Dual-lead deep brain stimulation decreases MS-related tremor in some patients

By Lorraine L. Janeczko

NEW YORK (Reuters Health) - Dual-lead deep brain stimulation (DBS) can safely decrease tremor related to multiple sclerosis (MS) in selected patients, a pilot study from the University of Florida in Gainesville suggests.

"The dual-lead thalamic stimulation technique used in this study appears to be safe and to hold substantial promise as an effective treatment for appropriately selected patients with debilitating tremor secondary to multiple sclerosis," principal investigator Dr. Kelly D. Foote told Reuters Health.

"MS tremor tends to be severe and disabling. It effects an estimated 30% of people with MS, and it responds poorly to medications, traditional thalamotomy, or single-lead DBS treatments that tend to be effective at suppressing the more common (and generally less severe) tremors associated with essential tremor or Parkinson's disease," he said in an email.

"While it is important to note that dual-lead thalamic DBS is not effective for treating cerebellar ataxia, a very common loss of coordinated motor control in MS, it does offer new hope to a subset of MS patients who have lost autonomy and quality of life due to severe tremor without significant cerebellar ataxia," he added.

Dr. Foote and his colleagues conducted a single-blind prospective pilot study at a university clinic to investigate the safety and efficacy of dual-lead thalamic DBS (the VIM lead targeting the ventralis intermedius–ventralis oralis posterior nucleus border, and the VO lead targeting the ventralis oralis anterior–ventralis oralis posterior border) to treat MS tremor.

As reported online June 20 in Lancet Neurology, over almost seven years, they enrolled 12 patients, ages 18 to 79, with refractory MS tremor.

Before the patients underwent surgery to implant both leads, they were randomly assigned to receive either VIM-only or VO-only stimulation during the first three months after their surgery. Everyone who participated in the study except the programming nurse was masked to the choice of lead. One patient from the VO-only group had the DBS explanted due to an infection and was excluded from the primary outcome assessment.

One month after their baseline visit, the participants were implanted with the dual lead DBS system. In a second surgery three to four weeks later, a pulse generator and two extension cables were implanted.

The patients then received three months of continuous stimulation of either the VIM or VO lead. At the end of three months, they received a safety assessment of their tremor during optimized VIM or VO lead stimulation using the Tolosa-Fahn-Marin Tremor Rating Scale (TRS).

After this visit, both leads were activated in all patients for three more months and optimally programmed during serial visits.

At six months, the patients retook the TRS, and mood and psychological tests were given under four stimulation conditions: VIM on, VO on, both on, and both off, in random order.

Each of four stimulation settings were tested over four consecutive days, with stimulation settings held constant for at least 12 hours before testing. Analysis was by intention to treat.

With both leads activated, the mean TRS score at six months dropped 29.6% from the mean baseline score (57.0 to 40.1; t=–0.28; p=0.03). Three patients did not respond to the surgery, and one died two years after surgery of unrelated causes.

The most common adverse events included headache and fatigue. Serious adverse events included late MS exacerbation and transient altered mental status in one patient and a superficial wound infection in another.

"Patients with severe MS tremor (and without significant cerebellar ataxia) may now have a new effective treatment where none existed before, but we are also hopeful that this technique might prove to be effective for the suppression of other severe tremor disorders that tend to respond less well to traditional single-lead DBS techniques, such as post-traumatic tremor, post-stroke tremor, and very severe cases of essential tremor," Dr. Foote said.

A strength of the study, Dr. Foote said, is its trial design, and a limitation is the small number of patients involved.

"We believe our experience with this study has improved our ability to identify MS patients with severe ataxia and avoid subjecting them to the risks of surgery when the functional outcome will be predictably poor," he said.

"It is important to emphasize that, while the results of this study warrant legitimate optimism regarding this new treatment modality for severe tremors, not all patients with severe MS tremor are likely to benefit from this treatment," Dr. Foote cautioned. "Patient selection is critically important because 30% of MS patients develop tremor, but 70% develop cerebellar ataxia. So most patients with severe tremor will also have some ataxia."

Dr. Alfonso Fasano, who wrote a commentary that accompanied the study, told Reuters Health that, while it's well known that thalamic DBS improves the tremor caused by MS, this study is novel because it's the first prospective randomized study to investigate DBS for this category of disease and it's the first to systematically assess the effect of dual targeting.

Dr. Fasano, of the University of Toronto in Ontario, Canada, said in an email that he values the work by the authors of this study. "However," he noted, "I feel that it is important to emphasize very important points: 1) a reduction of tremor scores, as shown in the paper, is not necessarily good for the patients because it might not translate into functional improvement; 2) the 6-month follow-up of the study was rather short; and 3) DBS is not risk-free in general and implanting two electrodes might increase risk without necessarily always helping. In fact, in some patients enrolled in the study, activating one electrode was as effective as using two simultaneously."

"I strongly believe that it is important to temper the enthusiasm of the medical community, patients and their families," Dr. Fasano advised. "Patients with MS have had enough disappointments in the past, very often on the basis of very poor scientific data. Certainly, that is not the case with this study; nonetheless, more studies are undoubtedly needed."

Dr. Foote's group is now exploring the feasibility of closed-loop adaptive DBS for essential tremor, including the use of dual-lead thalamic DBS to rescue patients with severe essential tremor.

The study was funded by the U.S. National Institutes of Health, the Cathy Donnellan, Albert E Einstein, and Birdie W. Einstein Fund, and the William Merz Professorship. The deep brain stimulation hardware was donated by Medtronic.

SOURCE: http://bit.ly/2uwTE2z and http://bit.ly/2uGbYqo

Lancet Neurol 2017.

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