Benefit of DBS in Parkinson's Sustained at 10 Years

Susan Jeffrey

August 09, 2011

August 9, 2011 — Ten-year follow-up of patients with Parkinson's disease (PD) treated with subthalamic nucleus deep brain stimulation (STN-DBS) shows sustained motor improvement associated with treatment. However, part of the initial benefit wore off over time, mostly due to a "striking" progressive loss of stimulation benefit on axial signs, the researchers report.

"To our knowledge, this is the first class III study (in which the outcome was independently assessed by a rater who was not part of the treatment team) focusing on 10-year postoperative motor outcomes of bilateral STN-DBS in advanced PD," the researchers, with senior author Elena Moro, MD, PhD, from the Movement Disorders Center at Toronto Western Hospital at the University of Toronto, Ontario, Canada, and colleagues conclude.

Their results provide "evidence that stimulation-induced motor improvement was sustained overall at 10 years, although part of the initial benefit wore off mainly because of progressive loss of benefit on axial signs over time."

The findings are published online August 8 in the Archives of Neurology. The first study author is Anna Castrioto, MD, from the Università degli Studi di Perugia, Italy.

Improvement Sustained

Previous studies have shown motor improvement with STN-DBS is sustained up to 8 years after surgery, although part of the initiate benefit progressively deteriorates, mainly due to worsening of axial signs, the study authors write.

The current study included follow-up to 10 years of 41 patients who received their surgery at the Movement Disorders Center at Toronto Western Hospital. All had advanced PD and bilateral STN-DBS.

Assessment was done using the Core Assessment Program for Surgical and Interventional Therapies in Parkinson's Disease protocol, and patients were videotaped at baseline and then at 1, 5, and 10 years after surgery. The 10-years video assessments were performed by an independent rater blinded to stimulation and medication condition of the patients.

The primary outcome was the change in blinded Unified Parkinson's Disease Rating Scale (UPDRS) motor scores/subscores between the no medication/stimulation condition vs the no medication/no stimulation condition at 10 years. Secondary outcomes were the changes in blinded UPDRS motor scores between the medication/no stimulation and medication/stimulation conditions, UPDRS II scores, UPDRS IV dyskinesia and motor fluctuations scores, and anti-PD medication dose (levodopa equivalent daily dose) at different points.

Of the 41 patients who underwent operations between 1996 and 2000 at their institution, 18 were available for assessment. Of the 23 remaining patients, 12 were dead: 3 of aspiration pneumonia, 2 of sepsis, 1 of gastric cancer, 1 of arrhythmia, 1 of stroke, and 1 of cerebral bleeding secondary to head trauma. A total of 11 were lost to follow-up, including 9 who were living abroad and unable to return for assessment and 2 lost for unknown reasons.

Comparing baseline characteristics of those available for the study and those lost to follow-up, they found age at disease onset and age at surgery were both significantly higher in the group lost to follow-up, the study authors note. No difference was seen comparing disease duration and sex.

Despite the high numbers lost to follow-up, STN-DBS still significantly improved UPDRS total motor score (P = .007), as well as resting tremor (P =.01), action tremor (P = .02), and bradykinesia (P = .01) subscores.

UPDRS II scores while not taking medication, UPDRS IV dyskinesia and motor fluctuation scores, and the levodopa equivalent daily dose were also significantly reduced compared with baseline, they report.

Axial Signs

As has previously been reported, axial signs showed the most striking progressive loss of stimulation benefit during follow-up.

"Our findings are overall in line with data from several previous 5-year outcome studies, and a more recent study in 20 patients with 8 years of follow-up reporting prolonged benefit of rigidity and tremor but progression of axial signs and thus suggesting lack of neuroprotective effects of stimulation," they write.

"Surprisingly, without stimulation and dopaminergic drugs, only bradykinesia worsened at 10 years compared with the preoperative no medication status, the note. "On the other hand, tremor was improved compared with baseline, suggesting a different effect of STN-DBS on this sign or reflecting the natural decay of tremor during the progression of the disease," the study authors note. "This lack of progressive worsening in the UPDRS total motor scores in the no medication/no stimulation condition (preoperatively vs 5 and 10 years postoperatively) is more likely due to the long-lasting effect of stimulation after switching off the stimulator, although this has not been systematically studied in our patients."

Adverse events were not substantially different at 10 years compared with at 1 and 5 years. Rate of infection was similar to previous reports they note, although 2 patients had a serious device-related infection between years 5 and 10, requiring removal of the lead in one case and the internal pulse generator in the other.

A trend to lose weight that had previously been gained after surgery was seen during follow-up. "Although the reasons are unknown, this weight loss might be related to disease progression," they speculate. Three patients developed impulse control disorders, but all were taking a dopamine agonist at the time, and the disorders resolved on drug withdrawal.

In the last 5 years of follow-up, 4 patients reached diagnostic criteria for dementia, they noted, adding that 10-year cognitive data will be published in a separate paper.

"Although lacking a control group of patients with PD without stimulation, these adverse events appear to be more related to PD progression rather than being stimulation induced," they conclude.

Their study has several limitations, they add, including lack of a control group and double-blind assessments, a high drop-out rate, and relatively small sample size. "Nevertheless, our findings further support the long-term response to STN stimulation in patients with advanced PD, showing a prolonged motor improvement up to 10 years."

Results 'Reassuring'

Asked for comment on these findings, Kapil D. Sethi, MD, professor of neurology and director of the Movement Disorders Program at the Medical College of Georgia in Augusta, pointed out, as the researchers did, that the study has several limitations, including a high drop-out rate and small numbers of patients followed up to 10 years.

"However, it is reassuring that many of the core motor features continue to respond to STN-DBS," he told Medscape Medical News.

The mechanism of improvement in the no medication/no stimulation period during the baseline 10 years previously probably reflects residual stimulation effects or a microsubthalamotomy effect, Dr. Sethi speculated.

"It is clear though, that many of the axial features become less responsive over time and the emergence of nonmotor problems, such as dementia and dysautonomia, causes disability in many patients with STN-DBS," he added. "The lack of definite disease-slowing agents remains a major unmet need in PD."

Dr Moro reports having occasionally received honoraria from Medtronic for lecturing and consultant service. She has received research grant support from the Canadian Institutes of Health Research, CurePSP, and St. Jude Medical. Dr. Sethi is an uncompensated member of the Editorial Advisory Board for Medscape Neurology. He owns stock, stock options, or bonds from Elan Pharmaceuticals Inc; has received grants for clinical research from ACADIA Pharmaceuticals Inc, Boehringer Ingelheim Pharmaceuticals Inc, GlaxoSmithKline, IMPAX Laboratories Inc, and Merck & Co Inc; has served as an adviser or consultant for Boehringer Ingelheim Pharmaceuticals Inc, GlaxoSmithKline, Ipsen, and Novartis Pharmaceuticals Corporation; and has served as a speaker or member of a speaker's bureau for Boehringer Ingelheim Pharmaceuticals Inc, GlaxoSmithKline, Ipsen, and Novartis Pharmaceuticals Corporation.

Arch Neurol. Published online August 8, 2011.