Temporal Course of the Tourette Syndrome Clinical Triad

Background: Tourette syndrome (TS) is a disorder characterized by childhood onset of motor and phonic tics, often with improvement of tic symptoms by young adult years. The temporal course of tics and commonly comorbid behavioral symptoms is still not well characterized. Methods: In order to clarify the time course of tics and comorbid attention deficit hyperactivity disorder (ADHD) or obsessive compulsive disorder (OCD) in TS, we administered a brief survey regarding the course of symptoms at a single point in time to 53 TS patients aged 13–31 years. Results: Mean age (±SD) at symptom onset was 7.9 (±3.6) years for tics, 7.9 (±3.5) for ADHD, and 9.2 (±5.0) for OCD. Age at peak symptom severity was 12.3 (±4.6) years for tics, 10.8 (±3.8) for ADHD, and 12.6 (±5.5) for OCD. Tics, ADHD, and OCD were reported to be no longer present in 32.0%, 22.8%, and 21.0% of subjects, respectively. Decline in symptom severity began at age 14.7 (±3.7) years for tics, 13.9 (±2.9) for ADHD, and 15.1 (±5.0) for OCD. Remission of symptoms occurred at age 17.4 (±3.8) years for tics, 17.4 (±1.3) for ADHD, and 15.6 (±2.3) for OCD. Discussion: Our data confirm and expand previously reported TS spectrum symptom milestones and may guide design of future research aimed at improving the course of TS. Keywords: Tourette, obsessive compulsive disorder, attention deficit hyperactivity disorder, tic Citation: Shprecher DR, Rubenstein LA, Gannon K, et al. Temporal course of the Tourette syndrome clinical triad. Tremor Other Hyperkinet Mov. 2014; 4. doi: 10.7916/D8HD7SV

Elucidating the Nature and Mechanism of Tic Improvement in Tourette Syndrome: A Pilot Study

Background: For unclear reasons, many Tourette syndrome (TS) children report near‐complete tic remission by young adulthood. Immature maturation of brain networks, observed with resting‐state functional MRI (rs‐fc‐MRI) in adolescents and adults with TS, might evolve to a mature pattern in adults who experience tic improvement or remission. We explored the feasibility of testing this hypothesis in our population of young adult TS males, each with prior clinical assessments completed during childhood as part of a separate TS Association Genetics Consortium study. Methods: A total of 10 TS males (off tic suppressing drugs for at least 6 months) aged 19–32 years, mean follow‐up interval 7.5 (2 to 13) years, and 11 neurologically normal controls were enrolled and underwent 3‐Tesla structural and rs‐fc‐MRI sequences. Results: The mean change in Yale Global Tic Severity Scale (YGTSS) was −31.5% (total) and −26.6% (YGTSS motor+vocal). Two subjects reported resolution of tic‐related disability, with drops from mean 45 to 16.5 (YGTSS‐total) and 25 to 11.5 (YGTSS motor+vocal.). Rs‐fc‐MRI revealed significantly increased connectivity between the ipsilateral anterior and mid cingulate cortex and striatum, increased connectivity between local connections, and decreased connectivity between more distant connections; representing an immature connectivity pattern. Discussion: Similar to previous reports, we found immature patterns of functional connectivity in adult TS subjects. Despite a lack of complete tic remission, two subjects exhibited dramatic drops in tic severity that correlated with tic‐related disability improvement. More work is needed to elucidate the mechanism of such dramatic improvement in TS

Non-REM sleep with hypertonia in Parkinsonian Spectrum Disorders: A pilot investigation.

INTRODUCTION: From an ongoing multicenter effort toward differentiation of Parkinsonian spectrum disorders (PSD) from other types of neurodegenerative disorders, the sleep biomarker non-rapid-eye-movement sleep with hypertonia (NRH) emerged. METHODS: This study included in the PSD group patients with dementia with Lewy bodies/Parkinson disease dementia (DLB/PDD = 16), Parkinson disease (PD = 16), and progressive supranuclear palsy (PSP = 13). The non-PSD group included patients with Alzheimer disease dementia (AD = 24), mild cognitive impairment (MCI = 35), and a control group with normal cognition (CG = 61). In-home, multi-night Sleep Profiler studies were conducted in all participants. Automated algorithms detected NRH, characterized by elevated frontopolar electromyographic power. Between-group differences in NRH were evaluated using Logistic regression, Mann-Whitney U and Chi-squared tests. RESULTS: NRH was greater in the PSD group compared to non-PSD (13.9 ± 11.0% vs. 3.1 ± 4.7%, P < 0.0001). The threshold NRH≥5% provided the optimal between-group differentiation (AUC = 0.78, P < 0.001). NRH was independently associated with the PSD group after controlling for age, sex, and SSRI/SNRI use (P < 0.0001). The frequencies of abnormal NRH by subgroup were PSP = 92%, DLB/PDD = 81%, PD = 56%, MCI = 26%, AD = 17%, and CG = 16%. The odds of abnormal NRH in each PSD subgroup ranged from 3.7 to 61.2 compared to each non-PSD subgroup. The night-to-night and test-retest intraclass correlations were excellent (0.78 and 0.84, both P < 0.0001). CONCLUSIONS: In this pilot study, NRH appeared to be a novel candidate sleep biomarker for PSD-related neurodegeneration. Future studies in larger cohorts are needed to confirm these findings, understand the etiology of NRH magnitude/duration, and determine whether it is an independent prodromal marker for specific neurodegenerative pathologies

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

High-Order Visual Processing, Visual Symptoms, and Visual Hallucinations: A Possible Symptomatic Progression of Parkinson's Disease

Objective: To determine whether Parkinson disease (PD) patients with (VH) have different clinical characteristics and gray-matter volume than those with visual misperceptions (VM) or other visual symptoms (OvS).Background: The spectrum of visual complaints in PD is broad and complex.Methods: We conducted a retrospective chart review of 525 PD patients to identify the frequency of visual symptoms and the association with clinical and radiological features. Brain volumetric MRI data was analyzed using multivariate logistic regression to differentiate cases with and without visual symptoms.Results: Among 525 PD cases, visual complaints were documented in 177 (33.7%). Among these, 83 (46.9%) had VH, 31 (17.5%) had VM, and 63 (35.6%) had OvS (diplopia, blurry vision, photophobia, dry eyes, and eye pain or soreness). When compared to OvS, patients with VH had significantly higher age, duration of disease, rate of REM sleep behavior disorder, and cognitive impairment. Visual hallucinations patients had decreased age-adjusted volumetric averages in 28/30 gray-matter regions when compared to PD without visual symptoms and 30/30 gray-matter regions when compared to VM patients.Conclusions: Visual symptoms in PD may represent a spectrum from OvS to VM to VH, with progression of the latter associated with older age, duration of disease, presence of REM sleep behavior disorder, cognitive impairment, and decreased gray-matter volume

Clinical Practice Patterns in Tic Disorders Among Movement Disorder Society Members

[Background] Tic disorders belong to the broad spectrum of pediatric and adult movement disorders. The wide variability in clinical presentations, applied assessment tools, and treatments are poorly understood.[Objectives] To map practices and knowledge base of movement disorder clinicians concerning clinical features, pathophysiology, and treatment approaches in tic disorders. [Methods] A 33-item survey was developed by the Tic Disorders and Tourette syndrome Study Group members of the Movement Disorder Society. The survey was distributed to the complete society membership and included responses from 346 members, 314 of whom reported treating tic disorders. [Results] Approximately one third of survey respondents (35%) frequently evaluated patients with tics. The data revealed widespread use of existing guidelines (about 70%) and screening for comorbid disorders (>90%). The most common investigations used to rule out secondary causes of tics were imaging (92%), laboratory tests (66%) and neurophysiology (38%). Functional tics were the second most common tic etiology following primary tics. Only 27% of respondents reported confidence in knowledge about tic pathogenesis. Top rated interventions to treat tics were psychoeducation, cognitive behavioral intervention for tics (CBIT) and treatment for neuropsychiatric comorbidities. Antipsychotics were ranked as the most effective pharmacologic tic intervention. Conclusions: The majority of movement disorders specialists do not frequently encounter tics. There was sparse knowledge about tic pathophysiology. Psychoeducation, CBIT, the treatment of neuropsychiatric comorbidities and use of antipsychotics emerged as the most common interventions to treat tics. These results provide insight into what will be needed to improve the diagnosis and treatment of tic disorders.CG is supported by the Freigeist Fellowship of the VolkswagenStiftung. He has served as ad hoc advisory board to Biomarin and received honoraria from the International Parkinsons Disease and Movement Disorders Society for educational activities

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

The RAB39B p.G192R mutation causes X-linked dominant Parkinson’s disease

Objective: To identify the causal gene in a multi-incident U.S. kindred with Parkinson’s disease (PD). Methods: We characterized a family with a classical PD phenotype in which 7 individuals (5 males and 2 females) were affected with a mean age at onset of 46.1 years (range, 29-57 years). We performed whole exome sequencing on 4 affected and 1 unaffected family members. Sanger-sequencing was then used to verify and genotype all candidate variants in the remainder of the pedigree. Cultured cells transfected with wild-type or mutant constructs were used to characterize proteins of interest. Results: We identified a missense mutation (c.574G > A; p.G192R) in the RAB39B gene that closely segregated with disease and exhibited X-linked dominant inheritance with reduced penetrance in females. The mutation occurred in a highly conserved amino acid residue and was not observed among 87,725 X chromosomes in the Exome Aggregation Consortium dataset. Sequencing of the RAB39B coding region in 587 familial PD cases yielded two additional mutations (c.428C > G [p.A143G] and c.624_626delGAG [p.R209del]) that were predicted to be deleterious in silico but occurred in families that were not sufficiently informative to assess segregation with disease. Experiments in PC12 and SK-N-BE(2)C cells demonstrated that p.G192R resulted in mislocalization of the mutant protein, possibly by altering the structure of the hypervariable C-terminal domain which mediates intracellular targeting. Conclusions: Our findings implicate RAB39B, an essential regulator of vesicular-trafficking, in clinically typical PD. Further characterization of normal and aberrant RAB39B function might elucidate important mechanisms underlying neurodegeneration in PD and related disorders. Electronic supplementary material The online version of this article (doi:10.1186/s13024-015-0045-4) contains supplementary material, which is available to authorized users

Parkinsonism Risk Factors in Salt Lake City, Utah: A Community-Based Study

Background: The prevalence of dream enactment behavior and other risk factors for a parkinsonian disorder is not well documented. Methods: A survey on prevalence of parkinsonism risk factors was designed using two validated instruments (REM behavior disorder single item question, bowel movement frequency for constipation) and three exploratory instruments (for hallucinations, cognitive and olfactory complaints.) It was sent by mail and email to patients aged 50 and over at two University of Utah community clinics in Salt Lake City. A total of 7888 unique patients were sent the survey, and 1607 responses were recorded (response rate 20%). Those whose age was missing (n = 117) or less than 50 years (n = 10) were excluded from the analysis. Results: Of the 1406 without personal diagnosis of neurodegenerative disease 62.7% were female, and median age was 63. Family history (FH) of Parkinson&#8217;s disease was endorsed by 9%, constipation (defined as a bowel movement less than once per day) by 19%, mild cognitive complaints (MCI) 15.8%, dream enactment 13.7%, subjective hyposmia or anosmia 18.2%, and at least one potential psychotic symptom in 37.6%. Multivariable logistic regression showed male gender, mild cognitive complaints, hearing voices, and at least one potentially psychotic symptom to be significantly associated with dream enactment. Conclusions: This survey shows that dream enactment, a strong predictor of risk for synucleinopathy, is relatively common in the older population; because such individuals rarely come to medical attention of a sleep clinic, such survey research may be useful to identify and recruit at-risk individuals for trials aimed at preventing neurodegenerative disease

Tourette's Disorder

OPINION STATEMENT: Tourette's disorder (TD) is a common childhood-onset neuropsychiatric disorder characterized by chronic motor and vocal tics. TD frequently occurs with other neuropsychiatric disorders, such as attention deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD), and may contribute to reduced quality of life and disability. Currently available treatments to reduce tics are limited by variable clinical response and frequent adverse effects. They include alpha-2 agonists, antipsychotics (first and second generation), tetrabenazine, benzodiazepines, and habit reversal therapy. Some new and emerging (but unproven) treatments are also discussed, including topiramate and dopamine agonists. In addition, there is increasing interest in deep brain stimulation, but this is not yet ready for general use