In SBMA, Cold Temperatures Slow Nerve Impulses to Arm Muscles
Slower impulses led to reduced grip strength in men in small study
Men with spinal and bulbar muscular atrophy (SBMA) had slower nerve impulses leading to their forearm muscles when their arms were exposed to cold temperatures, a small study reported.
These slower impulses correlated with reduced hand grip strength, and were significantly longer in adults with muscle weakness at cold temperatures than among those without.
Mexiletine, an oral medication used to treat abnormal heartbeats, did not affect nerve impulses at cold temperatures in these patients. But data showed it improved motor function in the hands and mouth — notable given that muscles involved with speech and swallowing are usually affected later in the course of SBMA.
Further studies are needed to verify the effects of mexiletine on motor function in patients with this genetic disorder, also commonly known as Kennedy’s disease, the researchers recommended.
The study,” Mexiletine in spinal and bulbar muscular atrophy: a randomized controlled trial,” was published in the Annals of Clinical and Translational Neurology.
SBMA is a slowly progressing condition characterized by weakness in the limbs and bulbar muscles of the mouth and throat. Muscle weakness is caused by the degeneration of motor neurons, the specialized nerve cells that control voluntary movement.
Impact of cold temperatures
People with SBMA — which mainly affects males and progresses very slowly — often experience nerve-related muscular weakness, called paresis, when exposed to cold temperatures. Such weakness is thought to be caused by muscle hyperexcitability, or an exaggerated response to nerve signal stimulation.
Mexiletine is an oral medication used to suppress muscle hyperexcitability, and is prescribed to treat abnormal heartbeats and restore nerve activity in several neuromuscular diseases. However, its impact on SBMA patients has not been confirmed thus far, especially in treating cold-exposure muscle weakness.
To learn more, researchers based at the Nagoya University Graduate School of Medicine, in Japan, conducted two studies. The first was an observational study to examine the effect of cold exposure in SBMA, while the second was Phase 2 interventional trial, dubbed MEXPRESS, to evaluate the efficacy and safety of mexiletine in SBMA.
The observational study included 51 male adults with SBMA, with a mean age of 55.7, plus a control group of 18 age-matched healthy men. Among the patients, 45 (88%) experienced paresis with cold exposure, occurring more often in the upper limbs than in the lower limbs or bulbar muscles.
About half of the patients first noticed cold paresis within five years from disease onset, and more experienced cold paresis after that. The team noted that 10 patients (22.2%) reported cold paresis even before the start of muscle weakness, suggesting that this symptom could be an early sign of SBMA — before the appearance of major symptoms.
Grip power, a measure of hand and forearm muscle strength, was significantly lower after cooling in cold water in SBMA patients than in controls.
The team also included a nerve conduction study (NCS) to measure distal latency, the speed of electrical impulses along the ulnar nerve that transmits signals to muscles in the forearm and hand, as well as compound muscle action potentials (CMAPs), the electrical signals received by muscle fibers.
As expected, distal latency was longer, and CMAP was lower in SBMA patients at room temperature than in controls. In comparison, at cold temperatures, the distal latency was significantly longer in patients than in controls (5.6 vs. 4.3 milliseconds). These changes in distal latencies between warm and cold correlated with the change in grip power in SBMA and were significantly larger in patients with cold paresis than in those without.
The MEXPRESS trial included 20 patients, ages 35–79. Half were assigned randomly to receive 100 mg mexiletine three times daily for four weeks, while the others were given a placebo on the same dosing regimen. After a one-week washout period, those receiving mexiletine were switched to a placebo, and patients receiving a placebo were treated with the same mexiletine regimen.
Effects of mexiletine treatment
Distal latencies at room temperature and under cold exposure — the study’s primary goal — were similar between the mexiletine-treated patients and the placebo groups. Disease severity, as assessed with the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), lessened with mexiletine, but the difference was not statistically different.
Motor function tests — such as tongue pressure and 10-second grip and release — were significantly improved in the mexiletine group. These are key clinical indices in patients with SBMA, the researchers noted.
Although grip strength, timed walking test, and lung function was improved with mexiletine, these values were not statistically different from the placebo. Mexiletine also reduced patient-reported body pain.
Secondary analysis examined the differences in nerve conduction and motor function between patients with and without prior use of leuprorelin acetate, an SBMA medication approved in Japan and intended to slow the progression of swallowing difficulties. After mexiletine, no differences between the two groups at room and cold temperatures were observed, including distal latency, motor function, and ALSFRS-R.
No serious adverse events were reported during MEXPRESS, with the most common adverse event being gastrointestinal problems; these occurred in eight mexiletine-treated patients and six placebo recipients.
“Most patients with SBMA experienced cold paresis, which was characterized by prolongation of distal latency in NCS,” the researchers concluded. “Prolongation of distal latency was correlated with a decrease in grip power.”
The team also noted that while mexiletine improved tongue pressure and scores in the grip and release test, it “did not restore the cold exposure-induced prolongation of distal latency in patients with SBMA.”
“Further parallel-group validation trials are warranted to verify the effects of mexiletine on motor function in patients with SBMA,” they concluded.