Amyotrophic lateral sclerosis, already a rare condition affecting one to three people in 100,000, nonetheless garners most of the attention in the field of motor neuron disease. Those conditions that affect motor neurons but are not ALS make up a tiny proportion of motor neuron disease (MND), and that makes scientific study significantly harder. “The cause and best treatments for ALS are not known,” wrote Paul Gordon, of the Gunpowder Hospital in Paris, in an e-mail to ARF. “It is even more difficult when the disease is 100 times more rare.” Two papers out this month give doctors more information on diagnosing and predicting prognoses for these supremely rare MNDs.

ALS typically features mainly lower motor neuron symptoms, with limited upper motor neuron involvement. In the June Archives of Neurology, Renske Van den Berg-Vos and colleagues at the University of Amsterdam, The Netherlands, describe the course of three conditions with lower motor neuron symptoms only: progressive muscular atrophy, segmental distal muscular atrophy, and segmental proximal muscular atrophy. And in the June issue of Neurology, Gordon and colleagues from Columbia University in New York offer an analysis of the features that distinguish “typical” ALS from upper motor neuron-dominant ALS and primary lateral sclerosis, which only includes upper motor neuron symptoms.

Doctors cannot diagnose a specific kind of MND about 5 percent of the time, Gordon estimated. “There is always some uncertainty in the diagnosis of MND because there is no defining test,” he wrote. “This results largely from the fact that the disorders have no known cause.” In the Dutch study, in fact, three patients initially diagnosed with non-ALS conditions were eventually reclassified as having true ALS.

The Dutch researchers sought to define muscular atrophy in a prospective study following 32 patients at three university hospitals over six years. All had had symptoms for at least four years. This eliminated most people with ALS, which is normally fatal within three years.

In 21 people with muscular atrophy in only specific parts of the arm, for more than four years, the prognosis was good: they were likely to survive for many years with little deterioration of muscle function. In eight people with progressive muscular atrophy who had more generalized symptoms, the muscle weakness worsened, leading to death because of respiratory failure in two people.

In the Neurology paper, Gordon and colleagues took a retrospective approach to distinguish different forms of lateral sclerosis from typical ALS. From records covering 1984-2007, they collected nine cases of primary lateral sclerosis (PLS), 15 cases of upper motor neuron (UMN)-dominant ALS, and 10 randomly selected control cases of more typical ALS.

PLS has a slower rate of progression than ALS (Gordon et al., 2006). In the present study, people with pure PLS were stronger than regular ALS subjects in muscle tests, with the UMN-focused ALS patients falling somewhere in between. People with ALS, regardless of motor neuron focus, were more likely to lose weight and show visible muscular atrophy.

Gordon noted that symptoms and progression are only part of the story. More work, including postmortem pathology, is needed to properly classify the rarer MNDs. “We won’t really know whether PMA and PLS are different from ALS until we can see differences in the brain,” he wrote.

People with a motor neuron disease naturally want to know what will happen to them. These two studies give doctors a little more guidance in making that prediction. Minimal muscle weakness, or weakness restricted to only a few body parts, appears to be good a good sign relative to more generalized weakness. But the authors of both studies cautioned that doctors should monitor patients closely to look for new symptoms such as decreased respiratory function, even if the disease progresses slowly. And given the four-year period to rule out ALS, the most accurate prognosis a doctor can give may be a frustrating “Wait and see.”—Amber Dance


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Paper Citations

  1. . The natural history of primary lateral sclerosis. Neurology. 2006 Mar 14;66(5):647-53. PubMed.

Further Reading


  1. . [Progressive muscular atrophy: clinical and laboratory study in eleven patients]. Arq Neuropsiquiatr. 2004 Mar;62(1):119-26. PubMed.
  2. . Neurofilament inclusion body disease with early onset frontotemporal dementia and primary lateral sclerosis. Clin Neuropathol. 2004 Jul-Aug;23(4):183-93. PubMed.

Primary Papers

  1. . A long-term prospective study of the natural course of sporadic adult-onset lower motor neuron syndromes. Arch Neurol. 2009 Jun;66(6):751-7. PubMed.
  2. . Clinical features that distinguish PLS, upper motor neuron-dominant ALS, and typical ALS. Neurology. 2009 Jun 2;72(22):1948-52. PubMed.