Although there is no cure for amyotrophic lateral sclerosis (ALS), therapies to slow disease progression are in clinical trials. The question of how to measure the effects of therapeutic intervention is critical. Generally accepted measures — assessments of physical strength and muscle function — lack precision and can require six to 12 months to give reliable results.
Neurologist Kevin Boylan, M.D., and colleagues at Mayo Clinic in Florida are working to develop a more reliable test. Their goal is a peripheral blood test that could be used to monitor the rate of nerve fiber loss in ALS by measuring the presence of a biomarker — a neurofilament subunit or protein — called pNF-H, which helps maintain the structure and shape of nerve fibers and is released as motor axons break down.
Previous studies have shown that levels of pNF-H are elevated in the cerebrospinal fluid (CSF) of ALS patients and that increasingly elevated levels correlate with patients' decline. Because serial lumbar puncture is not practical for routine monitoring, however, Dr. Boylan and colleagues hoped to develop a less invasive test.
Using a new monoclonal antibody and enzyme-linked immunosorbent assay (ELISA), they found that levels of pNF-H were elevated 2.8-fold in the circulating blood of ALS patients compared to healthy adults. Now they are investigating how well blood levels of pNF-H correlate with disease progression and with pNF-H levels in the CSF of a group of ALS patients.
If results continue to be promising, the test will be developed for a larger trial. Such a test would not only improve monitoring the effects of therapy, but also might offer a way to estimate the rate of progression in ALS.
Dr. Boylan and his colleagues are also conducting clinical trials on several novel therapies:
A drug being tested for its effectiveness in slowing ALS progression is the antibiotic ceftriaxone. Ceftriaxone is being evaluated in ALS because research suggests that it may reduce levels of glutamate near motor neurons, believed to be a factor in motor neuron loss in ALS. This study is currently open for enrollment.
Another drug, a combination of dextromethorphan hydrobromide and quinidine sulfate, has shown promise in modulating pseudobulbar affect (inappropriate laughing and crying) in people with ALS. Trials are under way to determine the optimal dose.
Not to be confused with a respiratory aid or pacemaker, a new diaphragm pacing stimulation device (see Figure) is intended to delay the decline of pulmonary function in ALS. An external electronic stimulator, attached to 4 wires implanted in the diaphragm, conditions the diaphragm by stimulating nerve fibers in the muscles so that they can function more effectively in the face of nerve fiber loss. Patients use it for fixed intervals several times a day.
"The hope is that electronic stimulation to exercise the diaphragm will delay the point at which mechanical ventilation is needed," Dr. Boylan explains. Mayo Clinic is one of 10 U.S. centers engaged in the study of 100 patients. Enrollment is complete and the patients are being monitored.
Dr. Boylan is the director of the ALS Clinic at Mayo Clinic in Jacksonville, Fla. Like Mayo's other two ALS clinics — in Rochester, Minn., and Phoenix, Ariz. — it is an ALS Association (ALSA)–designated Center of Excellence. Through its center program, ALSA "selects, certifies and supports distinguished regional institutions recognized as the best in the field" as centers with experience and knowledge of ALS, neurologic diagnostics and imaging, and on-site licensed and certified ancillary services.
The service providers at all three Mayo sites include neurologists, nurses, physical, occupational, and respiratory therapists, dietitians, psychologists, social workers, and speech-language pathologists. "The aim of the ALS clinical centers is to bring together key care providers so that each patient is monitored several times a year by the entire team," notes Dr. Boylan.
A comprehensive set of recommendations, arrived at in a team meeting, is communicated to the patient and to providers, physicians and medical equipment suppliers in the patient's community. Dr. Boylan adds, "Our clinics deal with all aspects of care — mobility, respiration, assistive communication, nutrition, and swallowing for the patient and social and psychological support for both patients and families."
As Mayo researchers continue to test new drugs, search for critical biomarkers and genetic mechanisms, and develop more precise means of monitoring response to therapy, the ALS clinical centers across Mayo continue to provide patients with intensive team care, focused on improving quality of life and slowing disease progression.