By Mary L. Vo, MD, PharmD
Assistant Professor of Neurology, Weill Cornell Medical College
SYNOPSIS: Concurrent cerebellar and spinal stimulation with a transcranial direct current stimulation device resulted in improvement of both motor and cognitive functions in patients with several different forms of neurodegenerative ataxia.
SOURCE: Benussi A, Cantoni V, Manes M, et al. Motor and cognitive outcomes of cerebello-spinal stimulation in neurodegenerative ataxia. Brain 2021;144:2310-2321.
Cerebellar ataxic syndromes are a heterogenous group of disorders characterized by gait instability appendicular ataxia, tremor, oculomotor abnormalities, and cognitive impairment resulting in progressive disability. The pathophysiologic mechanism of both genetic and acquired cerebellar disorders involves cumulative injury from oxidative stress, mitochondrial dysfunction, impaired deoxyribonucleic acid (DNA) repair, and abnormalities in cytoskeletal proteins. The absence of effective treatments or robust symptomatic therapies represents a large unmet need in this population. A growing body of literature has shown the benefit of transcranial magnetic stimulation (TMS) therapy for ataxia. More recently, there has been increasing interest in transcranial direct current stimulation (tDCS) of the cerebellum and spinal cord, since these areas are implicated in cerebellar ataxia. Treatment with tDCS can improve motor symptoms in patients with cerebellar ataxia by promoting neuroplasticity and restoring cerebellar inhibition.
The authors of this study explored the short-term and long-term effects of tDCS treatments on motor and cognitive function in patients with cerebellar ataxia. Additionally, the study design aimed to compare the duration of measurable improvement and the effect of a single treatment compared to two treatments. The study is a randomized, double-blind, sham-controlled trial of 61 patients with cerebellar ataxia recruited from a single specialized neurodegenerative clinic in Brescia, Italy. The study included subjects with molecularly confirmed spinal cerebellar ataxia (SCA), multisystem atrophy-cerebellar type (MSA-C), Friedreich’s ataxia, sporadic adult-onset ataxia, and cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS). All subjects had evidence of cerebellar or spinal cord atrophy on magnetic resonance imaging (MRI). Patients were randomized to receive sham stimulation vs. concurrent cerebellar and spinal tDCS over five sessions per week for two weeks. After a 12-week washout period, both groups were treated with tDCS administered in five sessions per week for two weeks in an open-label arm of the study. Primary outcome measures were change in motor score as measured by a scale for the assessment and rating of ataxia (SARA) and international cooperative ataxia rating scale (ICARS) as well as cognitive changes measured with cerebellar cognitive and affective syndrome scale (CCASS) scores. Secondary outcome measures were change in quality-of-life measures as well as cerebellar inhibition measured by transcranial magnetic stimulation. All assessments were conducted at weeks 0, 12, 14, 24, 36, and 52.
Statistical analysis used two-way analysis of covariance (ANCOVA) to assess changes in clinical scores and neurophysiologic measures over time and to measure differences between the two treatment groups. Post-hoc analysis with Hochberg’s step-up procedure was employed to analyze group differences at each time point. Spearman rank-order correlations were used to evaluate associations between improvement in functional scores, neurophysiological parameter, and clinical characteristics.
Twenty-eight subjects in group 1 received sham stimulation, whereas 33 subjects in group 2 were treated with tDCS. Seven patients were lost to follow-up for reasons unrelated to the study.
Modest but significant improvements in SARA scores (4.1; confidence interval [CI], 3.5 to 4.7; P < 0.001), ICARS (11; CI, 9.3 to 12.7; P < 0.001), CCASS (mean scores -7.0; CI, -10.4 to -3.5; P < 0.001), quality of life scores, motor cortex excitability, and cerebellar inhibition (0.24; CI, 0.19 to 0.30; P < 0.001) were observed in the treated group compared to sham stimulation at the end of the randomized, double-blind period. A greater marginal benefit in motor scores was noted between the two groups at the end of the open-label period, suggesting an additive benefit after two treatments. The degree of improvement measured by SARA and ICARS was inversely correlated with disease duration (rs =-0.37, P = 0.003), indicating that better clinical outcomes would be expected with earlier treatment. Significant clinical improvement was seen in both groups, regardless of etiology of cerebellar syndrome. Improvements in SARA score and cognitive scores correlated with the percentage of restoration in cerebellar inhibition measured by TMS (rs = 0.42, P = 0.004 and rs = 0.52, P < 0.001, respectively).
COMMENTARY
tDCS is a non-invasive, well-tolerated treatment that may confer motor and cognitive improvements. Findings in this study also suggest that repetitive treatments may confer modest longer-term symptomatic improvement if implemented earlier in the disease course.
One concern is limited access to treatment, since tDCS is only available at specialized centers and would require close follow-up by a movement specialist. Further study is needed to establish the benefit of tDCS in the treatment of cerebellar ataxia.
