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In the Clinic-Parkinson's Disease
Bilateral Deep Brain Stimulation Improves Non-Motor Symptoms of Parkinson's Disease Two Years After Surgery

ARTICLE IN BRIEF

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DR. MELISSA J. NIRENBERG: “The reader should be aware of study limitations, including the fact that this was an observational trial, and there was no comparison group. The outcome measures were subjective (self-reported and clinician-based scales), and neither the subjects nor the clinicians were blinded to the intervention. The size of the cohort was large for a DBS study, but still only 67 subjects.”

Researchers reported that daytime sleepiness, bladder control, ability to identify odors, and other non-motor symptoms associated with Parkinson's disease improved 24 months after surgery for deep brain stimulation.

Parkinson's disease (PD) patients who received bilateral subthalamic nucleus deep brain stimulation (DBS) experienced improvement in non-motor symptoms of the disease 24 months after the surgery, according to the Feb 21 online issue of Movement Disorders.

Among non-motor symptoms that improved were daytime sleepiness, bladder control, the ability to identify odors, and excessive sweating, and these improvements correlated with their improved quality of life.

Clinicians working on inpatient units at three sites (Cologne, Germany; Manchester, UK; and London, UK) recruited 67 patients with PD between 2013 and 2014 and performed bilateral DBS on them. They then assessed them for severity of motor and non-motor symptoms as well as quality of life at baseline, and then at five and 24 months after they received DBS.

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DR. ANDREW FEIGIN: “Though these data are compelling, it remains uncertain if the findings are specific or simply reflect that these advanced patients generally feel better after DBS and this general sense of well-being is being captured in these non-motor scales.”

“Deep brain stimulation had significant beneficial effects on non-motor symptoms in patients with Parkinson's disease, and this effect was sustained over 24 months in the clinician-rated assessment of Non-Motor Symptoms Scale (NMSS),” lead author Haidar S. Dafsari, MD, honorary research fellow in the neurology department at the University Hospital Cologne in Germany, told Neurology Today.

Dr. Dafsari and colleagues found that scores on the NMSS, which measures various non-motor symptoms such as cardiovascular, sleep/fatigue, mood/apathy, perceptual problems/hallucinations, attention/memory, gastrointestinal symptoms, urinary symptoms, and sexual function, improved significantly from baseline to the five-month follow-up. The same was true for the self-reported Non-Motor Symptoms Questionnaire (NMSQ) (p< 0.001).

At the five-month follow-up, the researchers found significant improvements for the sleep/fatigue, perceptual problems/hallucinations, urinary, and miscellaneous domains (all p≤ 0.008), again with improvements in inability to taste or smell (p=0.002) and excessive sweating (p=0.001). [For more data from the study, see “By the Numbers: Data on DBS and Non-Motor Symptoms.”]

Subsequent decrements in gains from five to 24-month follow-up were significant for NMSQ (p=0.005).

Dr. Dafsari speculated this rebounding effect might be an effect of the fine gradation of the NMSS, which he noted can detect smaller changes than the NMSQ. “However, it is also possible that the self-perceived non-motor symptoms burden might differ from the clinician-rated burden, possibly because over time the subjective reference point of symptom severity might change,” he said.

How exactly might subthalamic nucleus DBS work to improve non-motor symptoms of PD? Dr. Dafsari suggested that a direct modulation of basal ganglia-thalamo-cortical loops could be underlying the changes, or that a spread of neurostimulation current to other nuclei or brain regions in proximity of the subthalamic nucleus — the pedunculopontine nucleus or the thalamus — could improve sleep.

The improvement in symptoms may also be due to an indirect effect via changes of the medical regimen of dopaminergic medication, he noted. In addition, “deep brain stimulation may influence some non-motor symptoms via more specific mechanisms such as sensory gating, as in the case with pain or auditory symptoms,” Dr. Dafsari said.

He noted that previous studies in the general Parkinson's disease population have shown that, compared to motor symptoms, non-motor symptoms are more strongly correlated to quality of life, which also held true for his cohort of patients.

“One has to acknowledge that the indication for DBS is based on motor complications and medication-refractory motor symptoms such as tremor. Nonetheless, to ensure a holistic treatment of all aspects of Parkinson's disease, including motor and non-motor symptoms, we advocate routine assessments of non-motor symptoms with standardized, well-established, validated instruments, such as the NMSS and the NMSQ,” said Dr. Dafsari.

The study design limits interpretation of the findings — the sample size is small at 67, and the trial was observational, and non-randomized. The clinical rating scales were also performed by unblinded researchers.

“Further prospective studies are required to confirm our findings,” Dr. Dafsari said, noting that despite the small sample size, “the study is one of the largest in studies of its kind, and the multicenter design of our study is likely to reduce systematic bias caused by single-center studies.”

To further elucidate his results, he noted, he and his team plan to focus on the imaging data to investigate the neuroanatomical substrates and underlying mechanisms of the effects of DBS on specific non-motor domains. “Furthermore, with increasing cohort size, more sophisticated statistical methods can be applied focusing on specific non-motor aspects as well as motor and non-motor clinical subtypes,” he said.

The study was funded by the German Research Foundation, the National Institute of Health Research Mental Health Biomedical Research Centre and Dementia Unit at South London, and Maudsley NHS Foundation Trust and King's College London. In addition, an unrestricted peer-reviewed educational grant was provided to support coordination of the UK data set from Medtronic.

EXPERT COMMENTARY

“These findings are interesting and directly relevant to patient care,” Melissa J. Nirenberg, MD, PhD, FAAN, told Neurology Today.

Dr. Nirenberg, who is adjunct professor of neurology at NYU Langone Health and chief medical officer of the New York Stem Cell Foundation Research Institute, said it was significant that the authors demonstrated that some of the non-motor symptoms of PD showed persistent improvement even 24 months after DBS.

“The reader should be aware of study limitations, including the fact that this was an observational trial, and there was no comparison group,” she noted. “The outcome measures were subjective (self-reported and clinician-based scales), and neither the subjects nor the clinicians were blinded to the intervention. The size of the cohort was large for a DBS study, but still only 67 subjects,” Dr. Nirenberg said.

She also commented that some of the observed symptomatic improvement may have been indirect, due to motor benefit, reduction of motor fluctuations, or decreases in medication doses, rather than a direct effect of DBS on non-motor function.

“These findings are a welcome addition to our knowledge about the long-term benefits of DBS,” Dr. Nirenberg said.

Andrew Feigin, MD, who is professor of neurology and co-director of the Marlene and Paolo Fresco Institute for Parkinson's and Movement Disorders at NYU Langone Health, said the results lend support to earlier studies finding that subthalamic nucleus DBS may improve non-motor symptoms in patients with advanced Parkinson's disease, and that these benefits persist up to two years after surgery.

“In addition to the overall score on the Non-Motor Symptom Scale, specific non-motor symptoms that remained improved over baseline at 24 months included sleep/fatigue and urinary problems. Though these data are compelling, it remains uncertain if the findings are specific or simply reflect that these advanced patients generally feel better after DBS and this general sense of well-being is being captured in these non-motor scales,” Dr. Feigin said.

He also noted that due to the fact that the study was unblinded and non-randomized, “Conclusions regarding treatment effects need to be viewed with some caution...Nonetheless, these observations suggest DBS may provide broader benefits beyond motor improvements.”

DISCLOSURES

Dr. Dafsari's work was funded by the Prof. Klaus Thiemann Foundation of the German Society of Neurology (stipend), the Felgenhauer Foundation (stipend), and the German Research Foundation (Clinical Research Group 219; salary). Drs. Nirenberg and Feigin had no disclosures relevant to this study.

BY THE NUMBERS: DATA ON DBS AND NON-MOTOR SYMPTOMS

  • At baseline and the 24-month follow-up scores, there were no significant changes for the NMSQ, whereas the clinician-rated NMSS total score improved significantly (p=0.018).
  • All motor and quality of life outcomes also improved at the five-month follow-up (all p<0.001).
  • NMSS total score improvement was significantly correlated with improvements with quality of life at the two-year mark, as measured by the Parkinson's Disease Questionnaire-8 (p=0.012).
  • In an exploratory analysis of the NMSS comparing baseline with the 24-month follow-up scores, there were significant improvements for the sleep/fatigue (p<0.001), urinary (p=0.022), and miscellaneous (p<0.001) domains. The “inability to taste or smell” (p<0.001) and “sweating” (p=50.018) significantly improved from baseline to the 24-month follow-up.
  • In the sleep/fatigue domain, “falling asleep during daytime activities” (p=0.001), “fatigue” (p=0.016), and “difficulties falling or staying asleep” (p<0.001) improved.

LINK UP FOR MORE INFORMATION:

• Dafsari HS, Silverdale M, Strack M, et al; for the EUROPAR and the IPMDS Non Motor PD Study Group. Nonmotor symptoms evolution during 24 months of bilateral subthalamic stimulation in Parkinson's disease https://onlinelibrary.wiley.com/doi/abs/10.1002/mds.27283. Mov Disord 2018; 33(3):421–430.