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Background Clinical characteristics of isolated idiopathic cervical dystonia such as onset site and spread to and from additional body regions have been addressed in single-site studies with limited data and incomplete or variable dissociation of focal and segmental subtypes. The objectives of this study were to characterize the clinical characteristics and demographics of isolated idiopathic cervical dystonia in the largest standardized multicenter cohort. Methods The Dystonia Coalition, through a consortium of 37 recruiting sites in North America, Europe, and Australia, recruited 1477 participants with focal (60.7%) or segmental (39.3%) cervical dystonia on examination. Clinical and demographic characteristics were evaluated in terms of the body region of dystonia onset and spread. Results Site of dystonia onset was: (1) focal neck only (78.5%), (2) focal onset elsewhere with later segmental spread to neck (13.3%), and (3) segmental onset with initial neck involvement (8.2%). Frequency of spread from focal cervical to segmental dystonia (22.8%) was consistent with prior reports, but frequency of segmental onset with initial neck involvement was substantially higher than the 3% previously reported. Cervical dystonia with focal neck onset, more than other subtypes, was associated with spread and tremor of any type. Sensory tricks were less frequent in cervical dystonia with segmental components, and segmental cervical onset occurred at an older age. Conclusions Subgroups had modest but significant differences in the clinical characteristics that may represent different clinical entities or pathophysiologic subtypes. These findings are critical for design and implementation of studies to describe, treat, or modify disease progression in idiopathic isolated cervical dystonia. © 2016 International Parkinson and Movement Disorder Society.

Background In patients with motor fluctuations complicating Parkinson's disease (PD), delays in time‐to‐ON with levodopa are common. This open‐label study aimed to assess the effect of apomorphine on time‐to‐ON in PD patients with morning akinesia. Methods The safety population included 127 enrolled patients, and the full analysis set (FAS) included 88 patients. Patients completed a 7‐day levodopa baseline period recording their time‐to‐ON following each morning dose of levodopa. Patients were titrated to an optimal dose of apomorphine (2–6 mg) while taking trimethobenzamide antiemetic therapy. Apomorphine was injected each morning for a 7‐day treatment period and time‐to‐ON was self‐recorded in 5‐minute blocks. The primary efficacy variable was time‐to‐ON in the apomorphine treatment period versus the baseline levodopa period. Secondary assessments included and global impression scales. Safety and tolerability were assessed through adverse events (AEs). Results Patients receiving apomorphine achieved mean ± standard deviation (SD) time‐to‐ON 23.72 ± 14.55 minutes, reduced from 60.86 ± 18.11 minutes with levodopa (P < 0.0001). Dose failures (defined as time‐to‐ON >60 minutes) were more commonly reported with levodopa versus apomorphine (46% vs. 7% of diary entries, respectively). Secondary endpoints supported the primary efficacy findings, with significant improvements from levodopa baseline to apomorphine treatment period (all P < 0.0001). The most common AEs were nausea and dizziness. Most patients who discontinued because of AEs did so in the titration phase. Conclusions Apomorphine injections significantly reduced time‐to‐ON in PD patients experiencing delayed onset of their morning levodopa dose, and was well tolerated in most patients. After apomorphine treatment, fluctuating patients with morning akinesia experienced rapid and reliable improvement of time‐to‐ON.

Aim Assess efficacy and tolerability of gabapentin enacarbil (GEn) in adults with severe primary restless legs syndrome (RLS). Methods We pooled data from three 12-week, double-blind, placebo-controlled, randomized trials (NCT00298623, NCT00365352, NCT01332305) across GEn 600-mg, GEn 1200-mg, and placebo treatment groups for severe primary RLS (baseline International Restless Legs Scale (IRLS) total score ≥24). Co-primary end points at week 12 were mean change from baseline in IRLS total score and proportion of responders ("much"/very much" improved) on the investigator-rated Clinical Global Impression – Improvement (CGI-I) Scale. Outcomes for individual IRLS items (eg, sleep, mood, quality of life, pain, safety) were assessed. Results A total of 309 patients had severe primary RLS (placebo, n = 110; GEn 600 mg, n = 80; GEn 1200 mg, n = 119). GEn 600 mg and 1200 mg significantly improved least-squares mean IRLS total scores versus placebo at week 12 (placebo, −12.3; GEn 600 mg, −16.3; GEn 1200 mg, −18.0; treatment difference vs. placebo, both p 0.01). Significantly more patients with severe primary RLS treated with GEn 600 mg (64%) and 1200 mg (74%) were CGI-I responders at week 12 versus placebo (42%; p 0.01 for both GEn doses). Both GEn doses led to significant improvements in the other outcomes explored versus placebo at week 12. The most frequent treatment-emergent adverse events (TEAEs) were somnolence (GEn, 21–24%; placebo, 3%) and dizziness (GEn, 14–19%; placebo, 3%). Conclusions GEn (600 mg or 1200 mg) once daily significantly improved RLS symptoms and consequences of these symptoms in severe primary RLS. The most frequent TEAEs were somnolence and dizziness.

Highlights • Cervical dystonia has significant impact on quality of life of those affected. • Dilution options allow for treatment flexibility and individualized patient care. • AboBoNT-A is efficacious with similar safety and tolerability at either dilution., Introduction Cervical dystonia (CD) is a neurologic movement disorder with potentially disabling effects and significant impact on quality of life of those affected. AbobotulinumtoxinA (aboBoNT-A) was initially approved for a dilution of 500 U/1 mL and subsequently for a dilution of 500 U/2 mL, providing flexibility for clinicians to treat CD. Here, we explore the safety and efficacy of the 500 U/2 mL dilution versus 500 U/1 mL dilution of aboBoNT-A in a retrospective analysis based on published clinical trial data. Methods The safety and efficacy of aboBoNT-A in patients with CD was evaluated in three multicenter, double-blind, randomized, placebo-controlled trials and open-label extensions. Trials 1 (NCT00257660) and 2 (NCT00288509) evaluated the 500 U/1 mL dilution in 80 and 116 patients, respectively; Trial 3 (NCT01753310) evaluated the 500 U/2 mL dilution in 125 patients. Results Comparison of the adjusted mean difference in TWSTRS total scores at Week 4 from baseline for aboBoNT-A in Trial 1 (−6.0; 95% CI, −10.8, −1.3), Trial 2 (−8.8; 95% CI, −12.9, −4.7), and Trial 3 (−8.7; 95% CI, −13.2, −4.2) showed similar, significant improvements. Dysphagia and muscle weakness patterns were comparable across the three trials, indicating that an increased dilution of aboBoNT-A does not result in an increased risk of diffusion-related adverse events. Conclusion The results of these trials show that aboBoNT-A is similarly efficacious using either dilution, with similar safety and tolerability across trials. Having the 500 U/1 mL and 500 U/2 mL dilution volumes available provides further flexibility in administration, benefiting patient care.

Restless legs syndrome (RLS) is a common neurological condition defined by (1) an urge to move the legs, (2) worsening with inactivity, (3) improvement with movement, and (4) worsening at night. It effects women more than men and is most common in Northern Europeans. There is a strong genetic component, but other conditions including systemic iron deficiency, renal failure, and pregnancy also cause RLS symptoms. The main pathology is reduction in brain iron stores, even in the setting of normal serum iron measures. First-line treatments are dopamine agonists and alpha-2-delta blockers. Additional treatments include opioids and intravenous iron.

The clinical spectrum of restless legs syndrome (RLS) has not been described in a Chinese population. We aim to evaluate the detailed clinical profile in a cohort of unselected RLS patients in China.We enrolled RLS patients continuously according to the diagnostic criteria. Laboratory examinations were performed to exclude mimics and notable comorbidities.A total of 359 patients with RLS were enrolled. RLS symptoms were mostly symmetrical (65.2%), and purely unilateral RLS was not common (5.6%); however, unilateral dominant RLS was relatively more common. Only 1.1% of RLS patients reported no unpleasant sensations in the legs. The largest proportion of RLS patients described their uncomfortable sensation as indescribable (43.5%) and reported soreness (40.4%). In all, 8.9% of RLS patients described their abnormal sensation as painful, and 34.5% of RLS patients reported their symptoms fluctuated with seasonal trends. This population had a higher likelihood of an RLS family history. RLS patients with summer exacerbation had a younger age at RLS onset and longer disease duration (p 0.01). Iron deficiency without anemia was common in Chinese RLS patients. Early-onset RLS patients were more likely to have a positive family history (p 0.01), more summer worsening of symptoms (p 0.01) and more severely disturbed peripheral iron status (p 0.01) when compared to late-onset RLS patients.The subjective description is somewhat different, with Chinese RLS patients reporting less pain and more soreness than patients from Western countries. Seasonal fluctuation and iron deficiency without anemia are frequently seen in Chinese RLS patients and predict some other features. Differentiating these various subtypes can facilitate optimal management.

ObjectiveTo evaluate the long-term safety and efficacy of deutetrabenazine in patients with tardive dyskinesia (TD).MethodPatients 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.ResultsA 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).ConclusionsOverall, long-term treatment with deutetrabenazine was efficacious, safe, and well tolerated in patients with TD.Trial registration numberNCT02198794.

Study ObjectiveTo evaluate long-term efficacy of deutetrabenazine in patients with tardive dyskinesia (TD) by examining response rates from baseline in Abnormal Involuntary Movement Scale (AIMS) scores. Preliminary results of the responder analysis are reported in this analysis.BackgroundIn the 12-week ARM-TD and AIM-TD studies, the odds of response to deutetrabenazine treatment were higher than the odds of response to placebo at all response levels, and there were low rates of overall adverse events and discontinuations associated with deutetrabenazine.MethodPatients with TD who completed ARM-TD or AIM-TD were included in this open-label, single-arm extension study, in which all patients restarted/started deutetrabenazine 12mg/day, titrating up to a maximum total daily dose of 48mg/day based on dyskinesia control and tolerability. The study comprised a 6-week titration and a long-term maintenance phase. The cumulative proportion of AIMS responders from baseline was assessed. Response was defined as a percent improvement from baseline for each patient from 10% to 90% in 10% increments. AlMS score was assessed by local site ratings for this analysis.Results343 patients enrolled in the extension study (111 patients received placebo in the parent study and 232 patients received deutetrabenazine). At Week 54 (n=145; total daily dose [mean±standard error]: 38.1±0.9mg), 63% of patients receiving deutetrabenazine achieved ≥30% response, 48% of patients achieved ≥50% response, and 26% achieved ≥70% response. At Week 80 (n=66; total daily dose: 38.6±1.1mg), 76% of patients achieved ≥30% response, 59% of patients achieved ≥50% response, and 36% achieved ≥70% response. Treatment was generally well tolerated.ConclusionsPatients who received long-term treatment with deutetrabenazine achieved response rates higher than those observed in positive short-term studies, indicating clinically meaningful long-term treatment benefit.Presented at: American Academy of Neurology Annual Meeting; April 21–27, 2018, Los Angeles, California, USA.Funding Acknowledgements: This study was supported by Teva Pharmaceuticals, Petach Tikva, Israel.

There is limited data on motor restlessness in Parkinson's disease (PD). Here we evaluate for clinical differences between cohorts of idiopathic Restless Legs Syndrome (iRLS), PD patients with leg restlessness, and PD with RLS.We examined 276 consecutive PD patients for leg restlessness symptoms, we compared clinical features of PD patients with RLS, PD patients with leg restlessness but not meeting RLS criteria, PD patient without RLS and iRLS.A total of 262 PD patients who satisfied the inclusion criteria were analyzed. After excluding 23 possible secondary RLS or mimics, 28 were diagnosed with RLS and 18 with leg motor restlessness (LMR). Compared with iRLS patients, PD patients with RLS or LMR had older age of RLS/LMR onset, shorter duration of leg restlessness, less positive family history, different seasonal trends and more unilaterality of leg restlessness symptom (P0.01) which were often in accordance with dominant Parkinsonism side and related with Parkinsonism severity. PD patients with RLS/LMR had lower daily dosage (P0.01) and shorter duration (P0.05) of dopaminergic medication when RLS/LMR symptom onset than PD without leg restlessness. PD with LMR had less severe Parkinsonism (P0.05) and leg restlessness (P0.01) symptoms than PD with RLS.Clinical characteristics of PD patients with RLS and LMR were different from iRLS, differentiating these various subtypes can facilitate optimal treatment.

Objective This systematic review was performed to elucidate dosing practices, dosing conversions, and related outcomes from randomized, controlled trials that directly compared onabotulinumtoxinA (ONA) and abobotulinumtoxinA (ABO) at various dose conversion ratios for therapeutic use in movement disorders. Methods A systematic review of three medical literature databases (PubMed, the Cochrane Library, and EMBASE) was performed to identify relevant comparative clinical studies, systematic reviews, and meta-analyses published in the English language between January 1991 and January 2015. Studies that met predefined inclusion criteria were selected for formal data extraction and quality assessment. Results A total of 182 manuscripts were identified, of which four were included for analysis. Targeted clinical applications included neurological disorders. The studies compared ONA to ABO dose conversion ratios of 1:2.5 (n = 1), 1:3 (n = 2), and 1:4 (n = 2). One study compared both 1:3 and 1:4 ratios. An ONA:ABO conversion factor of 1:2.5 was associated with similar efficacy and side effects. An ONA:ABO ratio of 1:3 provided similar or higher efficacy, but an increased rate of adverse effects, and an ONA:ABO ratio of 1:4 was associated with higher efficacy, but with an excessive rate of intolerable side effects. Conclusion A dose conversion ratio of ONA to ABO between 1:2.5 and 1:3.0 provides comparable safety and efficacy for therapeutic movement disorders chemodenervation procedures.

Purpose/aim: AbobotulinumtoxinA (Dysport®, Ipsen Biopharmaceuticals, Inc., Basking Ridge, NJ, USA) is an acetylcholine release inhibitor and a neuromuscular blocking agent. The United States prescribing information for abobotulinumtoxinA previously indicated only one dilution for cervical dystonia: 500 U/1 mL. Clinical trial data supporting a larger volume with a 500 U/2 mL dilution would offer clinicians flexibility with injection volume to better meet patient needs.We conducted a 12-week, phase 3b, multicenter, randomized, double-blind, placebo-controlled trial (NCT01753310). Adult subjects with a primary diagnosis of cervical dystonia were randomized (2:1) to receive a single injection of either abobotulinumtoxinA, 500 U/2 mL dilution, or placebo. The primary efficacy endpoint was changed from baseline in Toronto Western Spasmodic Torticollis Rating Scale total score at Week 4.A total of 134 subjects (abobotulinumtoxinA, n = 89; placebo, n = 45) were randomized (intent-to-treat population) and 129 (abobotulinumtoxinA, n = 84; placebo, n = 45) completed the Week 4 primary endpoint evaluation (modified intent-to-treat population). In the modified intent-to-treat population, subjects receiving abobotulinumtoxinA experienced significantly greater changes from baseline versus placebo on the primary endpoint (weighted overall treatment difference -8.3, P0.001). The most common treatment-emergent adverse events (TEAEs) were dysphagia, muscle weakness, neck pain and headache. Overall, TEAEs were consistent with those reported in the abobotulinumtoxinA prescribing information (1 mL dilution) for cervical dystonia patients.This trial provides evidence that a 500 U/2 mL dilution is an effective treatment for cervical dystonia and exhibits a safety profile consistent with the known safety profile of abobotulinumtoxinA.

We discuss features of Parkinson’s disease psychosis (PDP) including symptomology and pathophysiology. Treatment options, including non-pharmacologic strategies, dose reduction of offending agents, and the addition of non-dopaminergic antipsychotics, are addressed. The efficacy of second-generation antipsychotics and novel agents is examined. Pimavanserin, a 5-HT2A/C receptor inverse agonist with no other receptor activity, has shown efficacy and tolerability and is now FDA approved for PDP treatment. Research into novel targets is ongoing. PDP is a morbid complication of Parkinson’s disease with complex incompletely understood mechanisms. Treatment is directed towards mitigation of psychosis without worsening of motor features.

Background The Fahn-Tolosa-Marin Clinical Rating Scale for Tremor (FTM) has been used in large trials for essential tremor (ET), but its anchors for ratings from 0 to 4 of upper limb tremor are probably too low for patients with severe tremor (tremor amplitude >4 cm; grade 4). The Essential Tremor Rating Assessment Scale (TETRAS) is a validated clinical scale designed specifically for the assessment of ET severity. TETRAS has anchors that span a larger range of tremor amplitudes (>20 cm = grade 4), making it more suitable for assessing patients with severe ET. However, there is no direct comparison of these scales in any clinical trial. Methods Upper limb postural and kinetic tremor items from both scales were compared using blinded, video-recorded examinations of patients with moderate-to-severe ET who participated in a trial of focused ultrasound thalamotomy. Results FTM ratings of postural and kinetic tremor correlated strongly with those of TETRAS. However, FTM exhibited a ceiling effect for severe tremor. Rest tremor, exclusive to FTM, correlated poorly with postural and kinetic tremor and had very poor test-retest reliability. In contrast, wing-beating postural tremor, exclusive to TETRAS, exhibited excellent test-retest reliability and a strong correlation with kinetic and limbs-extended-forward postural tremor. Test-retest reliabilities of the other TETRAS and FTM ratings were excellent, and both scales had good sensitivity to treatment effect. Conclusions TETRAS has 2 main advantages over FTM in the assessment of tremor severity: (1) the absence of a ceiling effect in patients with severe ET, and (2) the inclusion of wing-beating tremor.

Restless legs syndrome (RLS) is a chronic neurological disorder that interferes with rest and sleep. It has a wide spectrum of symptom severity, and treatment is started when symptoms become bothersome. Dopamine agonists and calcium channel apha-2-delta antagonists (gabapentin, gabapentin enacarbil and pregabalin) are first-line treatments; calcium channel alpha-2-deltas are preferred over dopamine agonists because they give less augmentation, a condition with symptom onset earlier in the day and intensification of RLS symptoms. Dopamine agonists can still be used as first-line therapy, but the dose should be kept as low as possible. Iron supplements are started when the serum ferritin concentration is ≤75 µg/L, or if the transferrin saturation is less than 20%. For severe or resistant RLS, a combined treatment approach can be effective. Augmentation can be very challenging to treat and lacks evidenced-based guidelines.

Parkinson's disease (PD) populations show that about 20% of patients meet criteria for restless legs syndrome (RLS). Nevertheless, pathological differences suggest RLS may actually prevent PD. Over 15 years, we collected patients with idiopathic RLS preceding onset of PD, as defined by onset of RLS greater than 5 years before motor symptoms of PD, or a family history of RLS and onset of RLS at least 1 year before PD. We then compared these to a control group of PD without RLS for demographics, age of onset, motor progression, dyskinesia, L-dopa equivalent dose, and PD phenotype at onset. The RLS/PD group (N = 36) had 13 females with 18 having a positive family history of RLS and six with a family history of PD. The PD control group (N = 36) had 10 females with 1 having a family history of RLS and nine with family history of PD. Age at motor onset of PD in the RLS/PD was older (64.15 ± 6.44 years vs. 56.81 ± 10.68) than for controls with PD (p < 0.001). After correcting for other risk factors and duration of follow-up, patients with idiopathic PD (21/36) developed dyskinesia more than RLS/PD (4/32) at final visit (p = 0.01). Our data suggest that idiopathic RLS may delay the onset of PD, reduce dyskinesia occurrence, and possibly reduce progression of PD.

Background In 2003, following a workshop at the National Institutes of Health, the International Restless Legs Syndrome Study Group (IRLSSG) developed updated diagnostic criteria for restless legs syndrome/Willis–Ekbom disease (RLS/WED). These criteria were integral to major advances in research, notably in epidemiology, biology, and treatment of RLS/WED. However, extensive review of accumulating literature based on the 2003 NIH/IRLSSG criteria led to efforts to improve the diagnostic criteria further. Methods The clinical standards workshop, sponsored by the WED Foundation and IRLSSG in 2008, started a four-year process for updating the diagnostic criteria. That process included a rigorous review of research advances and input from clinical experts across multiple disciplines. After broad consensus was attained, the criteria were formally approved by the IRLSSG executive committee and membership. Results Major changes are: (i) addition of a fifth essential criterion, differential diagnosis, to improve specificity by requiring that RLS/WED symptoms not be confused with similar symptoms from other conditions; (ii) addition of a specifier to delineate clinically significant RLS/WED; (iii) addition of course specifiers to classify RLS/WED as chronic-persistent or intermittent; and (iv) merging of the pediatric with the adult diagnostic criteria. Also discussed are supportive features and clinical aspects that are important in the diagnostic evaluation. Conclusions The IRLSSG consensus criteria for RLS/WED represent an international, interdisciplinary, and collaborative effort intended to improve clinical practice and promote further research.

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.

IntroductionTardive dyskinesia (TD) is an involuntary movement disorder resulting from exposure to dopamine-receptor antagonists. In the 12-week ARM-TD and AIM-TD studies, deutetrabenazine demonstrated significant improvements in Abnormal Involuntary Movement Scale (AIMS) scores at Week 12 compared with placebo, and was generally well tolerated.ObjectiveTo evaluate the efficacy and safety of long-term deutetrabenazine therapy in patients with TD.MethodsPatients with TD who completed the ARM-TD or AIM-TD studies were eligible to enter this open-label, single-arm, long-term safety study after they completed the 1-week washout period and final evaluation in the blinded portion of the trial. Efficacy endpoints included the change in AIMS score from baseline, and treatment success (defined as “much improved” or “very much improved”) on the Clinical Global Impression of Change (CGIC) and Patient Global Impression of Change (PGIC). This analysis reports results up to Week 54.Results304 patients enrolled in the extension study. At Week 54, the mean (standard error) change in AIMS score was –5.1 (0.52). After 6 weeks of deutetrabenazine treatment, the proportion of patients who achieved treatment success was 58% per the CGIC and 53% per the PGIC, and by Week 54 was 72% per the CGIC and 59% per the PGIC, thus demonstrating maintenance or enhancement of benefit over time. Deutetrabenazine was well tolerated for up to 54 weeks, and compared with the ARM-TD and AIM-TD studies, no new safety signals were detected.Conclusions54 weeks of deutetrabenazine treatment was generally efficacious, safe, and well tolerated in patients with TD.Presented at: The American Psychiatric Association 2017 Annual Meeting; May 20–24, 2017; San Diego, California, USA.Funding AcknowledgementsThis study was funded by Teva Pharmaceutical Industries, Petach Tikva, Israel.

Study ObjectiveTo evaluate the long-term safety and tolerability of deutetrabenazine in patients with tardive dyskinesia (TD) at 2years.BackgroundIn the 12-week ARM-TD and AIM-TD studies, deutetrabenazine showed clinically significant improvements in Abnormal Involuntary Movement Scale scores compared with placebo, and there were low rates of overall adverse events (AEs) and discontinuations associated with deutetrabenazine.MethodPatients who completed ARM-TD or AIM-TD were included in this open-label, single-arm extension study, in which all patients restarted/started deutetrabenazine 12mg/day, titrating up to a maximum total daily dose of 48mg/day based on dyskinesia control and tolerability. The study comprised a 6-week titration period and a long-term maintenance phase. Safety measures included incidence of AEs, serious AEs (SAEs), and AEs leading to withdrawal, dose reduction, or dose suspension. Exposure-adjusted incidence rates (EAIRs; incidence/patient-years) were used to compare AE frequencies for long-term treatment with those for short-term treatment (ARM-TD and AIM-TD). This analysis reports results up to 2 years (Week106).Results343 patients were enrolled (111 patients received placebo in the parent study and 232 received deutetrabenazine). There were 331.4 patient-years of exposure in this analysis. Through Week 106, EAIRs of AEs were comparable to or lower than those observed with short-term deutetrabenazine and placebo, including AEs of interest (akathisia/restlessness [long-term EAIR: 0.02; short-term EAIR range: 0–0.25], anxiety [0.09; 0.13–0.21], depression [0.09; 0.04–0.13], diarrhea [0.06; 0.06–0.34], parkinsonism [0.01; 0–0.08], somnolence/sedation [0.09; 0.06–0.81], and suicidality [0.02; 0–0.13]). The frequency of SAEs (EAIR 0.15) was similar to those observed with short-term placebo (0.33) and deutetrabenazine (range 0.06–0.33) treatment. AEs leading to withdrawal (0.08), dose reduction (0.17), and dose suspension (0.06) were uncommon.ConclusionsThese results confirm the safety outcomes seen in the ARM-TD and AIM-TD parent studies, demonstrating that deutetrabenazine is well tolerated for long-term use in TD patients.Presented at: American Academy of Neurology Annual Meeting; April 21–27, 2018, Los Angeles, California,USAFunding Acknowledgements: Funding: This study was supported by Teva Pharmaceuticals, Petach Tikva, Israel

Corticobasal degeneration (CBD) is a neurodegenerative, sporadic disorder of unknown cause. Few familial cases have been described.We aim to characterize the clinical, imaging, pathological and genetic features of two familial cases of CBD.We describe two first cousins with CBD associated with atypical MRI findings. We performed exome sequencing in both subjects and in an unaffected first cousin of similar age.The cases include a 79-year-old woman and a 72-year-old man of Native American and British origin. The onset of the neurological manifestations was 74 and 68 years respectively. Both patients presented with a combination of asymmetric parkinsonism, apraxia, myoclonic tremor, cortical sensory syndrome, and gait disturbance. The female subject developed left side fixed dystonia. The manifestations were unresponsive to high doses of levodopa in both cases. Extensive bilateral T1-W hyperintensities and T2-W hypointensities in basal ganglia and thalamus were observed in the female patient; whereas these findings were more subtle in the male subject. Postmortem examination of both patients was consistent with corticobasal degeneration; the female patient had additional findings consistent with mild Alzheimer's disease. No Lewy bodies were found in either case. Exome sequencing showed mutations leading to possible structural changes in MRS2 and ZHX2 genes, which appear to have the same upstream regulator miR-4277.Corticobasal degeneration can have a familial presentation; the role of MRS2 and ZHX2 gene products in CBD should be further investigated.

Lateral postural deviation in Parkinson's disease (PD) is not uncommon but has never been radiographically queried to evaluate for specific muscle anatomy. Ten subjects (9 female) were identified with paraspinal asymmetry on examination and MRI. Relative atrophy was seen diffusely in all paraspinal muscles (psoas, interspinalis, quadratus, multifidus, longissimus and ileocostalis). The quadratus, multifidus, longissimus and ileocostalis were the most asymmetric and equally involved. The interspinalis was less asymmetric, whereas the psoas was almost never asymmetric. Fatty infiltrates, consistent with radiographic myopathic degeneration, were often seen in the atrophic muscles. In 8/10 cases, the side of PD symptom onset demonstrated the greatest atrophy. Lateral postural deviation appears to result from ipsilateral paraspinal atrophy with fatty infiltration. Correlation with the most affected side suggests causality.

Uncontrolled pilot studies have suggested the efficacy of focused ultrasound thalamotomy with magnetic resonance imaging (MRI) guidance for the treatment of essential tremor.We enrolled patients with moderate-to-severe essential tremor that had not responded to at least two trials of medical therapy and randomly assigned them in a 3:1 ratio to undergo unilateral focused ultrasound thalamotomy or a sham procedure. The Clinical Rating Scale for Tremor and the Quality of Life in Essential Tremor Questionnaire were administered at baseline and at 1, 3, 6, and 12 months. Tremor assessments were videotaped and rated by an independent group of neurologists who were unaware of the treatment assignments. The primary outcome was the between-group difference in the change from baseline to 3 months in hand tremor, rated on a 32-point scale (with higher scores indicating more severe tremor). After 3 months, patients in the sham-procedure group could cross over to active treatment (the open-label extension cohort).Seventy-six patients were included in the analysis. Hand-tremor scores improved more after focused ultrasound thalamotomy (from 18.1 points at baseline to 9.6 at 3 months) than after the sham procedure (from 16.0 to 15.8 points); the between-group difference in the mean change was 8.3 points (95% confidence interval [CI], 5.9 to 10.7; P0.001). The improvement in the thalamotomy group was maintained at 12 months (change from baseline, 7.2 points; 95% CI, 6.1 to 8.3). Secondary outcome measures assessing disability and quality of life also improved with active treatment (the blinded thalamotomy cohort)as compared with the sham procedure (P0.001 for both comparisons). Adverse events in the thalamotomy group included gait disturbance in 36% of patients and paresthesias or numbness in 38%; these adverse events persisted at 12 months in 9% and 14% of patients, respectively.MRI-guided focused ultrasound thalamotomy reduced hand tremor in patients with essential tremor. Side effects included sensory and gait disturbances. (Funded by InSightec and others; ClinicalTrials.gov number, NCT01827904.).

Objective: To make evidence-based recommendations regarding restless legs syndrome (RLS) management in adults. Methods: Articles were classified per the 2004 American Academy of Neurology evidence rating scheme. Recommendations were tied to evidence strength. Results and recommendations: In moderate to severe primary RLS, clinicians should consider prescribing medication to reduce RLS symptoms. Strong evidence supports pramipexole, rotigotine, cabergoline, and gabapentin enacarbil use (Level A); moderate evidence supports ropinirole, pregabalin, and IV ferric carboxymaltose use (Level B). Clinicians may consider prescribing levodopa (Level C). Few head-to-head comparisons exist to suggest agents preferentially. Cabergoline is rarely used (cardiac valvulopathy risks). Augmentation risks with dopaminergic agents should be considered. When treating periodic limb movements of sleep, clinicians should consider prescribing ropinirole (Level A) or pramipexole, rotigotine, cabergoline, or pregabalin (Level B). For subjective sleep measures, clinicians should consider prescribing cabergoline or gabapentin enacarbil (Level A), or ropinirole, pramipexole, rotigotine, or pregabalin (Level B). For patients failing other treatments for RLS symptoms, clinicians may consider prescribing prolonged-release oxycodone/naloxone where available (Level C). In patients with RLS with ferritin ≤75 μg/L, clinicians should consider prescribing ferrous sulfate with vitamin C (Level B). When nonpharmacologic approaches are desired, clinicians should consider prescribing pneumatic compression (Level B) and may consider prescribing near-infrared spectroscopy or transcranial magnetic stimulation (Level C). Clinicians may consider prescribing vibrating pads to improve subjective sleep (Level C). In patients on hemodialysis with secondary RLS, clinicians should consider prescribing vitamin C and E supplementation (Level B) and may consider prescribing ropinirole, levodopa, or exercise (Level C).

To evaluate the efficacy and tolerability of lubiprostone (Amitiza) for constipation in Parkinson disease (PD) in a double-blind, randomized, controlled study.Patients with PD and clinically meaningful constipation (constipation rating scale score10 [range: 0-28]) were recruited from 2 academic movement disorder centers to participate in the study. After enrollment, patients were initially followed for 2 weeks and then were randomly assigned 1:1 to lubiprostone, and the dose was titrated up to 48 μg/day. They returned 4 weeks later for a final assessment. Data included stool diaries and global impressions (co-primary endpoints), demographics, Unified Parkinson's Disease Rating Scale scores, constipation scale scores, visual analog scale (VAS) scores, a stool diary, and adverse events.Fifty-four subjects (39 male, mean age 67.0 ± 10.1 years, and mean duration of PD 8.3 ± 5.4 years) were randomly assigned to lubiprostone or placebo. One patient in the drug group discontinued the study because of logistics, and one patient in the placebo group discontinued the study because of lack of efficacy. A marked or very marked clinical global improvement was reported by 16 of 25 (64.0%) subjects receiving drug vs 5 of 27 (18.5%) subjects receiving placebo (p = 0.001). The constipation rating scale (p0.05), VAS (p = 0.001), and stools per day in the diary (p0.001) all improved with drug compared with placebo. Adverse events with drug were mild, most commonly intermittent loose stools.In this randomized controlled trial, lubiprostone seemed to be well tolerated and effective for the short-term treatment of constipation in PD.

Stereotypies are frequently reported in frontotemporal dementia. Their pathophysiology and optimal treatment are largely unexplored. The author reports seven cases of marked stereotype in patients with probable frontotemporal dementia who were treated with tetrabenazine, a monoamine inhibitor. All patients had near-complete resolution of stereotypy. Six patients stopped tetrabenazine at some point, with return of their stereotype within 24 hours, which again improved in the four who restarted therapy. Efficacy has not waned over time. Tetrabenazine dramatically improved stereotypies in patients with dementia. This observation could increase understanding of this interesting phenotype.

Background: This evidence-based guideline is an update of the 2005 American Academy of Neurology practice parameter on the treatment of essential tremor (ET). Methods: A literature review using MEDLINE, EMBASE, Science Citation Index, and CINAHL was performed to identify clinical trials in patients with ET published between 2004 and April 2010. Results and Recommendations: Conclusions and recommendations for the use of propranolol, primidone (Level A, established as effective); alprazolam, atenolol, gabapentin (monotherapy), sotalol, topiramate (Level B, probably effective); nadolol, nimodipine, clonazepam, botulinum toxin A, deep brain stimulation, thalamotomy (Level C, possibly effective); and gamma knife thalamotomy (Level U, insufficient evidence) are unchanged from the previous guideline. Changes to conclusions and recommendations from the previous guideline include the following: 1) levetiracetam and 3,4-diaminopyridine probably do not reduce limb tremor in ET and should not be considered (Level B); 2) flunarizine possibly has no effect in treating limb tremor in ET and may not be considered (Level C); and 3) there is insufficient evidence to support or refute the use of pregabalin, zonisamide, or clozapine as treatment for ET (Level U). Neurology ® 2011;77:1752–1755

Background A genome-wide association study (GWAS) identified significant association between variants in MEIS1 , BTBD9 , and MAP2K5 / SKOR1 and restless legs syndrome (RLS). However, many independent replication studies are needed to unequivocally establish a valid genotype-phenotype association across various populations. To further validate the GWAS findings, we investigated three variants, rs2300478 in MEIS1 , rs9357271 in BTBD9 , and rs1026732 in MAP2K5 / SKOR1 in 38 RLS families and 189 RLS patients/560 controls from the US for their association with RLS. Method Both family-based and population-based case-control association studies were carried out. Results The family-based study showed that SNP rs1026732 in MAP2K5 / SKOR1 was significantly associated with RLS ( P =0.01). Case-control association studies showed significant association between all three variants and RLS ( P =0.0001/OR=1.65, P =0.0021/OR=1.59, and P =0.0011/OR=1.55 for rs2300478, rs9357271, and rs1026732, respectively). Conclusion Variants in MEIS1 , BTBD9 , and MAP2K5 / SKOR1 confer a significant risk of RLS in a US population.

SUMMARY Parkinson’s disease (PD) patients demonstrate a variety of sleep/wake complaints. Some of these are associated with dopaminergic dysfunction, some presumed to arise from nondopaminergic PD pathology, some from PD treatments and, in some, the etiologies are multifactorial or unknown. Optimal management of sleep/wake problems requires a good understanding of sleep/wake principals in the PD population, as there are few controlled trials to dictate therapy. In this article, we review the main causes of sleep/wake disorders in PD patients, namely sleep fragmentation, excessive daytime sleepiness, restless legs syndrome, periodic limb movement of sleep, rapid eye movement sleep behavioral disorder and sleep apnea. Available therapies and management recommendations for each disorder are given particular emphasis.

Background: The 24-week, double-blind Efficacy and Safety Evaluation in PD–Adjunct (EASE-PD Adjunct) study randomized patients with advanced Parkinson’s disease (PD) suboptimally controlled with levodopa to once-daily placebo or adjunctive ropinirole prolonged release (2–24 mg/day). We investigated the effect of ropinirole prolonged release on nocturnal symptoms in these patients. Methods: Total and grouped item PD Sleep Scale (PDSS) scores were analyzed post hoc in patients with baseline PDSS total scores ≤ 100 (troublesome nocturnal symptoms) and >100. Results: Baseline PDSS total score was ≤ 100 in 93 of 198 (47%) and 89 of 189 (47%) patients receiving ropinirole prolonged release and placebo, respectively; this subgroup displayed evidence at baseline of greater daily awake ‘off’ time, reduced night-time sleep and worse quality of life, than the PDSS >100 subgroup. Significant improvements with ropinirole prolonged release versus placebo in PDSS score from baseline to Week 24 last observation carried forward were observed for those with baseline PDSS ≤ 100 [adjusted mean treatment difference 9.0 (95% CI: 2.76, 15.33; P = 0.0051)], but not >100. The PDSS ≤ 100 subgroup demonstrated treatment benefits for PDSS groupings of motor symptoms on waking and global quality of sleep. Changes in daytime sleepiness were similar between treatment groups. The PDSS >100 subgroup demonstrated significant treatment benefit for global quality of sleep. The unadjusted odds ratio for a positive response with ropinirole prolonged release relative to placebo, for the PDSS ≤ 100 subgroup, was 2.90 (95% CI: 1.42, 5.95, P = 0.004). Conclusions: Once-daily ropinirole prolonged release improves nocturnal symptoms in patients with advanced PD not optimally controlled with levodopa who suffer troublesome nocturnal disturbance.

Summary Background Human retinal pigment epithelial (RPE) cells produce levodopa and their transplantation into the striatum might improve continuity of administration compared with that achieved with oral levodopa. We aimed to assess the safety, tolerability, and efficacy of transplantation of microcarrier-bound human RPE cells versus a sham surgery control in patients with advanced Parkinson's disease. Methods In this randomised, double-blind study eligible patients were aged 36–70 years, had been symptomatic for at least 5 years, were in Hoehn and Yahr stage 3–4 and had unified Parkinson's disease rating scale (UPDRS) motor scores of 38–70 when off medication (off state), and had symptoms that responded to oral levodopa but were insufficiently controlled by optimised pharmacotherapy. Randomisation was done in a 1:1 ratio. Only the neurosurgical team was aware of treatment assignments. During stereotactic transplantation around 325 000 cells per side were injected into the postcommissural putamen; sham surgery patients received partial burr holes. The primary efficacy endpoint was change in UPDRS off-state motor score at 12 months. This study is registered with ClinicalTrials.gov, number NCT00206687. Findings Of 71 enrolled patients, 35 underwent cell transplantation and 36 sham surgery. Change in mean motor scores did not differ significantly between groups (−10·5 [SD 10·26] for transplantation vs −10·1 [SD 12·26] for sham surgery, p=0·9). The overall rate of adverse events was similar in the two study groups, although the number attributable to surgery or RPE cells (mostly neurological or psychiatric) was higher in transplant recipients. Two and seven patients died in the sham surgery and transplantation group, respectively; one death in the latter group was possibly related to surgery or RPE cells. Interpretation Transplantation of human RPE cells provided no antiparkinsonian benefits compared with sham surgery. Funding Bayer HealthCare AG.

Restless legs syndrome (RLS, MIM 102300) is a common neurological disorder characterized by an urge to move the limbs and is usually accompanied by uncomfortable sensations that worsen with rest, improve with movement, and are worse in the evening or night.1 It can impair sleep and adversely affects health and quality of life. Epidemiological studies of RLS revealed a prevalence rate of 5 to 12% in Caucasian populations, which is much higher than the rate in Asian and African populations (0.1–0.6%), suggesting a possible role for racial or ethnic factors in the occurrence of RLS.2 Furthermore, RLS is as much as twice more common in females than in males.3 RLS is associated with a positive family history in 45 to 65% of patients, and twin studies showed a high concordant rate in monozygotic twins.4 Our familial aggregation analysis showed a correlation rate of 0.17 between first degree relatives and heritability of 0.60.5 All these results suggest that genetic factors play an important role in the pathogenesis of RLS. Genome-wide linkage studies have identified six genetic loci for RLS, including RLS1 on chromosome 12q12–q21,6 RLS2 on 14q13–21,7 RLS3 on 9p24-p22,5 RLS4 on 2q33,8 RLS5 on 20p13, and RLS6 on 16p12.1.9,10 Till date, no disease-causing mutations from these loci have been reported. A recent genome-wide association study (GWAS) in a Caucasian population showed that two single nucleotide polymorphisms (SNPs), including rs1975197 and rs4626664 located within introns of the PTPRD gene, were significantly associated with RLS.11 The PTPRD gene is located within the RLS3 locus reported by our group.5 In this study, we took advantage of the 15 large families used for identifying the RLS3 locus to independently assess whether SNPs in PTPRD (ENST00000381196) are associated with RLS using a family-based sibling transmission disequilibrium test (Sib-TDT). We also evaluated the association using a population- based association study in a cohort of 189 sporadic patients and 560 controls. To the best of knowledge, this is the first study to replicate the association between variants in PTPRD gene and RLS. Furthermore, we scanned the sequences of all coding exons and boundaries between exons and introns of PTPRD gene in the 15 probands from the 15 different families to identify potential disease-causing mutations.

Objective The aim of this study was to analyze outcomes after 1 year of bilateral STN deep brain stimulation (DBS) in relatively young-onset patients with multiple system atrophy-Parkinsonism (MSA-P). Background The efficacy of DBS has been demonstrated in idiopathic Parkinson's disease. However, the experience with DBS in relatively young-onset MSA-P is limited and controversial. Methods Information about the demographic and clinical data from five MSA patients treated with STN DBS was entered into a database and analyzed. Results Five patients with relatively young-onset MSA (mean age at onset 42.2 ± 2.2 years, 3 women, 2 men) have been treated with bilateral STN stimulators, the mean duration between DBS surgery and disease onset was 7.0 ± 3.5 years. All of the patients had dyskinesia and postural instability, and subjective benefit from levodopa. During the 6 months after surgery, the clinical status of three patients improved with a decrease of dyskinesia. However, by 1 year, the symptoms reappeared and progressed in all patients. Overall, the mean “off” medication UPDRS-III score worsened 23.5 ± 15.3 1 year after surgery and the levodopa dosage was not reduced. Conclusions This data does not support the use of STN DBS for relatively young-onset MSA-P.

Essential tremor (ET) is a common movement disorder with clinical features that manifest with both motor (tremor and balance disorders) and non-motor (such as mild cognitive deficits and hearing loss) symptoms. The diagnosis of ET is based on the presence of an action tremor of greater severity than enhanced physiological tremor, without other identifiable causes. Patients with ET experience a decrease in the performance of their motor skills and social activities, and a decline in their quality of life. The pathophysiology of ET is still not clear. Pharmacotherapy for ET is indicated if the disease interferes with the patient's quality of life. Propranolol, a nonselective β-adrenergic receptor antagonist, and primidone, an antiepileptic, remain the standard treatments for ET. However, studies show that several other agents, including topiramate, gabapentin and zonisamide, might also be beneficial. Local injections of botulinum toxins and surgical interventions such as thalamic deep brain stimulation play a role as alternative options when pharmacological treatment is not satisfactory. Several new agents including 1-octanol, pregabalin and sodium oxybate are currently under investigation.

Levodopa use in fluctuating Parkinson's disease (PD) is complicated by an inconsistent and prolonged onset to clinical improvement. An orally dissolved carbidopa/levodopa (OD C/L) preparation (Parcopa UCB Pharma) is available in the United States. This offers potential advantages to shorten the duration from ingestion to clinical improvement. Surprisingly, this has never been clinically assessed. We tested 20 patients with fluctuating PD and a Unified Parkinson's Disease Rating Scale (UPDRS) "off" motor score of ≥ 25 in a 2-day, single-dose, double-blind, double-dummy, crossover study. Patients arrived in the morning in the practically defined "off" state and were randomly assigned to receive identical doses of either oral C/L and OD placebo or OD C/L and oral C/L placebo on 1st day and the reverse combination on a 2nd day. After training, patients underwent bilateral hand tapping at baseline and every 5 minutes for 60 minutes after dose ingestion. Stride length (SL) was recorded at 5-minute intervals with an ambulatory gait monitor. Patients identified their subjective latency to "on" and noted drug preferences and adverse events. They also underwent a UPDRS motor examination at baseline and 60 minutes after dose. Twenty subjects [15 male, age 68.7 (9.7), PD duration 13.4 (6.8)] completed. There were no significant group differences in tapping speed, subjective time to "on," latency of increased SL, or overall preference. However, all trends did favor OD C/L. Adverse events were similar. This small pilot study did not show significant group differences favoring OD C/L; however, larger studies may be justified, and individual patients may benefit.

This randomized, double-blinded, placebo-controlled trial (NCT00135993) assessed efficacy and safety of the dopamine agonist rotigotine in the treatment of idiopathic restless legs syndrome (RLS) over a 6-month maintenance period. A total of 505 eligible participants with moderate to severe RLS (IRLS sum score >or= 15) were randomly assigned to five groups to receive either placebo or rotigotine (0.5, 1, 2, or 3 mg/24 hr) delivered by once-daily transdermal patch (fixed-dose regimen). The two co-primary efficacy parameters decreased from baseline to end of maintenance in IRLS sum score and in clinical global impressions (CGI-1) score. On both primary measures, 2 and 3 mg/24 hr rotigotine was superior to placebo (P < 0.001). Adjusted treatment differences to placebo for the IRLS sum score were -4.5 (95% CI: -6.9, -2.2) for 2 mg/24 hr rotigotine, -5.2 (95% CI: -7.5, -2.9) for 3 mg/24 hr rotigotine, and for CGI item 1 -0.65 (95% CI: -1.0, -0.3) and -0.9 (95% CI: -1.3, -0.5) for the 2 and 3 mg/24 hr doses, respectively. Skin reactions (27%) and known dopaminergic side effects such as nausea (18.1%) and headache (11.6%) were mostly mild or moderate in rotigotine subjects. Rotigotine transdermal patches releasing 2 to 3 mg/24 hr significantly reduced the severity of RLS symptoms. Treatment efficacy was maintained throughout the 6-month double-blind period.

This study was designed to follow the long-term efficacy, safety, and tolerability of rasagiline for Parkinson's disease (PD) with data collected from all patients who had ever taken rasagiline during the 12-month TEMPO monotherapy trial (N = 398) and subsequent open-label extension. Patients were followed for up to 6.5 years with a mean of 3.5 +/- 2.1 years. After 12 months, additional PD medications were added as required. Of patients remaining in the trial at 2 years, 46% were maintained on rasagiline monotherapy. The majority of patients received a dopamine agonist prior to levodopa as the first additional dopaminergic agent. Analysis using a Kaplan-Meier method indicated that by 5.4 years only 25% of patients progressed to Hoehn & Yahr stage III. Rasagiline was well tolerated, with 11.3% of patients (45/398) withdrawing because of an adverse event. Rasagiline therapy for PD was effective, well tolerated, and safe in this long-term trial.

IntroductionIn the 12-week ARM-TD and AIM-TD studies, deutetrabenazine showed clinically significant improvements in Abnormal Involuntary Movement Scale (AIMS) scores at Week 12 compared with placebo, and was generally well tolerated.ObjectiveTo evaluate the long-term safety/tolerability and efficacy of deutetrabenazine in patients with TD. Week 54 open-labelresults are reported in this interim analysis.MethodsPatients with TD who completed ARM-TD or AIM-TD were included in this open-label, single-arm extension study, in which all patients restarted/started deutetrabenazine 12 mg/day, titrating up to a maximum total daily dose of 48 mg/day based on dyskinesia control and tolerability. The study comprised a 6-week titration period and a long-term maintenance phase. Safetymeasures included incidence of adverse events (AEs), serious AEs (SAEs), drug-related AEs, and AEs leading to withdrawal, dose reduction, or dose suspension. This analysis reports results up to Week 54.Results304 patients enrolled in the extension study. There were 215 patient-years of exposure in this analysis, and exposure-adjusted incidence rates (EAIRs) of AEs (incidence/patient-years) were comparable to or lower than those observed with short-term deutetrabenazine treatment and placebo. The frequency of SAEs (EAIR 0.14) was similar to rates observed with short-termplacebo (EAIR 0.33) and deutetrabenazine (EAIR range 0.06–0.33) treatment. AEs leading to study discontinuation (EAIR 0.08), dose reduction (EAIR 0.17), and dose suspension (EAIR 0.09) were uncommon.ConclusionsLong-term treatment with deutetrabenazine was generally safe and well tolerated in patients with TD, and did not result in cumulative toxicity.Presented at: The American Psychiatric Association 2017 Annual Meeting; May 20–24, 2017; San Diego, California, USA.Funding AcknowledgementsThis study was funded by Teva Pharmaceutical Industries, Petach Tikva, Israel.

IntroductionTardive dyskinesia (TD) is an involuntary movement disorder that is often irreversible, can affect any body region, and can be debilitating. In the ARM-TDand AIM-TD studies, deutetrabenazine treatment demonstrated statistically and clinically significant reductions in Abnormal Involuntary Movement Scale (AIMS) scores at Week 12 compared with placebo (primary endpoint).ObjectiveTo evaluate the efficacy of deutetrabenazine, as measured by the Clinical Global Impression of Change (CGIC) scale, in patients with TD from the pooled ARM-TDand AIM-TD (24 and 36 mg/day doses) data sets, as compared with the pooled placebo cohort.MethodsARM-TD and AIM-TD were 12-week, randomized, double-blind, placebo-controlled studies that evaluated the safety and efficacy of deutetrabenazine for thetreatment of TD. The key secondary endpoint of each study was the proportion of patients “much improved” or “very much improved” (treatment success) at Week 12 on theCGIC.ResultsAt Week 12, the odds of treatment success among patients treated with deutetrabenazine (n=152) was more than double that of patients given placebo (n=107; odds ratio: 2.12; P=0.005). In a categorical analysis of CGIC ratings, patients treated with deutetrabenazine showed greater improvement than patients given placebo (P=0.003). Patients treated with deutetrabenazine also had a significantly better treatment response than those given placebo (least-squares mean CGIC score treatment difference: –0.4; P=0.006).ConclusionsDeutetrabenazine treatment led to statistically and clinically significant improvements in TD symptoms based on the CGIC result, suggesting that clinicians were able to recognize the benefit in patients treated with deutetrabenazine.Presented at: The International Congress of Parkinson’s Disease and Movement Disorders; June 4–8, 2017; Vancouver, British Columbia, Canada.Funding AcknowledgementsThese studies were funded by Teva Pharmaceutical Industries, Petach Tikva, Israel.

Magnetic resonance imaging (MRI) is increasingly integrated into neurological diagnostics. In addition to functional MRI, a large number of sequences (T1W, T2W, PD, T2*W gradient echo, diffusion-weighted imaging (DWI), and diffusion tensor imaging (DTI)), investigate CNS abnormalities. Objective quantification techniques (T1W voxel-based morphometry) can also discern subtle anatomical differences. Parkinsonian conditions such as Parkinson's disease, multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration and manganese-induced parkinsonism can clinically overlap, yet have very different prognoses and treatments. Relatively little radiographic interest has focused on movement disorders. Nevertheless in the past decade, a variety of findings, often subtle and routinely overlooked, have emerged to help the clinician differentiate these conditions. This review will summarize and discuss MRI findings in parkinsonian conditions. Most data concern either structural abnormalities or the imaging sequelae of abnormal iron deposition, common in some parkinsonian conditions.

Objective To assess the safety and adverse effect profile of continued use of intermittent subcutaneous apomorphine to treat "off" episodes in subjects with advanced Parkinson disease. Methods The study enrolled subjects with Hoehn and Yahr stage II-V Parkinson disease who were experiencing "off" events despite an optimized oral medication regimen. After baseline assessment and subcutaneous apomorphine dose titration (2-10mg/dose), subjects received > or =12 months of open-label treatment, as needed, for "off" episodes. Results Of the 546 subjects in the study population, the majority used apomorphine on a daily basis; the average dose was 4.0 mg. A total of 187 subjects discontinued treatment because of adverse events (AEs). Most AEs were mild to moderate and expected with apomorphine. The AEs most commonly classified as definitely, probably, or possibly treatment related were nausea and vomiting, dyskinesia, dizziness, somnolence, hallucination, yawning, and injection site bruising. Serious AEs occurred in 199 subjects, but only 27 were considered to be probably or possibly treatment related. None of the 45 deaths recorded in the study were attributed to apomorphine. Conclusions Long-term use of intermittent apomorphine dosing for treatment of "off" episodes was generally associated with mild-to-moderate AEs.

Objective To assess tetrabenazine (TBZ) efficacy by evaluating the change in Huntington disease-associated chorea resulting from TBZ treatment withdrawal. Methods Thirty patients treated in the long term were randomized to 1 of 3 groups assigned to withdraw from TBZ in a double-blind, staggered fashion during a 5-day period. Results The chorea scores of subjects withdrawn from TBZ treatment increased by 5.3 units from days 1 to 3, whereas the scores of the group with partial or no withdrawal of TBZ treatment increased by 3.0 units (P = 0.0773). A post hoc analysis of the linear trend was positive for reemergent chorea (P = 0.0486). No serious adverse events were reported after abrupt withdrawal of TBZ treatment. Conclusions The trend for reemergence of chorea in patients with Huntington disease who were withdrawn from TBZ treatment is consistent with the findings from previous studies, thus showing the effectiveness of TBZ in reducing chorea.

Freezing of gait (FOG) is common in advanced Parkinson’s disease (PD), is resistant to treatment and negatively impacts quality of life. In this study an ambulatory FOG monitor was validated in 11 PD patients. The vertical linear acceleration of the left shank was acquired using an ankle-mounted sensor array that transmitted data wirelessly to a pocket PC at a rate of 100 Hz. Power analysis showed high-frequency components of leg movement during FOG in the 3–8 Hz band that were not apparent during volitional standing, and power in this ‘freeze’ band was higher (p = 0.00003) during FOG preceded by walking (turning or obstacles) than FOG preceded by rest (gait initiation). A freeze index (FI) was defined as the power in the ‘freeze’ band divided by the power in the ‘locomotor’ band (0.5–3 Hz) and a threshold chosen such that FI values above this limit were designated as FOG. A global threshold detected 78% of FOG events and 20% of stand events were incorrectly labeled as FOG. Individual calibration of the freeze threshold improved accuracy and sensitivity of the device to 89% for detection of FOG with 10% false positives. Ambulatory monitoring may significantly improve clinical management of FOG. © 2007 Elsevier B.V. All rights reserved.

Item does not contain fulltext Essential tremor (ET) is a common cause of significant disability, but its etiologies and pathogenesis are poorly understood. Research has been hampered by the variable definition of ET and by non-standardized research approaches. The National Institute of Neurological Disorders and Stroke (USA) invited experts in ET and related fields to discuss current knowledge, controversies, and gaps in our understanding of ET and to develop recommendations for future research. Discussion focused on phenomenology and phenotypes, therapies and clinical trials, pathophysiology, pathology, and genetics. Across all areas, the need for collaborative and coordinated research on a multinational level was expressed. Standardized data collection using common data elements for genetic, clinical, neurophysiological, and pathological studies was recommended. Large cohorts of patients should be studied prospectively to collect bio-samples, characterize the natural history of the clinical syndrome including patient-oriented outcomes, investigate potential etiologies of various phenotypes, and identify pathophysiological mechanisms. In particular, cellular and system-level mechanisms of tremor oscillations should be elucidated because they may yield effective therapeutic targets and biomarkers. A neuropathology consortium was recommended to standardize postmortem analysis and further characterize neuropathological observations in the cerebellum and elsewhere. Furthermore, genome-wide association studies on large patient cohorts (>10,000 patients) may allow the identification of common genes contributing to risk, and whole exome or genome sequencing may enable the identification of genetic risk and causal mutations in cohorts and well-characterized families.