred in both anodic and cathodic regions. In addition, ACTH and/or steroids were found to reduce cathodic IgG synthesis more than anodic.

The importance of age effects on performance in the assessment of clinical trials

Abstract Forty young adult normal subjects, 10 Parkinsons disease patients and their 10 matched normal subjects, and 10 multiple sclerosis patients and their 10 matched normal subjects were evaluated in the Quantitative Examination of Neurological Function to determine age effects and the importance of selecting closely matched normal control groups for assessing the performance of patients. Where there are significant differences among the three normal subject groups, it is the oldest normal subject group that differs from the two younger subject groups. Significant decreases in performance with increasing age were found for the steadiness tests performed in the supported position, the sensation tests, two or five tests in the Neuro-Psychological Examination and tests requiring fine skilled movements primarily with the dominant hand. It was found that older subjects made fewer errors in coordinated tasks. A normalization technique, expressing performance as a percentage of normal function, was introduced. A method was developed to provide quantitative and meaningful indices of neurological function. The measure is obtained by averaging the percentage of normal function scores over several tests that belong to a primary category of neurological function. Young adult normal subjects do not perform significantly better than normal subjects in the age range of multiple sclerosis patients; however, young adult normal subjects do perform significantly better than normal subjects in the age range of Parkinsons disease patients, especially on tasks requiring fine skilled movements of the dominant hand and coordinated activities of the lower extremities. These results indicate that the performance of multiple sclerosis patients can be expressed as a percentage of the function of either age-matched normal controls or young adult normal controls. However, the performance of Parkinsons disease patients should be expressed only as a percentage of the function of age-matched normal controls.

Quantitative evaluation of neuropharmacological trials.

The clinicians ability to classify a patients neurophysiological deficits into such categories as mild, moderate, and severe does not readily allow the detection of small but significant changes in function over time. Clinical neurologists, for example, are discovering that the standard neurological examination is not sufficient to critically evaluate new drugs and surgical techniques that purport to improve the performance of patients in the activities of daily life.1 As a result, the quantitative evaluation of the functional capacity of patients with

Effects of d‐amphetamine on quantitative measures of motor performance

The effects of 10 mg. of d‐amphetamine and a placebo of similar appearance were determined by means of a battery of quantitative objective measures of motor performance in normal volunteers. The medication was administered in a random, double‐blind, crossover design on two occasions one week apart. No significant differences between the effects of the medications on resting and sustention tremor or precision hole steadiness were found. However, several compematory tracking tasks which required sustained concentration and motor coordination were significantly improved with d‐amphetamine.

Cyclobenzaprine: A new type of anti-parkinsonian drug

Abstract 1. 1. Nine different evaluation systems were used to assess the efficacy of cyclobenzaprine (Flexeril®) and benzotropine methanesulfonate (Cogentin®) in 24 men with Parkinsons disease. 2. 2. A randomized double-blind cross-over clinical trial was followed by an extension study, with patients permitted to choose either medication. 3. 3. Both medications were judged beneficial to a majority of patients. Of the 9 evaluation systems used, 8 revealed cyclobenzaprine was better, while the ninth indicated that neither drug affected cognition. Differences between the two medications were slight and not significant. 4. 4. In the extension study, 71% of patients selected cyclobenzaprine and 29% selected benzotropine methanesulfonate. 5. 5. The chemical structure of cyclobenzaprine differs from other anti-parkinsonian agents, and this drug may be effective for patients who do not tolerate or benefit appreciably from levodopa or other medicants.