Patient With Parkinsonism, Gene Mutation Improved With DBS

Pauline Anderson

November 22, 2016

Deep-brain stimulation (DBS) of the globus pallidus interna (GPi) significantly improved symptoms in a patient with refractory parkinsonism and a specific genetic mutation.

Researchers believe this is the first case of juvenile-onset levodopa-responsive parkinsonism secondary to a mutation in the spatacsin gene (SPG11) treated with GPi DBS.

They also collected what they think are the first electrophysiologic basal ganglia data in this condition.

"The importance of this report is to alert physicians that if they have a patient with symptoms that resemble Parkinson's disease in early adulthood, with stiffness in the legs, they should consider this mutation," author Adolfo Ramirez-Zamora, MD, Department of Neurology, Albany Medical Center, New York, told Medscape Medical News.

"Although rare, it is something that actually responds to DBS."

Dr Ramirez-Zamora and colleagues describe the case in a report published online November 7 in JAMA Neurology.

The case involved a young woman who presented with progressive gait difficulties that started in adolescence and were characterized by lower-extremity spasticity.

The patient developed more classic parkinsonism symptoms, such as tremors and dystonia, which were initially relieved by carbidopa and levodopa, but her symptoms eventually worsened.

Dr Ramirez-Zamora described her quality of life as "horrible." The effect of medications was short-lived, he said; she was slow when not taking medications, but in constant movement when taking them. "It was roller-coaster every day; up and down every few hours."

Results of genetic testing revealed a mutation in the SPG11 gene in chromosome 15. SPG11, an autosomal recessive condition, is among a group of "very complex" genetic conditions called hereditary spastic paraplegia, said Dr Ramirez-Zamora.

DBS Outcome

After bilateral GPI DBS, the patient's dystonia, dyskinesia, and tremors completed resolved, and she had marked improvement in parkinsonism and motor fluctuation. At 30 months after the intervention, she had more than 80% improvement in Unified Parkinson's Disease Rating Scale III motor scores in her "off" medication state, without dyskinesia during her "on" medication state.

These results are "remarkable," commented Dr Ramirez-Zamora. "Her excessive movements went away, her tremors went away, and the speed of her movements without medications improved dramatically."

The improvement in symptoms "was sustained for the next 2 and a half to 3 years," he added. "So it was not just a transient effect of the stimulation."

The procedure was well tolerated, without cognitive adverse events or complications.

Lower-extremity spasticity was not affected by the DBS procedure, and the patient's difficulty with gait and spasticity worsened over time.

The report was also unique in that, for the first time, researchers looked at brain electrical activity in this condition, according to Dr Ramirez-Zamora.

The patient's condition resembles Parkinson's disease (PD), but "the neuronal firing — the bursting of neuronal cells — is totally different," he said. "Although it looks like PD, this is a totally different disease that is affecting the brain differently."

The bursting index in this patient was significantly increased compared with that of patients with dystonia or PD, and such an abnormality may play a role in her motor symptoms.

"Bait and Switch"

Use of DBS in this case was off label. In a Viewpoint piece in the same issue of JAMA Neurology, P. Justin Rossi, BA, Center for Movement Disorders and Neurorestoration, University of Florida, Gainesville, and colleagues argue for the resolution of current "bait-and-switch tactics" by insurance companies — the preapproval and subsequent denial of off-label DBS coverage.

"Physicians (and patients) are baited to believe that coverage will be provided and then when the decision to subsidize switches and payment is denied, physicians must explain to patients and their families that coverage was refused and explain why."

This financial uncertainty can be stressful and poses an undue burden on patients, families, and physicians, say the authors.

Rossi and his colleagues retrospectively reviewed claims data for all DBS procedures performed during a 10-year period at a university-based movement disorder center. During that time, 74 DBS procedures were performed on 26 patients for non–US Food and Drug Administration–approved indications (including Tourette's syndrome, Alzheimer's disease, and obsessive-compulsive disorder).

The costs of 23 surgeries were covered by dedicated research grants. Of the remaining procedures requiring third-party coverage, 72% of lead implantations and 62.5% of implantable pulse generator procedures were not reimbursed, despite preapproval of all cases.

"A striking finding of our review was that greater than half of nonreimbursed procedures could be attributed to a government insurance provider's failure to pay," Rossi and coauthors write.

Dr Ramirez-Zamora said all neurologists have faced situations where insurance companies refuse to pay for DBS "when it's clear that it's the right thing to do."

He pointed out that those making decisions on coverage "are not physicians with experience with DBS; they are administrative people who are checking boxes."

That needs to change, he said. "There needs to be a better dialogue with insurance companies."

He pointed out that there is "plenty" of evidence of the long-term cost-benefits of DBS. "If you can prevent some of the complications of medications, then it leads to less expenses."

Dr Ramirez-Zamora reports receiving consultant honoraria from Teva Pharmaceuticals; receiving the Phyllis E. Dake Endowed Chair in Movement Disorders and support from Medtronic and Boston Scientific for the Department of Neurology, Albany Medical Center; and participating as a site principal investigator and/or co-investigator for several National Institutes of Health– and industry-sponsored trials over the years without receiving honoraria. Mr Rossi has disclosed no relevant financial relationships.

JAMA Neurol. Published online November 7, 2016. Letter, Viewpoint

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