Pallidal Connectivity Profiling of Stimulation-Induced Dyskinesia in Parkinson's Disease.

OBJECTIVES: The aim of this study is to identify anatomical regions related to stimulation-induced dyskinesia (SID) after pallidal deep brain stimulation (DBS) in Parkinson's disease (PD) patients and to analyze connectivity associated with SID. METHODS: This retrospective study analyzed the clinical and imaging data of PD patients who experienced SID during the monopolar review after pallidal DBS. We analyzed structural and functional connectivity using normative connectivity data with the volume of tissue activated (VTA) modeling. Each contact was assigned to either that producing SID (SID VTA) or that without SID (non-SID VTA). Structural and functional connectivity was compared between SID and non-SID VTAs. "Optimized VTAs" were also estimated using the DBS settings at 6 months after implantation. RESULTS: Of the 68 consecutive PD patients who underwent pallidal implantation, 20 patients (29%) experienced SID. SID VTAs were located more dorsally and anteriorly compared with non-SID and optimized VTAs and were primarily in the dorsal globus pallidus internus (GPi) and dorsal globus pallidus externus (GPe). SID VTAs showed significantly higher structural connectivity than non-SID VTAs to the associative cortex and supplementary motor area/premotor cortex (P < 0.0001). Simultaneously, non-SID VTAs showed greater connectivity to the primary sensory cortex, cerebellum, subthalamic nucleus, and motor thalamus (all P < 0.0004). Functional connectivity analysis showed significant differences between SID and non-SID VTAs in multiple regions, including the primary motor, premotor, and prefrontal cortices and cerebellum. CONCLUSION: SID VTAs were primarily in the dorsal GPi/GPe. The connectivity difference between the motor-related cortices and subcortical regions may explain the presence and absence of SID. © 2020 International Parkinson and Movement Disorder Society.

Longitudinal follow-up with VIM thalamic deep brain stimulation for dystonic or essential tremor.

OBJECTIVE: To assess longitudinal tremor outcomes with ventral intermediate nucleus deep brain stimulation (VIM DBS) in patients with dystonic tremor (DT) and to compare with DBS outcomes in essential tremor (ET). METHODS: We retrospectively investigated VIM DBS outcomes for 163 patients followed at our center diagnosed with either DT or ET. The Fahn-Tolosa-Marin tremor rating scale (TRS) was used to assess change in tremor and activities of daily living (ADL) at 6 months, 1 year, 2-3 years, 4-5 years, and ≥6 years after surgery. RESULTS: Twenty-six patients with DT and 97 patients with ET were analyzed. Compared to preoperative baseline, there were significant improvements in TRS motor up to 4-5 years (52.2%; p = 0.032) but this did not reach statistical significance at ≥6 years (46.0%, p = 0.063) in DT, which was comparable to the outcomes in ET. While the improvements in the upper extremity tremor, head tremor, and axial tremor were also comparable between DT and ET throughout the follow-up, the ADL improvements in DT were lost at 2-3 years follow-up. CONCLUSION: Overall, tremor control with VIM DBS in DT and ET was comparable and remained sustained at long term likely related to intervention at the final common node in the pathologic tremor network. However, the long-term ADL improvements in DT were not sustained, possibly due to inadequate control of concomitant dystonia symptoms. These findings from a large cohort of DT indicate that VIM targeting is reasonable if the tremor is considerably more disabling than the dystonic features. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that VIM DBS improves tremor in patients with DT or ET.

Tailored deep brain stimulation optimization for improved airway protective outcomes in Parkinson's disease.

There is no consensus regarding the effects of deep brain stimulation (DBS) surgery on swallowing outcomes in Parkinson's disease (PD). No prospective studies have compared airway protective outcomes following DBS to the subthalamic nucleus (STN) versus globus pallidus interna (GPi). A recent retrospective study described swallowing outcomes pre- and post-STN vs. GPi DBS in a cohort of 34 patients with PD. The results revealed that the patients who received GPi DBS maintained their swallowing function post-DBS, while those in the STN group significantly worsened in swallowing safety. As DBS surgery becomes a common management option in PD it is important to understand the impact of DBS on airway protective outcomes; especially given that aspiration pneumonia is the leading cause of death in this population. We present a case report in which optimizing DBS settings with the goal of improving laryngeal function resulted in immediate improvements to swallowing safety.

Deep Brain Stimulation in a Case of Mitochondrial Disease.

BACKGROUND: DBS has proven to be an effective therapy for Parkinson's disease, essential tremor, and primary dystonia. Mixed results have been reported in case series for other hyperkinetic disorders, and sparse data are available regarding secondary movement disorders. We report on the clinical effects of bilateral globus pallidus internus (GPi) DBS, a progressive mitochondrial cytopathy. METHODS: A single patient with myoclonus and dystonia syndrome secondary to a mitochondrial cytopathy with history of perinatal hypoxia was identified from our University of Florida DBS database. Demographics, clinical, surgical, and DBS data were documented. RESULTS: At 6 months post-DBS, we observed a 32% (361 to 527) improvement on quality of life (36-item Medical Outcome Study Short-Form Health Survey; SF-36). Objective clinical scales revealed a 33% (143 to 96) improvement in the Unified Myoclonus Rating Scale (UMRS) total score. The UMRS action myoclonus subsection revealed a 29% (69 to 46) improvement. No significant changes were observed in the Burke-Fahn-Mardsen Dystonia Rating Scale (BFMDRS). After 1-year follow-up, a worsening of 59% (527 to 215) was observed in the SF-36 scale, of 19% (28.5 to 35) in the BFMDRS, and of 23% (96 to 124) in the UMRS. However, the frequency and intensity of action myoclonus scores remained lower when compared to baseline scores. CONCLUSIONS: Although we observed a loss of benefit in the long term for most quality-of-life and clinical outcomes, the DBS effects on action myoclonus seemed to remain stable. Longer follow-up studies are necessary to confirm our short-term and unblinded findings.

Atrophy and other potential factors affecting long term deep brain stimulation response: a case series.

OBJECTIVE: To describe three DBS cases which presented with new side effects or loss of benefit from stimulation after long-term follow-up and to discuss the potential contributing factors. METHODS: A University of Florida (UF) database (INFORM) search was performed, identifying three patients, two Parkinson's disease (PD) and one Essential Tremor (ET), with an unexpected change in long-term programming thresholds as compared to initial evaluation. Clinical follow-up, programming, imaging studies, and lead measurements were reviewed. The UF Institutional Review Board (IRB) approved this study. RESULTS: A substantial increase in the 3rd ventricular width (120%), Evans index (6%), ventricular index (5%), and cella media index (17%) was uncovered. A change in thresholds across lead contacts with a decrease in current densities as well as a relative lateral change of lead location was also observed. Hardware-related complications, lead migration, and impedance variability were not identified. CONCLUSIONS: Potential factors contributing to long-term side effects should be examined during a DBS troubleshooting assessment. Clinicians should be aware that in DBS therapy there is delivery of electricity to a changing brain, and atrophy may possibly affect DBS programming settings as part of long-term follow-up.

Gait variability magnitude but not structure is altered in essential tremor.

Essential tremor (ET) is a common tremor disorder affecting postural/action tremor of the upper extremities and midline. Recent research revealed a cerebellar-like deficit during tandem gait in persons with ET, though spatiotemporal variability during normal gait in ET has been relatively ignored. The first purpose of this study was to investigate gait variability magnitude and structure in ET as compared to healthy older adults (HOA). To address this issue, 11 ET and 11 age-matched HOAs walked on a treadmill for 5min at preferred walking speeds. HOAs walked for an additional minute while speed-matched to an ET participant. The second purpose was to describe the clinical correlates of gait variability in this population. To address this aim, 31 persons with ET walked on a treadmill for 5min and completed the Fahn-Tolosa-Marin Tremor Rating Scale. Gait variability magnitude was derived by calculating coefficients of variation in stride length, stride time, step length, step time, and step width. Gait variability structure was derived using a detrended fluctuation analysis technique. At preferred walking speeds, ET participants walked significantly slower with significantly increased variability magnitude in all five spatiotemporal gait parameters. At speed-matched walking, ET participants exhibited significantly higher step width variability. Gait variability structure was not different between groups. We also observed that gait variability magnitude was predicted by severity of upper extremity and midline tremors. This study revealed that self-selected gait in ET is characterized by high variability that is associated with tremor severity in the upper extremity and midline.

Taking a better history for behavioral issues pre- and post-deep brain stimulation: issues missed by standardized scales.

OBJECTIVES: To screen for potentially underreported behavioral changes in patients with idiopathic Parkinson's disease (PD) pre- and post-deep brain stimulation (DBS), a retrospective data base review was performed. METHODS: In total, 113 patients who underwent unilateral or bilateral DBS at the University of Florida in either subthalamic nucleus or globus pallidus internus for PD were screened for behavioral issues by asking about the presence or absence of seven neuropsychiatric symptoms (panic, fear, paranoia, anger, suicidal flashes, crying, and laughing). RESULTS: There was a high prevalence of fear (16.3%), panic (14.0%), and anger (11.6%) at baseline in this cohort. In the first six months following DBS implantation, anger (32.6%), fear (26.7%), and uncontrollable crying (26.7%) were the most frequent symptoms reported. Those symptoms also were present following six months of DBS surgery (30.2%, 29.1%, and 19.8%, respectively). New uncontrollable crying occurred more in the acute postoperative stage (less than or equal to six months) (p = 0.033), while new anger occurred more in the chronic postoperative stage (greater than six months) (p = 0.017). The frequency of uncontrollable laughing significantly increased with bilateral DBS (p = 0.033). CONCLUSIONS: Many of the neuropsychiatric issues were identified at preoperative baseline and their overall occurrence was more than expected. There was a potential for worsening of these issues post-DBS. There were subtle differences in time course, and in unilateral vs. bilateral implantations. Clinicians should be aware of these potential behavioral issues that may emerge following DBS therapy, and should consider including screening questions in preoperative and postoperative interviews. Standardized scales may miss the presence or absence of these clinically relevant issues.

GPi and STN deep brain stimulation can suppress dyskinesia in Parkinson's disease.

OBJECTIVES: To compare subthalamic nucleus (STN) to globus pallidus internus (GPi) deep brain stimulation (DBS) for control of motor fluctuations and for potential dyskinesia-suppressing qualities. METHODS: We conducted a retrospective database review of all patients who underwent GPi or STN DBS for idiopathic Parkinson's disease. Direct dyskinesia suppression (dDS) was defined as improvement in dyskinesia subscore of the unified Parkinson's disease rating scale (UPDRS) part IV (items 32-34), despite lack of reduction in dopaminergic medication dosage. We analyzed the data using methods appropriate for a case-control study. RESULTS: A total of 133 patients were evaluated. At the last evaluation Dyskinesia scores and motor fluctuations significantly improved in both the GPi (p < 0.0001) and STN groups (p < 0.0001). The GPi group was more likely than the STN group to experience dDS (odds ratio = 1.95, 95% CI = 0.556, 3.21). However, the association between DBS target and dDS was not statistically significant (Pearson chi-square = 2.286, p = 0.131). CONCLUSIONS: The overall clinical outcome of STN and GPi DBS for control of dyskinesia and motor fluctuations was similar. STN and GPi DBS both had some direct dyskinesia suppression effects.

A closer look at unilateral versus bilateral deep brain stimulation: results of the National Institutes of Health COMPARE cohort.

OBJECT: In this paper, the authors' aim was to examine reasons underpinning decisions to undergo, or alternatively forgo, a second-sided deep brain stimulation (DBS) implantation in patients with Parkinson disease (PD). METHODS: Fifty-two patients with Parkinson disease (PD) were randomized to receive DBS to the subthalamic nucleus or globus pallidus internus (GPi) as part of the COMPARE trial. Forty-four patients had complete data sets. All patients were offered a choice at 6 months after unilateral implantation whether to receive a contralateral DBS implant. All patients had advanced PD. The mean patient age was 59.8 years (range 43-76 years), and the mean duration of disease was 12.2 years (range 5-21 years). The mean baseline Unified Parkinson's Disease Rating Scale (UPDRS)-III motor score was 42.7. The main outcome measures used in this study were the UPDRS-III Motor Scale and the UPDRS-IV Dyskinesia Scale. RESULTS: Twenty-one (48%) of the 44 patients in the cohort did not undergo bilateral implantation and have been successfully treated for an average of 3.5 years; of these, 14 (67%) had a GPi target. The most common reason for adding a second side was inadequacy to address motor symptoms. Patient satisfaction with motor outcomes after unilateral DBS implantation was the most common reason for not undergoing bilateral implantation. Those who chose a second DBS procedure had significantly higher baseline UPDRS-III motor and ipsilateral UPDRS-III scores, and a significantly lower asymmetrical index. The logistic regression analysis revealed that the odds of proceeding to bilateral DBS was 5.2 times higher for STN than for GPi DBS. For every 1% increase in asymmetry, the odds of bilateral DBS decreased [corrected] by 0.96. CONCLUSIONS: Unilateral DBS is an effective treatment for a subset of patients with PD. Baseline asymmetry is an important factor in the effectiveness and decision-making process between unilateral and bilateral DBS. Patients with GPi DBS in this cohort were more likely to choose to remain with unilateral implantation.

An evaluation of rating scales utilized for deep brain stimulation for dystonia.

The objective of this study was to examine globus pallidus internus deep brain stimulation (GPi-DBS) outcomes in primary and secondary dystonia, derived from blinded ratings using two scales and two raters. Twenty-five patients with variable presentations of dystonia were evaluated with videotaped standardized dystonia rating scales at preoperative baseline and at 6 and 12 months following GPi-DBS implantation. These 75 examination videos were retrospectively evaluated, independently and in random order, by two movement disorder neurologists who were blinded to the treatment status. Both neurologists scored each videotaped evaluation using the Burke-Fahn-Marsden Dystonia Rating Scale-motor part (BFMDRS-M) and the Unified Dystonia Rating Scale (UDRS). A final score for each video was assigned by averaging the raters' scores. An intra-class correlation coefficient was used to calculate inter-rater reliability. A linear mixed model was fitted to investigate the time effect and its interaction with type of dystonia (primary versus secondary) for each rating scale. Inter-rater reliability was excellent. Intraclass correlation coefficients ranged from 0.994 to 0.997 for both scales at baseline, 6 and 12 months. The average motor improvement scores after GPi DBS for the entire heterogeneous group of dystonia patients after 6 and 12 months of stimulation was 21.32% (p = 0.0010) and 28.95% (p = 0.0017), respectively, when the UDRS score was used. Similar levels of improvement 20.46% (p = 0.0055) at 6 months and 27.39% (p = 0.00197) at 12 months were found using the BFMDRS-M score. Analysis using unblinded scores from our database revealed a 32.99 and 37.27% UDRS improvement at 6 and 12 months, and an improvement in UDRS score of 38.5 and 43.7% when the analysis was limited to only primary dystonia. If the data were further segregated to include only cases of DYT-1 primary generalized dystonia, the UDRS benefit increased to 48.24%. Our primary dystonia group was diluted by the presence of both old- and young-onset patients, as well as focal, segmental and generalized dystonia. In conclusion, (1) evaluating motor outcomes of DBS therapy for dystonia using independent, randomized retrospective rating by blinded raters' results in lower improvement scores than when outcomes are rated by unblinded treating neurologists. Blinded methodology may be superior and might produce a more realistic assessment of motor outcomes after DBS in patients with dystonia; (2) outcomes were similar whether the BFMDRS-M or UDRS was utilized; (3) GPi-DBS was effective in treating sustained involuntary motor co-contractions in medication refractory dystonia patients, more so in primary dystonia.