Progressive Muscular Atrophy in the ALS Spectrum

Nicholas J. Maragakis


Abstract and Introduction


A large, retrospective analysis of patients with amyotrophic lateral sclerosis (ALS) and progressive muscular atrophy (PMA) indicates that a substantial proportion of PMA patients develop upper motor neuron signs indicative of an ALS diagnosis. The findings suggest that PMA should be considered as part of the ALS spectrum rather than as a distinct entity.


When a patient presents to the clinic with weakness, a frequent concern is whether the symptoms represent amyotrophic lateral sclerosis (ALS) or another form of 'motor neuron disease'. Patients with primarily lower motor neuron findings often receive conflicting opinions as to what their disorder represents, as the absence of signs of upper motor neuron dysfunction is inconsistent with a formal ALS diagnosis. Progressive muscular atrophy (PMA) is clinically characterized solely by signs of lower motor neuron dysfunction, so patients with this condition are commonly excluded from ALS clinical trials. The absence of a formal ALS diagnosis can also hinder the planning and medical management of PMA. In an attempt to address these problems, Kim et al. conducted a large study to establish whether PMA is a distinct motor neuron disease or part of the ALS spectrum.[1]

The researchers analyzed the medical records of 1,201 patients who had been diagnosed as having motor neuron disease at Columbia University, New York between 2000 and 2007. Patients in whom a limited number of nervous system segmental regions were affected (for example, cervical only), or who were diagnosed with flail arm or flail leg syndromes or other disorders such as spinal bulbar muscular atrophy or multifocal motor neuropathy, were excluded from analysis. PMA was diagnosed on the basis of presence of pure lower motor neuron findings at the initial visit.

Of the 1,201 patients, 91 (7.6%) were diagnosed as having PMA. ALS was seen in 916 patients (76.3%), 871 of whom were included in the analysis, and primary lateral sclerosis (PLS) was seen in 84 patients (7%). Significant differences were observed between the PMA and ALS groups with regard to age at symptom onset (63.4 ± 11.7 years for PMA versus 59.9 ± 13.2 years for ALS; P = 0.007), age at diagnosis (65.2 ± 11.5 years for PMA versus 61.3 ± 13.0 years for ALS; P = 0.003), and time from onset to diagnosis (20.8 ± 17.7 months for PMA versus 17.7 ± 20.9 months for ALS; P <0.009). The PMA group also included a greater proportion of men than the ALS group (74.6% versus 54.9%; P = 0.0006). Interestingly, the patients with PMA had longer survival times (48.3 months) than those with ALS (36 months), but the overall survival rate of patients with PMA at 80 months was similar to that of ALS, with approximately 14% of patients surviving this duration of disease.

Of the 91 patients originally diagnosed with PMA, 20 subsequently developed upper motor neuron signs, which would qualify them as having ALS with lower motor neuron onset. Furthermore, upper motor neuron abnormalities were noted in more than half of the PMA patients who underwent magnetic resonance spectroscopy studies. Importantly, however, the presence of upper motor neuron signs in the PMA patients was unrelated to survival time after diagnosis. This observation indicates that PMA with upper motor neuron signs is part of a disease continuum, and that the presence of upper motor neuron signs is not predictive of prognosis. Involvement of additional anatomical regions in the presentation of PMA increased the risk of death, suggesting more-widespread and advanced disease in such cases.

Factors that were predictive of survival in ALS included scores on the revised ALS Functional Rating Scale (ALSFRS-R), and pulmonary forced vital capacity. Patients with ALS who had impaired forced vital capacity and a lower ALSFRS-R score had shorter survival times. These observations also held true for PMA. We can conclude, therefore, that similar factors are likely to influence outcomes in PMA and ALS.

The Kim et al. study, with its large sample size and breadth of analysis, is of considerable importance in reaffirming and extending previous observations about PMA. The authors emphasize the important observation that many patients with PMA subsequently develop upper motor neuron findings, which, by the current El Escorial criteria, would result in a reclassification to ALS. In my view, the most important observations serve to reinforce the idea that PMA, ALS and PLS belong to a spectrum of motor neuron disease. Our criteria for including patients in the ALS category include findings of upper motor neuron dysfunction on physical examination. However, Kim et al. present a convincing case that upper motor neuron death or dysfunction can be seen at autopsy or via magnetic resonance spectroscopy or transcranial magnetic stimulation in patients who were thought to have only lower motor neuron dysfunction,[2–5] indicating that our current physical examination methods for determining upper motor neuron involvement are insensitive.

Kim et al. correctly assert that we are probably inappropriately excluding PMA patients from ALS clinical trials. Patients with PMA generally live longer than those with ALS but, provided that ALS clinical trials are appropriately powered, any potential confounding effects on the statistical analysis are likely to be counterbalanced by the lower incidence of PMA.

Interestingly, the authors recommend that the number of affected body regions should be incorporated into the definition of PMA, and that PMA with one affected body region, as seen in the flail arm and leg syndromes or monomelic amyotrophy, should be considered separately because progression in these syndromes is much slower than in other motor neuron diseases. Such a distinction could indeed be relevant to ensuring adequate inclusion of patients for study in clinical trials, but would only serve to further splinter and confuse the distinction between PMA, monomelic amyotrophy, and flail arm and leg syndromes. These conditions, along with ALS, are probably all part of a spectrum of motor neuron disease.

As technologies become more sophisticated, I suspect that we will uncover significant overlap between the various motor neuron disease groups that is not evident from physical examination. These advances will include the development of biomarkers in the cerebrospinal fluid and plasma, more-sophisticated imaging techniques, and innovations in electrophysiological measures such as electrical impedance myography and motor unit number estimation.

The observations of Kim et al. raise several questions. Why is PMA more common in men, whereas bulbar-onset ALS is more common in women? Why does PMA progress more slowly than the classic form of ALS? Do PMA, ALS and PLS have distinct etiologies? Also, what factors determine the site of disease onset, and what molecular mechanisms underlie the development of upper motor neuron findings? The use of combinations of diagnostic markers in humans, as well as the development of more-accurate and varied animal models of 'ALS', will probably shed light on many of these questions. The manuscript by Kim and colleagues represents an important resource for beginning to dissect the spectrum of motor neuronopathies.


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