ARTICLE IN BRIEF
Compared to sham stimulation, cerebello-spinal transcranial direct current stimulation showed a significant improvement across a broad range of performance measures and in motor cortex excitability and cerebellar brain inhibition in patients with neurodegenerative ataxias.
Cerebello-spinal transcranial direct current stimulation (tDCS) improved clinical scores and neurophysiological measures of motor cortex excitability and cerebellar-cerebral connectivity, compared with sham treatment, in a small group of patients with neurodegenerative ataxia, according to a study published in the August 22 online edition of Neurology.
“In most cases, neurodegenerative ataxias are untreatable progressive disorders affecting quality of life in young adulthood,” study author Barbara Borroni, MD, associate professor of neurology at the Centre for Neurodegenerative Disorders at the University of Brescia in Italy, told Neurology Today. “Given the limited pharmacologic and nonpharmacologic treatment options for patients with neurodegenerative ataxia, on the basis of the results of our study, a two-week treatment with cerebello-spinal tDCS could represent a promising approach to be added to rehabilitative interventions,” Dr. Borroni said.
“We proposed a safe, easy to perform, inexpensive, painless, and noninvasive treatment approach,” she said. “We demonstrated long-lasting effects, especially in less affected patients.”
“Neurodegenerative ataxias are rare, but if we consider each singular pathogenic mechanism, numbers grow significantly when we pull together all disease causes, ranging from hereditary to sporadic cases,” Dr. Borroni noted. “Finding innovative therapeutic approaches to reduce clinical symptoms can be useful for the entire spectrum of neurodegenerative cerebellar ataxias.”
For the study, 20 patients were randomized into receiving either anodal cerebellar tDCS and cathodal spinal tDCS or sham stimulation for five days a week over the course of two weeks. At baseline, each patient underwent a clinical evaluation, according to a standardized assessment, and cerebellar brain inhibition evaluation using transcranial magnetic stimulation. The same assessments were conducted at three time points: after two-weeks of either real or sham tDCS, at one-month, and at three-months follow up.
In the cross-over phase, following a wash-out period of three months after the final visit, each individual received the opposite treatment and was assessed using the same measures as before at two-weeks, one-month, and three-months follow up. The authors reported no significant difference in the perception of stimulation between sham and real therapy (p=0.205).
Compared to sham stimulation, cerebello-spinal tDCS showed a significant improvement across all performance measures — including the scale for the assessment and rating of ataxia (SARA), international cooperative ataxia rating scale (ICARS), 9-hole peg test (9HPT), 8-meter walking time (8MW) — and in motor cortex excitability and cerebellar brain inhibition. (See “By the Numbers: tDCS for Neurodegenerative Ataxia.”)
Dr. Borroni said that there were a number of questions that will need to be addressed going forward. For example, what is the best repetition rate, session duration, and number of sessions to achieve the best results? “Moreover, neurodegenerative cerebellar ataxias are considerably uncommon, and our group of patients was relatively small and heterogeneous, so its usefulness in each ataxia subgroup needs to be stated with caution,” she said.
In addition, she said, researchers will need to explore whether repeated stimulations over time would extend the duration of tDCS effects; the effect of tDCS on cognitive functions, which might be impaired in this group of patients; and the efficacy of tDCS in the different neurodegenerative ataxia subgroups, which would increase the sample size.
Previous small studies have indicated that administering tDCS to the spine after spinal cord injury and to the cerebellum for cerebellar ataxia may both be useful, said Maureen A. Leehey, MD, FAAN, professor of neurology and chief of the movement disorders division in the department of neurology at the University of Colorado-Denver. But this is the first randomized controlled study where tDCS was used in both regions.
If these findings are confirmed, it could potentially address a great need, as presently there are no consistently effective medications for cerebellar ataxia, Dr. Leehey said.
She applauded the study for its size — given the uncommon diagnosis of neurodegenerative cerebellar ataxia — and its strong design. One limitation, she noted, was the lack of measurements of changes in spinal cord effect, such as spasticity, or other central nervous system effects, such as cognition, orthostatic hypotension, and parkinsonian signs.
The fairly complex technology involved in this research will not be widely available and, at this stage, it is unlikely to be reimbursed by third parties, Dr. Leehey added. Other questions remain: For example, is administering tDCS to both regions better than cerebellar tDCS alone? What are the risks involved — short- and long-term? The lack of placebo effect was surprising, she added, as was the consistency and strength of the beneficial effect.
Deborah Hall, MD, PhD, FAAN, an adult neurologist and movement disorder specialist at Rush University Medical Center in Chicago, agreed. “In treatment trials for the cerebellar ataxias, it has been noted that European studies may have a smaller placebo effect than those conducted in North America.”
“This study also included patients with many etiologies of ataxia,” she noted. “With such low sample sizes, it is unclear if the therapy is more effective for certain etiologies of ataxia or should be considered in all ataxic patients.”
Dr. Hall suggested that one reason it may be so difficult to treat this population of patients is that it is challenging to gather enough patients with a particular ataxia to reach adequate sample size for later phase clinical trials, leading to a lack of appropriate therapeutics for symptom control. As noted in the accompanying editorial, many patients may have difficulty traveling to a center where trials are being conducted.
“Consortiums of ataxia clinicians focused on specific ataxias are ideal to test therapeutic compounds that are disease specific and would allow recruitment of a sufficient cohort for phase 3 studies. National organizations have facilitated these types of interactions. With the advent of possible antisense oligonucleotide therapies and other treatments, there is a pressing need for validated outcome measures across groups and adequate patient numbers in order to drive this field forward and provide relief for these patients,” said Dr. Hall.
“The cerebellar ataxias are rare enough that no study opportunity should be underutilized,” said Susan L. Perlman, MD, clinical professor of neurology at the David Geffen School of Medicine at the University of California, Los Angeles. Importantly, this study represented both genetic and non-genetic cerebellar ataxia, “supporting a symptomatic benefit for any cerebellar-mediated motor issue,” Dr. Perlman said.
But she said that one limitation of the trial was that it was not registered with the US Food and Drug Administration's (FDA) Investigational Device Exemption. “tDCS has to date not been approved for any use by the US Food and Drug Administration,” she said, noting that tDCS is an approved treatment for major depressive disorder in Europe.
Although no treatments have been approved yet, a large number of published studies “of variable validity” have looked at “drugs to modify cerebellar neurotransmitters and drugs to modify Purkinje cell electrical activity/stability,” Dr. Perlman said. “The results of this study support a targeted, non-drug intervention aimed at the latter approach. The need for daily treatments for two weeks every three months or more frequently could limit practical access to this technology.”
As the underlying pathophysiologic mechanisms of progressive cerebellar ataxias are becoming better understood, Dr. Perlman said, the doors are opening “to development of therapies specific for neuromodulation and disease modification. Both are critically important for these currently untreatable disorders.
“But with any rare disease, well-designed clinical treatment trials utilizing hundreds of patients for three to five years will be almost impossible to recruit and conduct in a timely and cost-effective fashion. Clinical research needs more trained research sites, better efficacy measures and biomarkers, better treatments in the pipeline, and better outreach to candidate subjects.”
Drs. Borroni, Leehey, and Perlman report no disclosures. Dr. Hall served or has served on the scientific advisory board of the National Fragile X Foundation, consults or has consulted for the National Institutes of Health, and has received research support from Pfizer, Neurocrine, AbbVie, NIH, Shapiro Foundation, Anti-Aging Foundation, and Parkinson Foundation. She is also an associate editor of Neurology Today.
BY THE NUMBERS: TDCS FOR NEURODEGENERATIVE ATAXIA
- For the scale for the assessment and rating of ataxia scores (SARA), the main effect of treatment showed a significant difference at all time points, between sham and real therapy (p<0.001) but not at baseline (p=0.422), while the main effect of time showed a significant difference in the real therapy group at all three time points compared to baseline (p<0.001), but not in the sham group (p>0.05).
- For the international cooperative ataxia rating scale (ICARS), the main effect of treatment showed a significant difference across all time points (p<0.001) but not at baseline (p=0.613), while the main effect of time showed a significant difference in the real therapy group compared to baseline (p<0.001), but not in the sham group (p>0.050).
- For 8-meter walking time, the main effect of treatment showed a significant difference between sham and real therapy across all time points (p<0.050) but not at baseline (p=0.414), while the main effect of time showed significant difference in the real therapy group compared to baseline (all p<0.050), but not in the sham group (p >0.050).
- For the 9-hole peg test the main effect of treatment showed a significant difference between real and sham therapy at all time points (p<0.010) in both the dominant and non-dominant hand but not at baseline (dominant p=0.670; non-dominant p=0.926), while the main effect of time showed a significant difference in the real group at all time points compared to baseline (p<0.050), but not in the sham tDCS group (p>0.050).
- For cerebellar brain inhibition, the main effect of treatment showed a significant difference between real and sham tDCS at the first two time points (p<0.001) but not at baseline (p=0.454) or the third time point (p=0.053), while the main effect of time showed significant difference in the real tDCS group at all three time points compared to baseline (p<0.050), but not in the sham tDCS group (p>0.050).