Deutetrabenazine Provides Long-Term Benefit for Tardive Dyskinesia Regardless of Underlying Condition and Dopamine Receptor Antagonist Use: A Post Hoc Analysis of the 3-Year, Open-Label Extension Study.

BACKGROUND: Deutetrabenazine is approved for adults with tardive dyskinesia (TD). Data based on underlying psychiatric condition and baseline dopamine receptor antagonist (DRA) use are limited. METHODS: Patients with TD who completed parent studies ARM-TD or AIM-TD were eligible for the 3-year, open-label extension study (RIM-TD; NCT02198794). In RIM-TD, deutetrabenazine was titrated based on dyskinesia control and tolerability. In this post hoc analysis of RIM-TD, total motor Abnormal Involuntary Movement Scale (AIMS) score and adverse events (AEs) were analyzed by underlying condition and DRA use at parent study baseline. RESULTS: Of 343 patients enrolled in RIM-TD, 336 were included in the analysis by underlying condition, and 337 were included in the analysis by DRA use. One hundred eighty-nine of 205 (92%) patients with psychotic disorders (schizophrenia/schizoaffective disorder) and 65 of 131 (50%) with mood and other disorders (depression/bipolar disorder/other) were receiving a DRA. Mean (SE) deutetrabenazine doses at week 145 were 40.4 (1.13), 38.5 (1.21), 39.9 (1.00), and 38.5 (1.48) mg/d for patients with psychotic disorders, those with mood and other disorders, and those receiving DRAs or not, respectively. Mean (SD) changes in total motor AIMS score from this study baseline to week 145 were -6.3 (4.53), -7.1 (4.92), -6.1 (4.42), and -7.5 (5.19). Exposure-adjusted incidence rates (number of AEs/patient-years) of AEs were similar across groups: any (1.02, 1.71, 1.08, 1.97), serious (0.10, 0.12, 0.10, 0.12), and leading to discontinuation (0.07, 0.05, 0.06, 0.05). CONCLUSIONS: Long-term deutetrabenazine provided clinically meaningful improvements in TD-related movements, with a favorable benefit-risk profile, regardless of underlying condition or DRA use.

Does the 5-2-1 criteria identify patients with advanced Parkinson's disease? Real-world screening accuracy and burden of 5-2-1-positive patients in 7 countries.

BACKGROUND: The burden of Parkinson's disease (PD) worsens with disease progression. However, the lack of objective and uniform disease classification challenges our understanding of the incremental burden in patients with advanced Parkinson's disease (APD) and suboptimal medication control. The 5-2-1 criteria was proposed by clinical consensus to identify patients with advancing PD. Our objective was to evaluate the screening accuracy and incremental clinical burden, healthcare resource utilization (HCRU), and humanistic burden in PD patients meeting the 5-2-1 screening criteria. METHODS: Data were drawn from the Adelphi Parkinson's Disease Specific Program (DSP™), a multi-country point-in-time survey (2017-2020). People with PD who were naive to device-aided therapy and on oral PD therapy were included. Patients meeting the 5-2-1 screening criteria had one or more of the three clinical indicators of APD: (i) ≥5 doses of oral levodopa/day, OR (ii) "off" symptoms for ≥2 h of waking day, OR (iii) ≥1 h of troublesome dyskinesia. Clinician assessment of PD stage was used as the reference in this study. Clinical screening accuracy of the 5-2-1 criteria was assessed using area under the curve and multivariable logistic regression models. Incremental clinical, HCRU, and humanistic burden were assessed by known-group comparisons between 5 and 2-1-positive and negative patients. RESULTS: From the analytic sample (n = 4714), 33% of patients met the 5-2-1 screening criteria. Among physician-classified APD patients, 78.6% were 5-2-1 positive. Concordance between clinician judgment and 5-2-1 screening criteria was > 75%. 5-2-1-positive patients were nearly 7-times more likely to be classified as APD by physician judgment. Compared with the 5-2-1-negative group, 5-2-1-positive patients had significantly higher clinical, HCRU, and humanistic burden across all measures. In particular, 5-2-1-positive patients had 3.8-times more falls, 3.6-times higher annual hospitalization rate, and 3.4-times greater dissatisfaction with PD treatment. 5-2-1-positive patients also had significantly lower quality of life and worse caregiver burden. CONCLUSIONS: 5-2-1 criteria demonstrated potential as a screening tool for identifying people with APD with considerable clinical, humanistic, and HCRU burden. The 5-2-1 screening criteria is an objective and reliable tool that may aid the timely identification and treatment optimization of patients inadequately controlled on oral PD medications.

Deep Brain Stimulation of the Pallidofugal Pathways to Rescue Severe Life-Threatening Dyskinesias after STN-DBS Lead Implantation.

We present a patient with severe life-threatening dyskinesias due to a persistent microlesion effect after STN-DBS electrode implantation. The pallidofugal pathways were identified using patient-specific tractography, and steering the current toward this white matter structure resulted in complete resolution of the severe dyskinesias.

Directional Deep Brain Stimulation for Parkinson's Disease: Results of an International Crossover Study With Randomized, Double-Blind Primary Endpoint.

OBJECTIVE: Published reports on directional deep brain stimulation (DBS) have been limited to small, single-center investigations. Therapeutic window (TW) is used to describe the range of stimulation amplitudes achieving symptom relief without side effects. This crossover study performed a randomized double-blind assessment of TW for directional and omnidirectional DBS in a large cohort of patients implanted with a DBS system in the subthalamic nucleus for Parkinson's disease. MATERIALS AND METHODS: Participants received omnidirectional stimulation for the first three months after initial study programming, followed by directional DBS for the following three months. The primary endpoint was a double-blind, randomized evaluation of TW for directional vs omnidirectional stimulation at three months after initial study programming. Additional data recorded at three- and six-month follow-ups included stimulation preference, therapeutic current strength, Unified Parkinson's Disease Rating Scale (UPDRS) part III motor score, and quality of life. RESULTS: The study enrolled 234 subjects (62 ± 8 years, 33% female). TW was wider using directional stimulation in 183 of 202 subjects (90.6%). The mean increase in TW with directional stimulation was 41% (2.98 ± 1.38 mA, compared to 2.11 ± 1.33 mA for omnidirectional). UPDRS part III motor score on medication improved 42.4% at three months (after three months of omnidirectional stimulation) and 43.3% at six months (after three months of directional stimulation) with stimulation on, compared to stimulation off. After six months, 52.8% of subjects blinded to stimulation type (102/193) preferred the period with directional stimulation, and 25.9% (50/193) preferred the omnidirectional period. The directional period was preferred by 58.5% of clinicians (113/193) vs 21.2% (41/193) who preferred the omnidirectional period. CONCLUSION: Directional stimulation yielded a wider TW compared to omnidirectional stimulation and was preferred by blinded subjects and clinicians.

Ensemble deep model for continuous estimation of Unified Parkinson's Disease Rating Scale III.

BACKGROUND: Unified Parkinson Disease Rating Scale-part III (UPDRS III) is part of the standard clinical examination performed to track the severity of Parkinson's disease (PD) motor complications. Wearable technologies could be used to reduce the need for on-site clinical examinations of people with Parkinson's disease (PwP) and provide a reliable and continuous estimation of the severity of PD at home. The reported estimation can be used to successfully adjust the dose and interval of PD medications. METHODS: We developed a novel algorithm for unobtrusive and continuous UPDRS-III estimation at home using two wearable inertial sensors mounted on the wrist and ankle. We used the ensemble of three deep-learning models to detect UPDRS-III-related patterns from a combination of hand-crafted features, raw temporal signals, and their time-frequency representation. Specifically, we used a dual-channel, Long Short-Term Memory (LSTM) for hand-crafted features, 1D Convolutional Neural Network (CNN)-LSTM for raw signals, and 2D CNN-LSTM for time-frequency data. We utilized transfer learning from activity recognition data and proposed a two-stage training for the CNN-LSTM networks to cope with the limited amount of data. RESULTS: The algorithm was evaluated on gyroscope data from 24 PwP as they performed different daily living activities. The estimated UPDRS-III scores had a correlation of [Formula: see text] and a mean absolute error of 5.95 with the clinical examination scores without requiring the patients to perform any specific tasks. CONCLUSION: Our analysis demonstrates the potential of our algorithm for estimating PD severity scores unobtrusively at home. Such an algorithm could provide the required motor-complication measurements without unnecessary clinical visits and help the treating physician provide effective management of the disease.

Local field potentials of subthalamic nucleus contain electrophysiological footprints of motor subtypes of Parkinson's disease.

Although motor subtypes of Parkinson's disease (PD), such as tremor dominant (TD) and postural instability and gait difficulty (PIGD), have been defined based on symptoms since the mid-1990s, no underlying neural correlates of these clinical subtypes have yet been identified. Very limited data exist regarding the electrophysiological abnormalities within the subthalamic nucleus (STN) that likely accompany the symptom severity or the phenotype of PD. Here, we show that activity in subbands of local field potentials (LFPs) recorded with multiple microelectrodes from subterritories of STN provide distinguishing neurophysiological information about the motor subtypes of PD. We studied 24 patients with PD and found distinct patterns between TD (n = 13) and PIGD (n = 11) groups in high-frequency oscillations (HFOs) and their nonlinear interactions with beta band in the superior and inferior regions of the STN. Particularly, in the superior region of STN, the power of the slow HFO (sHFO) (200-260 Hz) and the coupling of its amplitude with beta-band phase were significantly stronger in the TD group. The inferior region of STN exhibited fast HFOs (fHFOs) (260-450 Hz), which have a significantly higher center frequency in the PIGD group. The cross-frequency coupling between fHFOs and beta band in the inferior region of STN was significantly stronger in the PIGD group. Our results indicate that the spatiospectral dynamics of STN-LFPs can be used as an objective method to distinguish these two motor subtypes of PD. These observations might lead to the development of sensing and stimulation strategies targeting the subterritories of STN for the personalization of deep-brain stimulation (DBS).

Effect of Urate-Elevating Inosine on Early Parkinson Disease Progression: The SURE-PD3 Randomized Clinical Trial.

Importance: Urate elevation, despite associations with crystallopathic, cardiovascular, and metabolic disorders, has been pursued as a potential disease-modifying strategy for Parkinson disease (PD) based on convergent biological, epidemiological, and clinical data. Objective: To determine whether sustained urate-elevating treatment with the urate precursor inosine slows early PD progression. Design, Participants, and Setting: Randomized, double-blind, placebo-controlled, phase 3 trial of oral inosine treatment in early PD. A total of 587 individuals consented, and 298 with PD not yet requiring dopaminergic medication, striatal dopamine transporter deficiency, and serum urate below the population median concentration (<5.8 mg/dL) were randomized between August 2016 and December 2017 at 58 US sites, and were followed up through June 2019. Interventions: Inosine, dosed by blinded titration to increase serum urate concentrations to 7.1-8.0 mg/dL (n = 149) or matching placebo (n = 149) for up to 2 years. Main Outcomes and Measures: The primary outcome was rate of change in the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS; parts I-III) total score (range, 0-236; higher scores indicate greater disability; minimum clinically important difference of 6.3 points) prior to dopaminergic drug therapy initiation. Secondary outcomes included serum urate to measure target engagement, adverse events to measure safety, and 29 efficacy measures of disability, quality of life, cognition, mood, autonomic function, and striatal dopamine transporter binding as a biomarker of neuronal integrity. Results: Based on a prespecified interim futility analysis, the study closed early, with 273 (92%) of the randomized participants (49% women; mean age, 63 years) completing the study. Clinical progression rates were not significantly different between participants randomized to inosine (MDS-UPDRS score, 11.1 [95% CI, 9.7-12.6] points per year) and placebo (MDS-UPDRS score, 9.9 [95% CI, 8.4-11.3] points per year; difference, 1.26 [95% CI, -0.59 to 3.11] points per year; P = .18). Sustained elevation of serum urate by 2.03 mg/dL (from a baseline level of 4.6 mg/dL; 44% increase) occurred in the inosine group vs a 0.01-mg/dL change in serum urate in the placebo group (difference, 2.02 mg/dL [95% CI, 1.85-2.19 mg/dL]; P<.001). There were no significant differences for secondary efficacy outcomes including dopamine transporter binding loss. Participants randomized to inosine, compared with placebo, experienced fewer serious adverse events (7.4 vs 13.1 per 100 patient-years) but more kidney stones (7.0 vs 1.4 stones per 100 patient-years). Conclusions and Relevance: Among patients recently diagnosed as having PD, treatment with inosine, compared with placebo, did not result in a significant difference in the rate of clinical disease progression. The findings do not support the use of inosine as a treatment for early PD. Trial Registration: ClinicalTrials.gov Identifier: NCT02642393.

Distinct subthalamic coupling in the ON state describes motor performance in Parkinson's disease.

OBJECTIVE: Cross-frequency coupling has been reported in the STN of patients with PD, but its significance and functional role are still not well understood. This study investigates pharmacological modulations of subthalamic oscillations and their nonlinear cross-frequency interactions across three consecutive cycles over unique 24-hour-long recordings. BACKGROUND: Identifying neurobiomarkers for PD can drive the development of novel personalized treatments by providing objective assessment of impairment. In particular, distinct frequency bands in LFP recordings and their interaction with one another have been shown to modulate with dopaminergic medication and thus, proposed as such biomarkers. METHODS: We recorded local field potentials 3 weeks postoperatively from externalized leads in 9 patients and correlated the neural patterns with improvements in motor signs over three medication intake cycles. We used two modalities to assess symptoms in the unmedicated OFF and the l-dopa-induced motor ON state: a subsection of the UPDRS and a keyboard tapping score measuring bradykinesia. RESULTS: In the OFF state, the amplitude of high-frequency oscillations in the 200- to 300-Hz range was coupled with the phase of low-beta (13-22 Hz) in all patients. After transition to the ON state, three distinct coupling patterns were observed among subjects. Among these, patients showing ON coupling between high-beta (22-30 Hz) and high-frequency oscillations in the 300- to 400-Hz range had significantly greater improvement in bradykinesia, according to the keyboard scores. CONCLUSION: Observing diminished coupling in the ON state, previous studies have hypothesized that the sole existence of coupling in STN has an "impeding" effect on normal processes, and thus it was considered to be pathological. In contrast, our observation of ON state coupling at distinct frequencies associated with the improvements in motor features suggest that the underlying mechanism of coupling might have impeding or enhancing effects depending on the coupled frequencies. © 2019 International Parkinson and Movement Disorder Society.

Long-term safety and efficacy of deutetrabenazine for the treatment of tardive dyskinesia.

OBJECTIVE: To evaluate the long-term safety and efficacy of deutetrabenazine in patients with tardive dyskinesia (TD). METHOD: Patients with TD who completed the 12 week, phase 3, placebo-controlled trials were eligible to enter this open-label, single-arm study. The open-label study consisted of a 6 week dose-escalation phase and a long-term maintenance phase (clinic visits at Weeks 4, 6 and 15, and every 13 weeks until Week 106). Patients began deutetrabenazine at 12 mg/day, titrating up to a dose that was tolerable and provided adequate dyskinesia control, based on investigator judgement, with a maximum allowed dose of 48 mg/day (36 mg/day for patients taking strong cytochrome P450 2D6 (CYP2D6) inhibitors). Safety measures included incidence of adverse events (AEs) and scales used to monitor parkinsonism, akathisia/restlessness, anxiety, depression, suicidality and somnolence/sedation. Efficacy endpoints included the change in Abnormal Involuntary Movement Scale (AIMS) score (items 1 to 7) from baseline and the proportion of patients rated as 'Much Improved' or 'Very Much Improved' on the Clinical Global Impression of Change. RESULTS: A total of 343 patients enrolled in the extension study, and there were 331 patient-years of exposure in this analysis. The exposure-adjusted incidence rates of AEs with long-term treatment were comparable to or lower than those observed in the phase 3 trials. The mean (SE) change in AIMS score was -4.9 (0.4) at Week 54 (n = 146), - 6.3 (0.7) at Week 80 (n = 66) and -5.1 (2.0) at Week 106 (n = 8). CONCLUSIONS: Overall, long-term treatment with deutetrabenazine was efficacious, safe, and well tolerated in patients with TD. TRIAL REGISTRATION NUMBER: NCT02198794.

Wearable Sensors for Estimation of Parkinsonian Tremor Severity during Free Body Movements.

Tremor is one of the main symptoms of Parkinson's Disease (PD) that reduces the quality of life. Tremor is measured as part of the Unified Parkinson Disease Rating Scale (UPDRS) part III. However, the assessment is based on onsite physical examinations and does not fully represent the patients' tremor experience in their day-to-day life. Our objective in this paper was to develop algorithms that, combined with wearable sensors, can estimate total Parkinsonian tremor as the patients performed a variety of free body movements. We developed two methods: an ensemble model based on gradient tree boosting and a deep learning model based on long short-term memory (LSTM) networks. The developed methods were assessed on gyroscope sensor data from 24 PD subjects. Our analysis demonstrated that the method based on gradient tree boosting provided a high correlation (r = 0.96 using held-out testing and r = 0.93 using subject-based, leave-one-out cross-validation) between the estimated and clinically assessed tremor subscores in comparison to the LSTM-based method with a moderate correlation (r = 0.84 using held-out testing and r = 0.77 using subject-based, leave-one-out cross-validation). These results indicate that our approach holds great promise in providing a full spectrum of the patients' tremor from continuous monitoring of the subjects' movement in their natural environment.

Hybrid Feature Extraction for Detection of Degree of Motor Fluctuation Severity in Parkinson's Disease Patients.

The success of medication adjustment in Parkinson's disease (PD) patients with motor fluctuation relies on the knowledge about their fluctuation severity. However, because of the temporal and spatial variability in motor fluctuations, a single clinical examination often fails to capture the spectrum of motor impairment experienced in routine daily life. In this study, we developed an algorithm to estimate the degree of motor fluctuation severity from two wearable sensors' data during subjects' free body movements. Specifically, we developed a new hybrid feature extraction method to represent the longitudinal changes of motor function from the sensor data. Next, we developed a classification model based on random forest to learn the changes in the patterns of the sensor data as the severity of the motor function changes. We evaluated our algorithm using data from 24 subjects with idiopathic PD as they performed a variety of daily routine activities. A leave-one-subject-out assessment of the algorithm resulted in 83.33% accuracy, indicating that our approach holds a great promise to passively detect degree of motor fluctuation severity from continuous monitoring of an individual's free body movements. Such a sensor-based assessment system and algorithm combination could provide the objective and comprehensive information about the fluctuation severity that can be used by the treating physician to effectively adjust therapy for PD patients with troublesome motor fluctuation.

Pseudobulbar Affect Correlates With Mood Symptoms in Parkinsonian Disorders but Not Amyotrophic Lateral Sclerosis.

Pseudobulbar affect (PBA) is a syndrome of affective disturbance associated with inappropriate laughter and crying, independent of mood. PBA is common in amyotrophic lateral sclerosis (ALS) and increasingly recognized in Parkinson's disease (PD) and atypical parkinsonism (aP). Correlates of PBA have not been systematically studied. The purpose of this study was to determine whether cognitive and psychiatric comorbidities correlated with patient-reported symptoms of PBA by using the Center for Neurological Study-Lability Scale among patients with ALS, PD, and aP. A total of 108 patients (PD, N=53; aP, N=29; ALS, N=26) completed a cognitive screener and self-reported measures of lability, depression, anxiety, apathy, and quality of life. Statistical analyses included one- and two-way analyses of covariance to evaluate group differences, Pearson's correlations to determine relationships between PBA symptoms and comorbidities, multiple regression for predicting PBA symptom severity in clinical correlates, and chi-square t tests for predicting demographic variables. PBA symptom severity did not vary between the three groups. Younger age and worse anxiety correlated with PBA symptom severity in all three groups, whereas depression and poor mental health/quality of life only correlated with PBA symptom severity in the PD and aP groups. PD and aP patients may be more likely to benefit from treatment with antidepressants. Increased PBA symptoms were associated with declines in cognitive functioning in the aP group, but sufficient numbers of PD and ALS patients with cognitive dysfunction may not have been recruited. The results suggest the possibility of an alternate pathophysiologic mechanism for PBA, which may vary between neurological disorders and disease progression. Mood and cognition are of particular relevance and should be evaluated when symptoms of PBA are suspected.

Effect of Deutetrabenazine on Chorea Among Patients With Huntington Disease: A Randomized Clinical Trial.

IMPORTANCE: Deutetrabenazine is a novel molecule containing deuterium, which attenuates CYP2D6 metabolism and increases active metabolite half-lives and may therefore lead to stable systemic exposure while preserving key pharmacological activity. OBJECTIVE: To evaluate efficacy and safety of deutetrabenazine treatment to control chorea associated with Huntington disease. DESIGN, SETTING, AND PARTICIPANTS: Ninety ambulatory adults diagnosed with manifest Huntington disease and a baseline total maximal chorea score of 8 or higher (range, 0-28; lower score indicates less chorea) were enrolled from August 2013 to August 2014 and randomized to receive deutetrabenazine (n = 45) or placebo (n = 45) in a double-blind fashion at 34 Huntington Study Group sites. INTERVENTIONS: Deutetrabenazine or placebo was titrated to optimal dose level over 8 weeks and maintained for 4 weeks, followed by a 1-week washout. MAIN OUTCOMES AND MEASURES: Primary end point was the total maximal chorea score change from baseline (the average of values from the screening and day-0 visits) to maintenance therapy (the average of values from the week 9 and 12 visits) obtained by in-person visits. This study was designed to detect a 2.7-unit treatment difference in scores. The secondary end points, assessed hierarchically, were the proportion of patients who achieved treatment success on the Patient Global Impression of Change (PGIC) and on the Clinical Global Impression of Change (CGIC), the change in 36-Item Short Form- physical functioning subscale score (SF-36), and the change in the Berg Balance Test. RESULTS: Ninety patients with Huntington disease (mean age, 53.7 years; 40 women [44.4%]) were enrolled. In the deutetrabenazine group, the mean total maximal chorea scores improved from 12.1 (95% CI, 11.2-12.9) to 7.7 (95% CI, 6.5-8.9), whereas in the placebo group, scores improved from 13.2 (95% CI, 12.2-14.3) to 11.3 (95% CI, 10.0-12.5); the mean between-group difference was -2.5 units (95% CI, -3.7 to -1.3) (P < .001). Treatment success, as measured by the PGIC, occurred in 23 patients (51%) in the deutetrabenazine group vs 9 (20%) in the placebo group (P = .002). As measured by the CGIC, treatment success occurred in 19 patients (42%) in the deutetrabenazine group vs 6 (13%) in the placebo group (P = .002). In the deutetrabenazine group, the mean SF-36 physical functioning subscale scores decreased from 47.5 (95% CI, 44.3-50.8) to 47.4 (44.3-50.5), whereas in the placebo group, scores decreased from 43.2 (95% CI, 40.2-46.3) to 39.9 (95% CI, 36.2-43.6), for a treatment benefit of 4.3 (95% CI, 0.4 to 8.3) (P = .03). There was no difference between groups (mean difference of 1.0 unit; 95% CI, -0.3 to 2.3; P = .14), for improvement in the Berg Balance Test, which improved by 2.2 units (95% CI, 1.3-3.1) in the deutetrabenazine group and by 1.3 units (95% CI, 0.4-2.2) in the placebo group. Adverse event rates were similar for deutetrabenazine and placebo, including depression, anxiety, and akathisia. CONCLUSIONS AND RELEVANCE: Among patients with chorea associated with Huntington disease, the use of deutetrabenazine compared with placebo resulted in improved motor signs at 12 weeks. Further research is needed to assess the clinical importance of the effect size and to determine longer-term efficacy and safety. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01795859.

National Randomized Controlled Trial of Virtual House Calls for People with Parkinson's Disease: Interest and Barriers.

BACKGROUND: Delivering specialty care remotely directly into people's homes can enhance access for and improve the healthcare of individuals with chronic conditions. However, evidence supporting this approach is limited. MATERIALS AND METHODS: Connect.Parkinson is a randomized comparative effectiveness study that compares usual care of individuals with Parkinson's disease in the community with usual care augmented by virtual house calls with a Parkinson's disease specialist from 1 of 18 centers nationally. Individuals in the intervention arm receive four virtual visits from a Parkinson's disease specialist over 1 year via secure, Web-based videoconferencing directly into their homes. All study activities, including recruitment, enrollment, and assessments, are conducted remotely. Here we report on interest, feasibility, and barriers to enrollment in this ongoing study. RESULTS: During recruitment, 11,734 individuals visited the study's Web site, and 927 unique individuals submitted electronic interest forms. Two hundred ten individuals from 18 states enrolled in the study from March 2014 to June 2015, and 195 were randomized. Most participants were white (96%) and college educated (73%). Of the randomized participants, 73% had seen a Parkinson's disease specialist within the previous year. CONCLUSIONS: Among individuals with Parkinson's disease, national interest in receiving remote specialty care directly into the home is high. Remote enrollment in this care model is feasible but is likely affected by differential access to the Internet.

The safety and efficacy of thalamic deep brain stimulation in essential tremor: 10 years and beyond.

BACKGROUND: Deep brain stimulation (DBS) has proven to be a safe and effective therapy for refractory essential tremor, but information regarding long-term outcomes is lacking. OBJECTIVES: We aimed to assess the long-term safety and efficacy of DBS in patients with essential tremor. METHODS: Patients treated with DBS for essential tremor for at least 8 years were evaluated in the 'on' and 'off' state using the Fahn-Tolosa-Marin tremor rating scale, and their medical records were reviewed to assess complications related to this therapy. RESULTS: We studied 13 patients (7 men): median age at evaluation 79 years (range 47-88), median age at electrode implantation 68 years (range 37-78) and mean time since electrode implantation 132.54±15.3 months (range 114-164). The difference between the 'off' and 'on' state on the motor items of the tremor rating scale was 41.9% (58.62 vs. 34.08, p<0.001) in the non-blinded and 37.2% (56.07 vs. 35.23, p<0.001) in the blinded rating. DBS provided a functional improvement of 31.7% in the 'on' state (15.07 vs. 22.07, p<0.001). A total non-blinded improvement in the tremor rating scale of 39% was observed in the 'on' state (49.15 vs. 80.69, p<0.001). Dysarthria and disequilibrium were common in patients with bilateral stimulation. A DBS-related surgery (electrode revision or internal pulse generator exchange) was necessary on average every 47.9 months to continue with the DBS therapy. CONCLUSIONS: Thalamic DBS is a safe and effective therapy in patients with essential tremor followed for up to 13 years.

Habituation and rebound to thalamic deep brain stimulation in long-term management of tremor associated with demyelinating neuropathy.

Some patients may experience tolerance to chronic ventral intermediate (ViM) thalamic deep brain stimulation (DBS), which may include habituation (loss of sustained tremor control over weeks to days after an adjustment) and rebound (a temporary increase in tremor intensity after stopping DBS). We observed an association between these efficacy limiting phenomena with co-morbid demyelinating sensorimotor peripheral neuropathy (MRT-PN). The clinical and treatment characteristics of neuropathy and tremor pre- and post-DBS are described through retrospective chart review of five patients with MRT-PN. Programming strategies (number of programming visits/implant years and number of major parameter changes/electrode) were compared in MRT-PN patients to a group of seven ET patients without neuropathy, who had > 4 years continuous follow-up. The presence of habituation and rebound were recorded. All MRT-PN patients had initial good response to DBS followed by habituation and/or rebound of tremor control, some asymmetrically. Compared to ET without neuropathy (mean follow-up 5.83 ± 0.78 years), MRT-PN patients (mean follow-up 4.90 ± 3.73 years) required more programming visits/year (p = 0.12) and major parameter changes/electrode/implant year (p = 0.03). The presence of neuropathy may alter tremor characteristics and result in temporary re-setting of thalamic oscillatory drive after DBS in MRT-PN patients. Clinicians should be aware of the risk for tolerance to DBS in MRT-PN and patients should be counseled about possible suboptimal sustained tremor control.

Rechargeable deep brain stimulation implantable pulse generators in movement disorders: patient satisfaction and conversion parameters.

OBJECTIVES: Rechargeable (RC) implantable pulse generators (IPGs) for deep brain stimulation (DBS) in movement disorders have recently become available. No guidelines exist for parameter adjustment after conversion of non-RC to RC IPGs, or reports of patient satisfaction with RC IPGs when used as initial DBS device or after conversion from non-RC IPGs. MATERIALS AND METHODS: Patients who underwent placement of Activa RC IPG (Medtronic, Inc.) were surveyed by phone about device satisfaction. Their charts were retrospectively reviewed and DBS settings were analyzed. The stimulation settings before and after conversion to RC were compared. RESULTS: Thirty-one patients (age 15-90; 18 male) with movement disorders (nine Parkinson's disease, nine dystonia, eight essential tremor, five others) were identified. Twelve subjects had initial RC IPG implantation; 19 were converted from non-RC IPGs (Soletra; Medtronic, Inc.) 2-14 years after initial DBS implant (mean 6.3 ± 3.44 years). Twenty-six patients (17 conversions) were surveyed an average of 12.1 months since RC IPG implantation. Overall satisfaction with RC was high. Patients converted to RC were more likely to choose it again than those with initial RC. Patients denied differences in symptom control after conversion. Mean amplitude, pulse width, and frequency were slightly lower after conversion regardless of diagnosis and remained lower after three postconversion reprogramming with slow drift of amplitude back to preconversion settings, more in the GPi group. CONCLUSIONS: RC IPGs in DBS for movement disorders are well received by patients as initial therapy and after conversion. Mild reduction in stimulation parameters might be allowed after conversion to RC IPG.

Reinforcement Learning-Based Adaptive Classification for Medication State Monitoring in Parkinson's Disease.

Parkinson's Disease (PD) patients frequently transition between the 'ON' state, where medication is effective, and the 'OFF' state, affecting their quality of life. Monitoring these transitions is vital for personalized therapy. We introduced a framework based on Reinforcement Learning (RL) to detect transitions between medication states by learning from continuous movement data. Unlike traditional approaches that typically identify each state based on static data patterns, our approach focuses on understanding the dynamic patterns of change throughout the transitions, providing a more generalizable medication state monitoring method. We integrated a deep Long Short-Term Memory (LSTM) neural network and three one-class unsupervised classifiers to implement an RL-based adaptive classifier. We tested on two PD datasets: Dataset PD1 with 12 subjects (14-minute average recording) and Dataset PD2 with seven subjects (120-minute average recording). Data from wrist and ankle wearables captured transitions during 2 to 4-hour daily activities. The algorithm demonstrated its effectiveness in detecting medication states, achieving an average weighted F1-score of 82.94% when trained and tested on Dataset PD1. It performed well when trained on Dataset PD1 and tested on Dataset PD2, with a weighted F1-score of 76.67%. It surpassed other models, was resilient to severe PD symptoms, and performed well with imbalanced data. Notably, prior work has not addressed the generalizability from one dataset to another, essential for real-world applications with varied sensors. Our innovative framework revolutionizes PD monitoring, setting the stage for advanced therapeutic methods and greatly enhancing the life quality of PD patients.

Safety of Deutetrabenazine for the Treatment of Tardive Dyskinesia and Chorea Associated with Huntington Disease.

INTRODUCTION: Deutetrabenazine is a vesicular monoamine transporter 2 inhibitor used to treat tardive dyskinesia (TD) and chorea associated with Huntington disease (HD). To enhance detection of safety signals across individual trials, integrated safety analyses of deutetrabenazine in TD and HD chorea were conducted. METHODS: For TD, safety data were integrated from two 12-week pivotal studies (ARM-TD and AIM-TD) and through week 15 of the open-label extension (OLE) study (RIM-TD). Data were analyzed by deutetrabenazine treatment group and placebo. For HD, safety data were integrated from the 12-week pivotal study (First-HD) and through week 15 of the OLE study (ARC-HD) for patients previously receiving placebo. Integrated deutetrabenazine data were compared with placebo from the pivotal study. RESULTS: For TD, deutetrabenazine (n = 384) was generally well tolerated compared with placebo (n = 130). Adverse event (AE) incidence was numerically higher in the response-driven deutetrabenazine vs the fixed-dose deutetrabenazine and placebo groups, respectively (any AE, 59.5% vs 44.4-50.0% and 53.8%; treatment-related AE, 38.1% vs 18.1-25.0% and 30.8%). Serious AEs were reported for 2.8-8.3% of patients in the deutetrabenazine groups and 6.9% in the placebo group. Common AEs (≥ 4%) included headache, somnolence, nausea, anxiety, fatigue, dry mouth, and diarrhea. AE incidence was higher during the titration vs maintenance periods. For HD, AE incidence was numerically higher with deutetrabenazine (n = 84) vs placebo (n = 45; any AE, 64.3% vs 60.0%; treatment-related AE, 38.1% vs 26.7%); serious AEs were reported for similar proportions for the deutetrabenazine and placebo groups, 2.4% and 2.2%, respectively. Common AEs (≥ 4%) included irritability, fall, depression, dry mouth, and fatigue. CONCLUSIONS: Data from an integrated analysis of studies in TD and an integrated analysis of studies of chorea in HD showed that deutetrabenazine has a favorable safety profile and is well tolerated across indications. TRIAL REGISTRATION: ClinicalTrials.gov identifiers, NCT02291861, NCT02195700, NCT01795859, NCT02198794, NCT01897896.

Unintended movements are often the first sign of Huntington disease. This type of unintended movement is called chorea in Huntington disease. Tardive dyskinesia causes unintended body movements. Deutetrabenazine is a medicine used to treat both types of movements. This report summarizes deutetrabenazine safety across five clinical studies. Safety was assessed via adverse events (side effects). Adverse events were compared between deutetrabenazine and inactive treatment (placebo). Serious adverse events were also compared. Serious adverse events cause substantial impairment or disruption. In tardive dyskinesia and chorea in Huntington disease studies, most patients kept taking deutetrabenazine. Adverse events were not a common reason to stop treatment. For tardive dyskinesia, adverse event rates were similar between deutetrabenazine (≤ 60%) and placebo (54%). Serious adverse event rates were also similar for deutetrabenazine (≤ 8%) and placebo (7%). Adverse events tended to be reported earlier in treatment. Common adverse events were headache, sleepiness, nausea, anxiety, fatigue, dry mouth, and diarrhea. For chorea in Huntington disease, adverse event rates were similar for deutetrabenazine (64%) and placebo (60%). Serious adverse event rates were also similar for deutetrabenazine (2%) and placebo (2%). Irritability, fall, depression, dry mouth, and fatigue were common adverse events. Adverse events were similar between deutetrabenazine and placebo in both conditions. Deutetrabenazine was well tolerated for patients with either tardive dyskinesia or chorea in Huntington disease.