Patricia L. Andres

Quantitative motor assessment in amyotrophic lateral sclerosis

Reliable measurements are needed to document the natural history of ALS and to determine therapeutic efficacy. We have devised a standardized protocol that generates interval data sensitive to change—the Tufts Quantitative Neuromuscular Exam (TQNE). The TQNE consists of the following four major categories: pulmonary function, oropharyngeal function, timed functional activities, and isometric strength using an electronic strain gauge. The 29-item exam takes about 1 hour to administer and has excellent test-retest reliability.

The natural history of motoneuron loss in amyotrophic lateral sclerosis

Using a quantitative, reliable, sensitive and valid measurement technique, we analyzed the rate and pattern of motor deterioration in 50 strictly defined ALS patients for up to 67 months. We observed that the rate of motoneuron loss was linear and symmetric. Bulbar function deteriorated more slowly than respiratory, arm, and leg function. The loss of leg strength was slower than in the arm. No correlation was observed between age at onset and rate of deterioration, or with different regions of onset. Arm strength changed more slowly in women, but other functions showed no male-female differences. These data should prove useful in the design of clinical trials and in generating testable hypotheses of the etiology of this disease.

Use of composite scores (megascores) to measure deficit in amyotrophic lateral sclerosis.

The Tufts Quantitative Neuromuscular Exam (TQNE) consists of 28 items that were designed to measure voluntary motor deficit in amyotrophic lateral sclerosis (ALS) and related diseases. Individual raw data were converted to Z scores for standardization and then grouped into five megascores with statistical and clinical relevance. The derived megascores were Mega 1, pulmonary function; Mega 2, bulbar function; Mega 3, timed hand activities; Mega 4, isometric arm strength; and Mega 5, isometric leg strength. Megascores should enhance the usefulness of testing in therapeutic trials and in analyzing the natural history of ALS and related diseases.

The natural history of amyotrophic lateral sclerosis and the use of natural history controls in therapeutic trials

We analyzed the natural history of amyotrophic lateral sclerosis in 277 patients. Our goal was to develop a better understanding of the clinical disease and thus improve the design of therapeutic trials. The Tufts Quantitative Neuromuscular Exam (TQNE) was used as the primary assessment instrument. Our analysis suggested that although more observations are desirable, six monthly TQNEs were adequate to establish the rate of disease progression. We observed a spectrum of deterioration rates without definable subgroups. The striking linearity of deterioration was confirmed. We found a high correlation between deterioration rates in arm and leg strength for individual patients, but a wide range between different patients. Sex and the age at clinical onset did not affect the deterioration rate. As compared with patients without a positive family history, those with other affected family members had a slower loss in arm but not leg strength. We propose that natural history controls can be used effectively in the design of ALS therapeutic trials.

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.

Guidelines for the use and performance of quantitative outcome measures in ALS clinical trials

ALS is a motor neuron disease defined as a progressive, neurological disorder, resulting from variable and combined degeneration of upper and lower motor neurons. The heterogeneity of clinical involvement early in the course of the disease makes it difficult to diagnose, as well as to identify one unique outcome measure to quantify neurological changes in the course of the disease. Since clinical evidence of upper and lower motor neuron degeneration must exist in four anatomical regions (bulbar, cervical, thoracic, and lumbosacral), outcome measures should assess these regions. The WFN Airline House recommendations specify the purpose, properties, and the preferred parameters which serve as outcome measures in ALS clinical trials. The purpose of this document is to serve as a review of these outcome measures in terms of their advantages, disadvantages, sensitivity, reliability, and other characteristics, as well as their proper performance in ALS clinical trials. Generally these outcome measures are allocated to four areas: respiratory function, muscle strength, general function, and bulbar function. Our review leads us to believe that respiratory function and strength provide the most useful information, both for research and clinical purposes, and are essential as outcome measures. Inclusion of bulbar and general function parameters in trial design may increase the possibility of identifying a beneficial effect of therapeutic intervention. It is essential to note that the guidelines and recommendations put forth are intended to provide initial evaluation and critique of the proper employment and performance of these outcome measures in ALS clinical trials, based on the available literature and our experience.

Total body irradiation not effective in inclusion body myositis

Four patients with inclusion body myositis were treated with 150 rad of total body irradiation given in 5 weeks. One patient responded subjectively and transiently, but no patient showed clear benefit. This treatment is not recommended for inclusion body myositis.

Lower extremity Muscle force measures and functional ambulation in patients with amyotrophic lateral sclerosis

OBJECTIVE To examine the relation between lower extremity muscle force production and functional ambulation in patients with amyotrophic lateral sclerosis (ALS). DESIGN Retrospective analysis of data collected from 1979 to 1995. PATIENTS Two hundred forty ALS patients referred to the New England Medical Center Neuromuscular Research Unit. MAIN OUTCOME MEASURES Muscle force production during a maximum, voluntary isometric contraction of ankle dorsiflexors, knee flexors, knee extensors, hip flexors, and hip extensors was calculated as percent predicted maximal force (PPMF). Functional ambulation status was classified as unable, home, or community. RESULTS The probability of community ambulation compared with home increased with progressively higher PPMF for all muscle groups. Subjects with knee flexion strength greater than 75% PPMF were 395 times more likely to ambulate in the community. Subjects with hip extension strength over 50% PPMF showed improved chance of ambulation at home. CONCLUSION Lower extremity PPMF is a critical factor determining functional ambulation in patients with ALS. Knee flexors play an important role in community ambulation while the hip extensors are important for home ambulation.