A new treatment for focal dystonias: incobotulinumtoxinA (Xeomin®), a botulinum neurotoxin type A free from complexing proteins

Dystonia is a movement disorder of uncertain pathogenesis that is characterized by involuntary and inappropriate muscle contractions which cause sustained abnormal postures and movements of multiple or single (focal) body regions. The most common focal dystonias are cervical dystonia (CD) and blepharospasm (BSP). The first-line recommended treatment for CD and BSP is injection with botulinum toxin (BoNT), of which two serotypes are available: BoNT type A (BoNT/A) and BoNT type B (BoNT/B). Conventional BoNT formulations include inactive complexing proteins, which may increase the risk for antigenicity, possibly leading to treatment failure. IncobotulinumtoxinA (Xeomin®; Merz Pharmaceuticals GmbH, Frankfurt, Germany) is a BoNT/A agent that has been recently Food and Drug Administration-approved for the treatment of adults with CD and adults with BSP previously treated with onabotulinumtoxinA (Botox®; Allergen, Inc, Irvine, CA) – a conventional BoNT/A. IncobotulinumtoxinA is the only BoNT product that is free of complexing proteins. The necessity of complexing proteins for the effectiveness of botulinum toxin treatment has been challenged by preclinical and clinical studies with incobotulinumtoxinA. These studies have also suggested that incobotulinumtoxinA is associated with a lower risk for stimulating antibody formation than onabotulinumtoxinA. In phase 3 noninferiority trials, incobotulinumtoxinA demonstrated significant improvements in CD and BSP symptoms in both primary and secondary measures, compared with baseline, and met criteria for noninferiority versus onabotulinumtoxinA. In placebo-controlled trials, incobotulinumtoxinA also significantly improved the symptoms of CD and BSP, with robust outcomes in both primary and secondary measures. The use of incobotulinumtoxinA has been well tolerated in all trials, with an adverse event profile similar to that of onabotulinumtoxinA. Based on these data, incobotulinumtoxinA is a safe and effective BoNT/A for the treatment of CD and BSP, and may pose a lower risk for immunogenicity leading to treatment failure compared with other available BoNT agents. This paper reviews the treatment of focal dystonias with BoNTs, in particular, incobotulinumtoxinA. Controlled trials from the existing incobotulinumtoxinA literature are summarized

Deep Brain Stimulation for Obsessive Compulsive Disorder: Evolution of Surgical Stimulation Target Parallels Changing Model of Dysfunctional Brain Circuits

Obsessive compulsive disorder (OCD) is a common, disabling psychiatric disease characterized by persistent, intrusive thoughts and ritualistic, repetitive behaviors. Deep brain stimulation (DBS) is thought to alleviate OCD symptoms by modulating underlying disturbances in normal cortico-striato-thalamo-cortical (CSTC) circuitry. Stimulation of the ventral portion of the anterior limb of the internal capsule (ALIC) and underlying ventral striatum (“ventral capsule/ventral striatum” or “VC/VS” target) received U.S. FDA approval in 2009 for patients with severe, treatment-refractory OCD. Over the decades, DBS surgical outcome studies have led to an evolution in the electrical stimulation target. In parallel, advancements in neuroimaging techniques have allowed investigators to better visualize and define CSTC circuits underlying the pathophysiology of OCD. A critical analysis of these new data suggests that the therapeutic mechanism of DBS for OCD likely involves neuromodulation of a widespread cortical/subcortical network, accessible by targeting fiber bundles in the ventral ALIC that connect broad network regions. Future studies will include advances in structural and functional imaging, analysis of physiological recordings, and utilization of next-generation DBS devices. These tools will enable patient-specific optimization of DBS therapy, which will hopefully further improve outcomes

Randomized controlled trial of deutetrabenazine for tardive dyskinesia: The ARM-TD study

OBJECTIVE: To determine the efficacy and safety of deutetrabenazine as a treatment for tardive dyskinesia (TD). METHODS: One hundred seventeen patients with moderate to severe TD received deutetrabenazine or placebo in this randomized, double-blind, multicenter trial. Eligibility criteria included an Abnormal Involuntary Movement Scale (AIMS) score of ≥6 assessed by blinded central video rating, stable psychiatric illness, and stable psychoactive medication treatment. Primary endpoint was the change in AIMS score from baseline to week 12. Secondary endpoints included treatment success at week 12 on the Clinical Global Impression of Change (CGIC) and Patient Global Impression of Change. RESULTS: For the primary endpoint, deutetrabenazine significantly reduced AIMS scores from baseline to week 12 vs placebo (least-squares mean [standard error] -3.0 [0.45] vs -1.6 [0.46], p = 0.019). Treatment success on CGIC (48.2% vs 40.4%) favored deutetrabenazine but was not significant. Deutetrabenazine and placebo groups showed low rates of psychiatric adverse events: anxiety (3.4% vs 6.8%), depressed mood/depression (1.7% vs 1.7%), and suicidal ideation (0% vs 1.7%, respectively). In addition, no worsening in parkinsonism, as measured by the Unified Parkinson's Disease Rating Scale motor subscale, was noted from baseline to week 12 in either group. CONCLUSIONS: In patients with TD, deutetrabenazine was well tolerated and significantly reduced abnormal movements. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in patients with TD, deutetrabenazine reduces AIMS scores

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

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

Tremor is one of the main symptoms of Parkinson&rsquo;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&rsquo; 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&rsquo; tremor from continuous monitoring of the subjects&rsquo; movement in their natural environment