ARTICLE IN BRIEF
In an open label trial in patients with Tourette syndrome using deep brain stimulation of different target areas in the basal ganglia network, the Yale Global Tic Severity Scale score improved 45.1 percent at one year.
In patients with Tourette syndrome, deep brain stimulation was found to improve symptoms, but also to have unfavorable side effects, a new study reported.
Results of the prospective analysis involving a multinational cohort of patients were published online in the January 16 issue of JAMA Neurology.
The International Deep Brain Stimulation Database and Registry, composed of 185 patients from 31 different institutions in 10 countries, found that the mean Yale Global Tic Severity Scale score improved 45.1 percent at one year after deep brain stimulation. The most common adverse events were dysarthria (6.3 percent) and paresthesias (8.2 percent). [For more data from the study, see “By the Numbers: Study Design, Results.”]
“We're logging all the cases as they come in from all over the world,” said Michael S. Okun, MD, FAAN, the report's senior author and the Adelaide Lackner Professor and chair of neurology in the Fixel Center for Neurological Diseases at the University of Florida in Gainesville.
Patients with medically refractory symptoms were exposed to different brain targets in the basal ganglia network, which led to comparable suppression of motor tics based on 12-month outcomes of the pooled data. However, “we need to follow these patients longer, and we need to get more patients in each target,” Dr. Okun told Neurology Today.
The authors noted that the overall small number of deep brain stimulation procedures performed for Tourette syndrome per year has made it challenging to evaluate the outcomes among patients with the disorder. This dearth of cases led the Tourette Association of America to organize the international multicountry study, launching the database and registry in 2012.
Deep brain stimulation is approved by the U.S. Food and Drug Administration (FDA) for selected cases of Parkinson disease and essential tremor. It also has FDA approval under a humanitarian device exemption for dystonia and obsessive-compulsive disorder.
Despite the lack of approval for Tourette syndrome, “multiple single reports and case series have collectively demonstrated that DBS could be a potentially valuable therapy for select cases of medication-resistant Tourette syndrome,” the authors wrote. [For more details from the study, see “By the Numbers: Study Design, Results.”]
Commenting on the study, Jeremiah M. Scharf, MD, PhD, co-director of the Tic Disorders Center of Excellence at Massachusetts General Hospital and an assistant professor of neurology and psychiatry at Harvard Medical School, said: “This is really a superb example of recent efforts to encourage open-data sharing,” a scientific mission espoused by the National Institutes of Health.
“The amount of effort that went into contacting all these sites and to get each of them to contribute their data and put it in a central place that everybody can look at and analyze is truly a landmark achievement,” Dr. Scharf said. “It really lays the groundwork for definitive randomized controlled trials.”
Harvey S. Singer, MD, FAAN, professor of neurology and pediatrics at the Johns Hopkins University School of Medicine, was cautiously optimistic about the findings of the multinational collaboration. “Deep brain stimulation should be considered a promising emerging therapy and future studies are required,” Dr. Singer said. “There are still many unanswered questions.”
Among the study's limitations are the collection of data from multiple sites, the lack of standard inclusion criteria, potentially different surgical techniques and stimulation settings, and no magnetic resonance imaging confirmation of electrode placement — all of which the authors acknowledged in the report. Several different targets were utilized for placement of electrodes within the brain, but the number of subjects evaluated at each site was quite variable, affecting one's ability to compare the data, Dr. Singer said.
While it is difficult to design a double-blind, placebo-controlled trial, he noted that some studies have compared results measured when the stimulator was turned “on” to when it was turned “off.” Further confusing the results was the fact that some patients also took tic-suppressing medications during the DBS treatment period.
Dr. Singer said several confounding factors make it difficult to draw firm conclusions from the study. He cited, for example, the small number of subjects, the broad age range, insufficient data about the effects of comorbid symptoms, such as obsessive-compulsive disorder, anxiety, depression, and self-injurious behaviors, and the study's lack of clear consensus guidelines. “This is a potentially beneficial therapy, but there is a need for additional studies, including the assessment of other DBS targets,” he said.
With only a couple of patients at experienced centers undergoing deep brain stimulation within a span of a few years, Dr. Okun told Neurology Today that implementing strict enrollment criteria and study methodology were not feasible options for this research endeavor.
“Our aim was never a randomized trial, although other people may use this data to devise a randomized trial,” he said. “One may argue that as the procedure becomes safer and more available, perhaps more patients may be eligible for it. A lot of what's being done is reserved for patients who have really terrible symptoms, but that can change as things develop in the field.”
“It's really important for people to remember that these types of procedures are mostly performed in the research setting and anybody who is interested in performing deep brain stimulation for Tourette syndrome should always employ an interdisciplinary approach and team,” Dr. Okun said.
That team should include a neurologist, psychiatrist, neuropsychologist, neurosurgeon, and rehabilitation expert to screen candidates carefully and ensure that patients have been offered adequate alternatives. In addition, the team should strongly consider including a social worker or counseling psychologist to help patients reintegrate into society and the workforce — important outcomes that can be missed even in cases where tics are successfully suppressed.
A specialized group of experts who understand the various reasons for failing treatment for Tourette syndrome would conduct a comprehensive evaluation scrutinizing the patient's medical history, said John T. Walkup, MD, a professor and chair of psychiatry at the Ann and Robert H. Lurie Children's Hospital of Chicago, which is affiliated with Northwestern University Feinberg School of Medicine.
For instance, an incorrect diagnosis may be at the root of the problem or other conditions could be responsible for exacerbating the motor tics. Sometimes it isn't the dosage or duration of treatment that was insufficient, but rather, the lack of an appropriate “sequential strategy,” Dr. Walkup said. “There are a lot of factors involved in treatment failure, not just intractable disease.”
Documenting the brain targets in a registry such as the one spearheaded by Dr. Okun for the Tourette Association of America will help foster collaboration among researchers to study a larger sample size of subjects and provide greater awareness of adverse events, Dr. Walkup said.
“A number of years ago, deep brain stimulation came on the scene really unbeknownst to almost all experts in Tourette's,” he added. “It's a bit surprising to me how many cases actually have been done.”
Multiyear outcomes will be updated on a public website (https://tourettedeepbrainstimulationregistry.ese.ufhealth.org).
BY THE NUMBERS: STUDY DESIGN, RESULTS
- Patients with bilateral and medically refractory Tourette symptoms underwent DBS implantation from January 1, 2012 to December 31, 2016. They were drawn from institutions across Australia, Europe, Asia, and North America.
- Participants received DBS implantation in the centromedian thalamic region (57.1 percent), the anterior globus pallidus internus (25.2 percent), the posterior globus pallidus internus (15.3 percent), and the anterior limb of the internal capsule (2.5 percent).
- The mean total Yale Global Tic Severity Scale score improved from 75.01 (18.36) at baseline to 41.19 (20.00) at one year after DBS implantation (p<.001). The mean motor tic subscore improved from 21.00 (3.72) at baseline to 12.91 (5.58) after one year (p<.001), and the mean phonic tic subscore improved from 16.82 (6.56) at baseline to 9.63 (6.99) at one year (p<.001).
- The overall adverse event rate was 35.4 percent (56 of 158 patients): Two patients had intracranial hemorrhage; four patients had an infection in four patients with five events (3.2 percent), and lead explantation in one patient (0.6 percent).