SAN FRANCISCO—Investigators are one step closer to confirming several technologic measures as reliable objective markers of upper and lower motor neuron involvement in amyotrophic lateral sclerosis (ALS). The findings from teams at Columbia and Cornell universities may help lead to earlier and more accurate diagnosis of ALS and allow patients more timely access to treatment.

In data presented at the 56th Annual Meeting of the American Academy of Neurology, 48 patients with different forms of ALS—sporadic, familial, pure lower motor neuron type, or pure upper motor neuron type, as determined on clinical examination—were prospectively studied. Patients were examined clinically and underwent neuroimaging studies and electrophysiologic measures every three months. Results were compared with those from a control group of 26 healthy volunteers.

Two of the technologic measures—multiple-voxel magnetic resonance spectroscopy imaging (MRSI), which specifically analyzes motor cortex, and transcranial magnetic stimulation—were effective in distinguishing upper motor neuron disease from lower motor neuron disease. A third measure—motor unit number estimation, which uses multiple-point stimulation technology—was shown to be a reliable objective marker for detecting changes over time.

The results are significant, given the absence of objective or quantitative markers for both upper and lower motor neuron function in ALS and the need to differentiate the two sources of motor impairment in individual patients, said Hiroshi Mitsumoto, MD, DSc, who is the Wesley J. Howe Professor of Neurology at Columbia University at Columbia-Presbyterian Medical Center in New York City and principal investigator of the study. “We need to exclude all other definable diagnoses,” he said. “It is imperative to have objective markers so we can make the diagnosis sooner and more accurately. [Here] we are confirming that MRSI and transcranial magnetic stimulation are highly reliable ways to predict upper motor neuron dysfunction. Motor unit number estimation is the most reliable way to follow the disease course, but our preliminary study indicated not with MRSI or transcranial magnetic stimulation.”

AN EXPANDING SET OF TECHNOLOGIC OPTIONS

Currently, the diagnosis of ALS is based on recognition of both upper and lower motor neuron signs detected mainly by clinical evaluation. The only objective technologic measure of ALS that is available to clinicians is electromyography, but, according to Dr. Mitsumoto, it is useful in identifying only lower motor neuron dysfunction; assessment of upper motor neuron involvement in ALS has been based solely on neurologic examination.

But clinical evaluation alone is insufficient in distinguishing among certain ALS-related syndromes. Purely lower motor neuron syndromes, for example, can be caused by ALS, motor neuropathy, or spinal muscular atrophy, itself a purely lower motor neuron disease. With autopsy data revealing that half to three quarters of patients clinically diagnosed with progressive muscular atrophy had corticospinal tract degeneration, clinical examination appears to be especially unreliable for detecting upper motor neuron dysfunction when lower motor neuron involvement is pronounced.

Objective upper motor neuron markers would therefore improve not only diagnostic accuracy but also our understanding of the disease and clinicians’ ability to determine the prognosis. These, in turn, would enable patients diagnosed with ALS to have more timely access to clinical trials as well as earlier treatment.

For the past decade, both MRSI and transcranial magnetic stimulation have been investigated as markers of upper motor neuron function. Either single-voxel or multiple-voxel MRSI can provide a quantitative assessment of regional biochemistry in vivo, including detection of such metabolites as N-acetyl aspartate (NAA) and creatine (Cr). A significant decrease in the ratio of NAA to Cr has been found in the motor cortex of ALS patients and is thought to be a marker of the disease. Transcranial magnetic stimulation, for its part, evaluates central motor pathways. This may be useful in the diagnosis of ALS since more than half a dozen studies have reported a slowing of central motor conduction time in up to 100% of patients with ALS in a given study.

Dr. Mitsumoto addressed the question of why electromyography is insufficient as a reliable or effective early diagnostic or surrogate marker of ALS overall, as well as the promise these newer techniques offered at the start of his study. “Electromyography is the most reliable test to identify lower motor neuron dysfunction,” he emphasized. “On the other hand, this technique has no ability when it comes to assessing upper motor neuron dysfunction. Magnetic resonance spectroscopy is the first technologic marker to make this possible, but the technology has not been perfected and has caused conflicting results. This is still very new, and thus investigators are trying different MR units, different software, and different magnet strengths that have yet to be standardized.”

SUPPORTING STUDY

In a retrospective study published earlier this year, Dr. Mitsumoto and colleagues at Columbia University evaluated single-voxel MRSI and transcranial magnetic stimulation in 164 ALS patients who had been originally referred to the university’s Eleanor and Lou Gehrig MDA/ALS Research Center for diagnostic evaluation. The investigators found MRSI to be highly sensitive, more so than transcranial magnetic stimulation, and to correlate well with clinical detection of upper motor neuron signs. They concluded that early diagnosis of ALS may be aided by a combined use of the two technologies.

Now, with findings from their present study, Dr. Mitsumoto and his collaborators have identified an expanding set of promising technologic options, including two different forms of MRSI. “Taken together, our previous data using single-voxel MRSI and the current study with the multiple-voxel method show that the two techniques are equally reliable,” he said. “Since we don’t know which is better, we need to analyze those data further.”

In the more recent study, the wide array of technologic and clinical diagnostic tests, employed to evaluate controls as well as different patients with different subtypes of ALS, enabled investigators to cross-validate their results several ways. As expected, the patients with ALS had a significantly reduced NAA/Cr ratio, compared with healthy patients. When results for patients with conditions involving upper motor neuron dysfunction were combined, the group also had a significantly reduced NAA/Cr ratio, compared with either those with progressive muscular atrophy (ie, lower motor neuron disease) or the control group. This same group with upper motor neuron disease had an abnormal central motor conduction time, compared with those with progressive muscular atrophy.

Motor unit number estimation, an electromyography technique that has been used to measure the degree of lower motor neuron dysfunction, showed promise in its ability to differentiate lower from upper motor neuron involvement. The average estimate in patients with primary lateral sclerosis, a purely upper motor neuron disease, was significantly lower than that in controls, indicating that motor unit number estimation could be useful in diagnosing primary lateral sclerosis. In addition, baseline motor unit number estimation scores were highly correlated with such clinical measures as pinch strength, grip strength, and total manual muscle testing. The fact that clinical measures gave strong correlation coefficients with each other at baseline suggests that these measures are highly related.

TOO SOON FOR CLINICAL PRACTICE?

Because some of the data from quantitative measures overlapped between controls and patients with upper motor neuron syndromes, further refinement of the technology is needed before these markers can be used reliably in clinical practice. Despite that pressing need, Dr. Mitsumoto envisions widespread clinical use within the next five years.

“Neuroimaging is an evolving field,” Dr. Mitsumoto observed. “Upper motor neuron technology is not available everywhere, and the results are tricky. But eventually, clinical neurologic evaluation of ALS will be supplemented and perhaps even replaced by the advent of technologic measures—that is the future implication of all this. At a facility like our ALS Center, we can already use this technology to make a reliable diagnosis. We continue to collect the data and refine them.”

NR

—Fred Balzac

Suggested Reading
Chan S, Kaufmann P, Shungu DC, Mitsumoto H. Amyotrophic lateral sclerosis and primary lateral sclerosis: evidence-based diagnostic evaluation of the upper motor neuron. Neuroimaging Clin N Am. 2003;13:307-326.
Kaufmann P, Mitsumoto H. Amyotrophic lateral sclerosis: objective upper motor neuron markers. Curr Neurol Neurosci Rep. 2002;2:55-60.
Kaufmann P, Pullman SL, Shungu DC, et al. Objective tests for upper motor neuron involvement in amyotrophic lateral sclerosis (ALS). Neurology. 2004;62:1753-1757.

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