A comparison of three measures of disease progression in ALS.

Effective clinical trials in neuromuscular research require accurate and sensitive methods to quantitate disease progression. The purpose of this study was to concurrently compare manual muscle testing (MMT), maximal voluntary isometric contraction (MVIC), and a functional scale (the ALS Score). Twenty patients with ALS were tested ten times at monthly intervals using each of the three methods. High inter-rater reliability for each of the three methods was demonstrated. All three methods demonstrated a decline over the testing period. However, MMT and the ALS Score were less sensitive to early change. A wide variation of percent of normal MVIC was demonstrated within each MMT grade and extensive overlap between MMT grades was observed. MVIC is the method of choice in studying patients in the early stages of ALS and in studies conducted over a short period of time.

Intrathecal thyrotropin-releasing hormone does not alter the progressive course of ALS: experience with an intrathecal drug delivery system.

Evidence that thyrotropin-releasing hormone (TRH) has prominent trophic effects on the motor system led to several negative therapeutic trials in amyotrophic lateral sclerosis, a disease of the motor system. Since TRH crosses the blood-brain barrier poorly, if at all, we postulated that the negative parenteral clinical trials could be a result of insufficient drug-receptor interaction. We thus carried out a blinded, placebo-controlled, crossover study of intrathecal TRH in 36 patients by delivery through an implanted, constant infusion pump achieving a steady-state CSF level comparable with that shown to be effective in tissue culture experiments. Utilizing a quantitative measurement technique to assess motor unit loss, we did not observe any alteration of the progressive course during 6 months on TRH and 6 months on saline placebo. However, the implanted pump delivery system proved to be safe, reliable, and well tolerated.

Phenotypic heterogeneity of spinal muscular atrophy mapping to chromosome 5q11.2-13.3 (SMA 5q).

We made phenotypic analysis of 14 families with spinal muscular atrophy (SMA) linking to chromosome 5q11.2-13.3 (SMA 5q), and 2 that may not map to this locus, to assess clinical symptoms among SMA families known to result from mutation at the identical gene/locus. Although the current number of families is still small, the correlation of clinical phenotype and molecular genotype supports 2 observations. First, SMA mutations at the 5q locus present with a broad continuum of clinical abnormalities, and 2nd, the single clearly unlinked family presents with an unusual phenotype characterized by relatively late onset and early death. Thus, there are as yet no unambiguous cases of typical SMA families that are clearly unlinked to the locus at 5q-ie, no clear cases of nonallelic heterogeneity. Analysis of SMA 5q families supports the view that, with certain exceptions, there is little phenotypic intrafamilial variability. When families were ranked by severity of disease there was a strong correlation with age of onset. Onset within the 1st few months was associated with early death, but not in all cases. With rare exception, onset after 1 year of age was associated with less severe disease and greater longevity.