ARTICLE IN BRIEF
In a retrospective study of hospitalizations for Guillain-Barré syndrome (GBS) and recent vaccinations, of any kind, over a 13-year period, investigators found a very small risk for GBS.
The Food and Drug Administration approved deep brain stimulation (DBS) for the treatment of primary generalized or segmental dystonia under a Humanitarian Device Exemption in 2003. Nevertheless, many questions remained: how long would this treatment effect be sustained? Would serious adverse events arise after years of treatment?
The first long-term study of DBS treatment for primary dystonia (DYT1), published online ahead of the July print issue of Neurosurgery, is now providing some answers. In the study, investigators found that DBS is safe and effective in DYTI patients for up to eight years.
Senior author Ron L. Alterman, MD, chief of the Division of Neurosurgery at Beth Israel Deaconess Medical Center in Boston, told Neurology Today: “The purpose [of our study] was to relate the positive, longer term outcomes of deep brain stimulation in a very specific dystonia subpopulation.” Most of the previous studies, he added, have been in mixed dystonia populations.
“These results reinforce what is already out there in the neurology and neurosurgery literature, which is that primary dystonia patients — particularly those with juvenile-onset primary dystonias who respond poorly to medications — should be operated on,” said Dr. Alterman, a consultant for Medtronic, the manufacturer of the DBS system. “The risks are more than acceptable. We had no neurologic injuries in any of these patients — no hemorrhages, no strokes. The main risk is infection, which is manageable.”
STUDY PROTOCOLS, FINDINGS
The investigators performed a retrospective chart review of 47 consecutive DYT1 patients who were all treated by Dr. Alterman, a neurosurgeon, and neurologist Michele Tagliati, MD, at two hospitals — Beth Israel Medical Center and Mount Sinai Medical Center in New York — over a 10-year period. Patients were followed for up to 96 months (46 months on average). Each patient had genetically confirmed DYT1-associated torsion dystonia and received GPi (globus pallidus interna) DBS between the years 2000 and 2010.
[The DBS procedure is performed in two stages: While the patient is awake, leads are inserted streotactically into the GPi using both image and electrophysiological guidance. During the second stage, which is performed under general anesthesia, the leads are connected to programmable pulse generators via extension cables that are tunneled under the skin from the head to the chest wall, where the generator is implanted.]
Dr. Alterman and colleagues assessed the severity of motor symptoms and disability as measured by the Burke-Fahn-Marsden Dystonia Rating Scale at baseline and at each annual follow-up [See sidebar: “Burke-Fahn-Marsden Dystonia Rating Scale” for a description of the scale.] After two years of DBS, the severity of symptoms was reduced to less than 20 percent of baseline (p=.001), and disability scores were reduced to less than 30 percent of baseline (p=.001). For up to eight years, participants experienced significant improvements in motor symptoms, according to the paper. Improved motor scores were statistically significant for the first six years (p<.001) and at year 7 (p =.04). At their last follow-up, 61 percent of patients had discontinued all dystonia-related medications and 91 percent had discontinued at least one class of medication. Also important, Dr. Alterman said, was their successful use of a lower frequency of 60 Hz stimulation (rather than 130 Hz) in many of these patients.
Eleven of the 47 patients (23.4 percent) had to return to the operating room for reasons other than routine battery replacement. Four out of the 47 patients (8.5 percent) developed infection that required device removal and later reimplantation, and 8.5 percent of patients also reported hardware malfunctions. The most significant complication, said Dr. Alterman, was infection. “All of the infections occurred in patients under the age of 15, which confirmed the findings of an earlier study from the University of California, San Francisco. They also found that most — if not all of their infections — occurred in patients who were under 15 years of age,” he added.
The retrospective study design is a limitation of the current review, Dr. Alterman acknowledged. “It's open-label and not controlled in any way, so one could argue that there is significant placebo effect here. However, other studies — prospective randomized, controlled studies — have demonstrated that stimulation is necessary to achieve effect.” He also added that the study is “not as long term as we would like, but I think that this is the longest follow-up in such a large population so far.” Additionally, the patients all have DYT1 dystonia, which is the most common of the genetic dystonias, but not the most common form of the condition, he said, so these results cannot be generalized to the dystonia population as a whole.
Overall, “we found little evidence — none in our series — of patients having a return of symptoms or exhibiting any loss of efficacy of stimulation over an extended period. We also show that that was true without any significant increases in stimulation requirements,” Dr. Alterman said.
Dr. Alterman added that they still don't know why this treatment works. “Because of MRI safety issues, the young age of many of our patients, and other factors, we have very little functional imaging data documenting the physiologic changes in the brain that underlay this response. We don't understand how we're affecting the network, why it takes weeks of stimulation to see the effects — as opposed to minutes or even seconds as we see in tremor or Parkinson's disease.”
Once they develop an understanding of physiologic changes induced by DBS, he added, it will “give us clues to potentially understand how we might deliver the therapy better, and perhaps give us a means of selecting patients in other dystonia categories that would be responsive to the surgery.”
“Previously the only available treatment [for dystonia patients] was oral trihexyphenidyl and intrathecal baclofen, which were fraught with serious adverse events,” Janis Miyasaki, MD, associate clinical director of the Movement Disorders Centre at Toronto Western Hospital in Canada, told Neurology Today. In her own center in Toronto, Dr. Miyasaki said, they implanted the first DYT1 patient (a child) in the 1990s. She added that Dr. Alterman's findings were in line with her clinical experience.
“This is an interesting single-center study and as such is prone to bias by its open-label nature, single site, and perhaps more homogeneous patients compared to those seeking surgery elsewhere,” she pointed out. “The authors did include very young patients in this study, however the numbers are small. To make truly meaningful recommendations, a multicenter collection of all generalized dystonia patients should be reported.”
Zoltan Mari, MD, assistant professor of neurology and interim director of the Movement Disorders Division of Johns Hopkins University, noted that the potential of DBS in DYT1 dystonia had been demonstrated by others, but this study differed from previous research in two respects: it demonstrated that there is no consistent loss of long-term benefit, and the investigators used lower than conventional stimulation frequencies, 72 Hz, for the procedure.
Dr. Mari pointed out that the investigators excluded DYTI negative generalized dystonia patients. “Those patients are phenotypically very similar, essentially identical to their DYT1 gene positive counterparts,” he wrote in an e-mail to Neurology Today. “It would be very important to know if they have similar DBS outcomes.”
One strength of the study, said Mwiza Ushe, MD, an instructor in the Division of Movement Disorders at Washington University in St. Louis, was the homogeneous patient population with genetically confirmed DYT1 dystonia, so the findings are easily translatable to DYT1 patients.
Nevertheless, “this is a very small and special patient population which is meticulously cared for by these physicians,” he pointed out, so the study investigators offer a great “proof of concept and they are to be commended for their patient care. However, it does raise the concern of how we can generalize their experience to other centers and then to less academic practices.” Another limitation, he added, is that the report does not provide the reasons why some patients were chosen or not chosen to receive GPi DBS.
Dr. Ushe said he was looking forward to future reports from this group “as their cohort continues to age with GPi DBS. While they had 47 patients in the study, only 24 completed four years of follow up. It will be nice to see many of these patients at 10 years of follow up to determine how truly long-lasting this benefit is,” he said.
Additionally, future research, Dr. Miyasaki said, should look at the minimum age for effective surgery as well as what to do as the child ages — “for example, do the leads require adjustment?”
Dr. Mari agreed that more prospective studies are needed to review the durability of benefits, and also to determine whether GPi is the best target for stimulation.
THE BURKE-FAHN-MARSDEN DYSTONIA RATING SCALE
* The BFMDRS-motor score (range, 0-120) is the sum of 9 body region subscores, which were grouped into 4 anatomical areas: face (eyes and mouth), speech and swallowing (SS), axial (neck and trunk), and limbs.
* The total BFMDRS-disability score (range, 0-30) is the sum of individual ratings for 7 activities: speech, handwriting, and the degree of dependence with respect to hygiene, dressing, feeding, swallowing, and walking. Higher scores indicate worse motor impairment and disability.
—Source: Isaias IU, Alterman RL, Tagliati, M. Deep Brain Stimulation for Primary Generalized Dystonia. Arch Neurol 2009; 66(4):465-470.
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