Deep-Brain Stimulation May Be Safe in Parkinson's Dementia

December 20, 2017

Deep-brain stimulation of a novel brain region can be safely performed in patients with Parkinson's disease dementia, and although it may not improve cognition, it does appear to have benefits on other Parkinson's symptoms, a new study suggests.

"This was a proof-of-concept study. We have demonstrated that it is possible to use deep-brain stimulation safely in patients with Parkinson's disease dementia by targeting different areas of the brain," senior author, Thomas Foltynie, MD, the National Hospital for Neurology and Neurosurgery, London, United Kingdom, told Medscape Medical News.

"We didn't see an improvement in cognition as hoped for, but we did show benefits on movement symptoms and on hallucinations. These results open up the possibility of using deep-brain stimulation in this population for whom it has so far not been recommended."

The study was published in JAMA Neurology on December 18.

Dr Foltynie explained that deep-brain stimulation treatment in Parkinson's is known to help with the movement issues characteristic of the disease, but stimulation of the usual target — the subthalamic nucleus — also carries a risk of upsetting other brain functions, including cognition, so it is not performed in patients with Parkinson's dementia.

For the current study, the researchers targeted a different part of the brain: the nucleus basalis of Meynert. "Animal studies have suggested that stimulation of this area leads to an increase in acetylcholine throughout critical regions of the brain and improves memory, and there has been a case report in which brain stimulation of the nucleus basalis of Meynert showed a striking increase in cognitive performance in a dementia patient," Dr Foltynie said. "This part of the brain represents a novel target, and we wanted to pursue this further."

The nucleus basalis of Meynert is just below another region of the brain, the globus pallidus, which has also been used as a target for deep-brain stimulation. "Stimulation of the globus pallidus is also associated with benefits on movement in Parkinson's and is more forgiving in terms of cognitive issues, so in our study we placed the stimulation electrodes so that they went through both the globus pallidus and the nucleus basalis of Meynert, with contacts in both sites.  These were activated separately so we could discern which region was associated with any effects seen," Dr Foltynie noted.   

"Our hypothesis was that by selecting new regions as targets for deep-brain stimulation we may be able help patients with Parkinson dementia with both movement and cognition symptoms."

The randomized, double-blind, crossover clinical trial involved six patients (average age, 65 years) with Parkinson's disease dementia who underwent surgery for electrode implantation and were assigned to receive either low-frequency (20-Hz) active stimulation to the nucleus basalis of Meynert or sham stimulation for 6 weeks, followed by the opposite treatment for 6 weeks.

Results showed that surgery and stimulation were well tolerated by all six patients, with no serious adverse events during the trial. No consistent improvements were observed in the primary cognitive outcomes or in results of resting state functional MRI.

However, scores on the Neuropsychiatric Inventory improved by 5 points with the stimulation. This improvement was driven primarily by a reduction in hallucinations subscale scores in two patients.

In the paper, the researchers report that the two patients with hallucinations both experienced "near-complete cessation of visual hallucinations after surgery when nucleus basalis of Meynert stimulation was turned on, followed by a resurgence of hallucinations when stimulation was subsequently turned off."

Dr Foltynie elaborated: "Two patients with quite troublesome hallucinations showed a dramatic improvement. This was an unexpected benefit. However, this was a secondary outcome, and we have to be cautious about overinterpreting these observations. But I would say it is something to be investigated in future studies."

Three patients showed improvement in levodopa-induced dyskinesias during on-stimulation.

The researchers suggest this may be explained by spread of current from the nucleus basalis of Meynert to the overlying globus pallidus. They add that conventional deep-brain stimulation of the globus pallidus for dyskinesia control in Parkinson disease is delivered at high frequency, "so the finding that low-frequency stimulation directed toward the nucleus basalis of Meynert also attenuated dyskinesias warrants further study."

Dr Foltynie noted that two patients went on to receive long-term stimulation of the globus pallidus and showed clear movement benefits.  

He explained that deep-brain stimulation works best for the Parkinson's symptoms of slowness, stiffness, and tremor but does not have much impact on balance and freezing. It is appropriate for only a small percentage of patients with Parkinson's disease — probably less than 10%.

"There is a window of opportunity — we don't use it in early disease as symptoms can be well controlled with medication and we wouldn't want to expose these patients to the risk of surgery. But when patients start to become refractory to dopamine therapies, deep-brain stimulation can still show a benefit.  Although when patients deteriorate further then it too will become ineffective."

He noted that it is easier to place the electrodes correctly in the younger brain, where there hasn't been too much shrinkage. "The best candidates are patients with early-onset Parkinson's disease — those in their 50s or 60s — who could have benefit for up to 10 years. While not many of these younger patients will have Parkinson's dementia, there will be some who do and our study opens up this therapy to them. "

He cautioned, however, that such treatment should still be viewed as experimental and should be performed only at one of the specialist centers with particular expertise in deep-brain stimulation. 

What Now for Deep-Brain Stimulation in Dementia?

Dr Foltynie said the future for deep-brain stimulation in dementia is uncertain. "A Canadian group is looking at targeting stimulation to the fornix area of the brain in Alzheimer's, but their results have not been encouraging either. Other research has suggested that while high-frequency stimulation in the subthalamic nucleus makes dementia worse, using low-frequency stimulation may show some benefit, and further research on this approach is ongoing," he reported.

In an accompanying editorial, Wissam Deeb, MD, Michael S. Okun, MD, and Leonardo Almeida, MD, Center for Movement Disorders and Neurorestoration, University of Florida, Gainesville, state: "Although the primary outcome of this study was not met, these results challenge the consensus in the field that DBS [deep-brain stimulation] is contraindicated in PDD [Parkinson's disease dementia]."

They add: "The authors provide evidence for the safety and the tolerability of nucleus basalis of NBM [Meynert] DBS, albeit in a small number of patients. There will need to be more work to refine the target and trajectory, as well as programming strategies (duty cycle, frequency, and pulse shapes). The findings from the current study will require replication in larger cohorts. Finally, this and future DBS studies in Parkinson's disease dementia could provide insights into the cholinergic network underpinning cognitive dysfunction."

This study was funded by a grant from the Brain Research Trust and was sponsored by University College London. Dr Foltynie reports receiving honoraria from Medtronic, St Jude Medical, Profile Pharma, Bial, AbbVie Pharmaceuticals, UCB Pharmaceuticals, and Oxford Biomedica.

JAMA Neurol. Published December 18, 2017. Full text, Editorial

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