The hallmark of ALS is the degeneration of two kinds of motor neurons — upper, which are in the brain, and lower, which are in the anterior horn (front section) of the spinal cord and in the brainstem. These two sets of motor neurons work together to drive movement and locomotion, but have separate, important functions as well.
Sometimes people come to a neuromuscular disease clinic who have only upper motor neuron (UMN) or only lower motor neuron (LMN) involvement. There’s usually an important question on everyone’s mind: Is this disorder likely to progress to ALS, or not?
The answer, unfortunately, usually requires waiting a few years to find out.
Stop, go or modify
LMNs provide “go” signals directly to muscles. When they’re lost, muscles become weak and eventually unable to contract effectively, although they may twitch (fasciculate) involuntarily.
UMNs are different. They don’t go directly to muscles; they go to the LMNs, and they refine muscle movement from the raw “go” signal of these spinal nerve cells into the highly specialized movements needed for walking, running, typing, talking and hundreds of other motor activities. Without UMN control, muscles become tight (spastic) as well as weak, and reflexes may be accentuated. Muscles generally don’t atrophy or fasciculate (twitch) if only UMN loss occurs.
After five years, ALS diagnosis unlikely if only UMNs involved
Michael Singer at the University of Texas Southwestern Medical Center in Dallas, and colleagues, reviewed in the March issue of Muscle & Nerve the likely outcomes for people with only UMN damage. Gil Wolfe, co-director of the MDA clinic at UT Southwestern, was also an author.
“For patients with exclusive upper motor neuron symptoms acquired in middle age or later, the two main diseases to consider are ALS and primary lateral sclerosis,” the review says. “ALS [with UMN and LMN symptoms] is more common, and is usually the ultimate diagnosis.” However, they refer to studies that suggest that if LMN symptoms haven’t appeared after three years (one study) or five years (another study), it’s likely they won’t occur.
A third study found that when people developed LMN loss after having only UMN deficits, 77 percent did so within four years of symptom onset.
Better prognosis, slower progression
The prognosis in these UMN-only cases, which are referred to as “primary lateral sclerosis” (PLS), is better than it is for ALS, and the progression of the disease is generally slow.
Drugs that combat spasticity, such as baclofen (Lioresal), are often prescribed, with a variety of supportive care measures.
“As difficult as it is to wait, the benefit of PLS as the diagnosis is undeniable,” Singer says. “Studies of PLS patients show them surviving nearly eight years or longer after diagnosis. In cases where deaths were discussed in medical journals, survival ranged from one to 15 years, and notably, none of the deaths were directly attributable to PLS.”
Wolfe concurs. “Compared to ALS, patients with PLS display more muscle stiffness, but they have less weakness and less respiratory compromise, and their prognosis as a result is much more favorable. The dilemma is separating PLS from ALS early on in the disease course so that we can provide some degree of reassurance to patients.
“This can be challenging, but if several years pass without clinical evidence of LMN involvement, one can be reasonably confident in making the diagnosis of PLS. Even having a UMN-predominant presentation of ALS casts a more favorable light on the situation.”
With LMN disease, respiratory muscle weakness remains a threat
Although not part of this recent review, people can also have only LMN symptoms that don’t progress to full-blown ALS. This condition, sometimes called “progressive muscular atrophy” (PMA), also usually carries a better prognosis than ALS, although weakness of respiratory muscles can be life-threatening.
“PMA is ... usually described as a disease characterized by slow progression and long duration,” with survival from onset ranging from three and a half years to 34 years (average 13 years), wrote Paul Ince of Sheffield (UK) University and colleagues in 2003 in the journal Neurology. The authors note, however, that much of the literature on PMA predates modern molecular diagnostic techniques.
In reviewing the medical records of LMN-onset disease seen at the Motor Neurone Disease Clinic in Newcastle upon Tyne (UK) between 1985 and 1999, Ince’s group found that six progressed to ALS, and 12 didn’t.
Presence of nogo-A may be key to ALS prediction
Data published April 23 in Neurology by a French team suggest that the presence of a protein called nogo-A in a muscle biopsy sample may be a good predictor of the development of ALS in patients who have only LMN symptoms.
In this study, Pierre-Francois Pradat at the Hopital de la Pitie-Salpetriere in Paris studied 33 people who underwent muscle biopsies during their diagnostic workup. Doctors measured nogo-A levels in the biopsy samples and then observed the patients for a year.
The investigators found nogo-A in 17 patients and didn’t find it in 16.
Of the 17 whose muscles contained the protein, 15 developed ALS. Of the 16 in which nogo-A was absent from the biopsy samples, only one developed ALS.
“This study in LMN patients shows that the nogo-A test is able to identify ALS early in the course of the disease,” the authors write.
They note that, since muscle biopsies are invasive, this approach should be used only when other disease processes that might be causing the LMN symptoms have been ruled out.
Emotional, cognitive function preserved in LMN-only study
In 2006, Laura Goldstein at King’s College in London, and colleagues, compared 12 people with PMA to 25 healthy people (control group) on measures of cognitive, behavioral and emotional function, and found no differences. The researchers admit their sample was small, but they say the rarity of this condition made that limitation necessary.
At the time of the psychological testing, the people in the PMA group had been experiencing symptoms for two to 11 years. The researchers rated their average level of disability on a standardized scale as “moderate.”