MIAMI—Advances in genetic testing have enabled precise identification of many spinocerebellar ataxias, but no pharmacologic therapy for the disorders has been approved, according to an overview presented at the First Pan American Parkinson’s Disease and Movement Disorders Congress. Nevertheless, the literature does indicate that various therapies have beneficial effects, said Theresa Zesiewicz, MD, Director of the University of South Florida Ataxia Research Center in Tampa.
She and her colleagues examined the evidence from the past 40 years of research on ataxia. The recommendations that they developed about treatment options currently are in press.
The Evidence for Pharmaceutical Treatment
“One of the most robust treatments for spinocerebellar ataxias … is going to be 4-aminopyridine for episodic ataxia type II,” said Dr. Zesiewicz. The drug is approved as a treatment for multiple sclerosis, and researchers have examined it in a double-blind, placebo-controlled trial of patients with episodic ataxia type II. After three months of treatment, the median number of monthly attacks was about 1.5 in participants who received 15 mg/day of 4-aminopyridine, compared with 6.5 for controls. The drug is fairly well tolerated and also can be used to treat downbeat nystagmus.
Two recent studies have investigated the effects of riluzole, a treatment for amyotrophic lateral sclerosis, in patients with various ataxias. Ristori et al examined 40 patients with ataxia of mixed etiology (eg, fragile X-associated tremor/ataxia syndrome, Friedreich’s ataxia, spinocerebellar ataxia, and multiple system atrophy). Patients received 100 mg/day of riluzole or placebo for eight weeks. After four weeks of treatment, about 47% of the riluzole group had a five-point improvement on the International Cooperative Ataxia Rating Scale (ICARS), compared with 5% in the placebo group. After eight weeks, 68% of the riluzole group had this outcome, compared with 5% of the placebo group.
In a 12-month study, Romano et al randomized 60 patients with spinocerebellar ataxia or Friedreich’s ataxia to 50 mg of riluzole b.i.d. or placebo. At 12 months, the proportion of patients with a decrease in Scale for the Assessment and Rating of Ataxia (SARA) score was 50% in the riluzole group, compared with 11% in the placebo group. The mean change in SARA score was greater in the riluzole group (2.6), compared with controls (1.39). The clinical relevance of the improvements in these two studies, however, is uncertain, said Dr. Zesiewicz.
An ongoing phase III study is examining a prodrug of riluzole in 120 patients with spinocerebellar ataxia. Various doses are being examined, and the treatment period will be eight weeks.
In a 1983 study, 250 patients with spinocerebellar ataxia were randomized to thyrotropin-releasing hormone or placebo. Outcomes were reported using a visual analog scale. Participants receiving thyrotropin-releasing hormone had improvement in dysarthria, stance, and gait, but the clinical significance is questionable, said Dr. Zesiewicz.
She and her colleagues compared varenicline, a drug approved for smoking cessation, with placebo in patients with spinocerebellar ataxia type III. After a four-week titration period, patients received treatment for four weeks. The investigators observed significant improvements in gait, stance, and rapid alternating movements among patients receiving varenicline. After data correction, the improvement in rapid alternating movements remained significant. Varenicline has been associated with suicide risk, but Dr. Zesiewicz and colleagues noted a trend toward improvement in Beck Depression Scale among treated participants. Approximately 40% of patients receiving varenicline dropped out of the study, however, because of tremulousness, weakness, and unpleasant dreams.
Examining Nonpharmacologic Options
In addition to pharmacotherapy, some nonpharmacologic treatments may improve function in spinocerebellar ataxia. In one double-blind trial, researchers randomized participants with various ataxias to a single session of transcranial magnetic stimulation (TMS) or sham stimulation. TMS was associated with improvement in SARA score and cerebellar motor function at 21 days. “Harvard just finished a TMS study, and we are waiting for results from that,” said Dr. Zesiewicz.
“Physical therapy is vital for patients with spinocerebellar ataxia,” she continued. One study indicated that intensive exercises such as core strength training, stepping, and dynamic balance yielded significant increases in the Berg Balance Scale. In another randomized controlled trial, four weeks of physical and occupational therapy were associated with a three-point decrease in SARA score. In addition, patients with spinocerebellar ataxia had a two-point decrease in ICARS score after undergoing four weeks of intensive cycling.
A Search for Future Therapies
Investigations of new potential treatments for spinocerebellar ataxia are ongoing. Researchers published the results of a phase II study of IV trehalose in January. Participants’ SARA score remained stable after six months of treatment.
Mesenchymal stem cells may one day provide benefits for patients. After one month of treatment with mesenchymal stromal cells, study participants with spinocerebellar ataxia had improved walking, standing, slow movement, and fine movements. Patients returned to their pretreatment condition after a few months, however.
In addition, screens of small molecules may reveal possible new therapies. One such screen identified aripiprazole as a candidate, and the drug increased longevity in a Drosophila model of Machado-Joseph disease.
“We are looking for great things. We are looking for a cure. But we will use what we have now,” Dr. Zesiewicz concluded.
Lei LF, Yang GP, Wang JL, et al. Safety and efficacy of valproic acid treatment in SCA3/MJD patients. Parkinsonism Relat Disord. 2016;26:55-61.
Ristori G, Romano S, Visconti A, et al. Riluzole in cerebellar ataxia: a randomized, double-blind, placebo-controlled pilot trial. Neurology. 2010;74(10):839-845.
Romano S, Coarelli G, Marcotulli C, et al. Riluzole in patients with hereditary cerebellar ataxia: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2015;14(10):985-891.
Strupp M, Kalla R, Claassen J, et al. A randomized trial of 4-aminopyridine in EA2 and related familial episodic ataxias. Neurology. 2011;77(3):269-275.
Zesiewicz TA, Greenstein PE, Sullivan KL, et al. A randomized trial of varenicline (Chantix) for the treatment of spinocerebellar ataxia type 3. Neurology. 2012;78(8):545-550.