David Shprecher

Parkinson disease The enteric nervous system spills its guts

Lewy pathology in Parkinson disease (PD) extends well beyond the CNS, also affecting peripheral autonomic neuronal circuits, especially the enteric nervous system (ENS). The ENS is an integrative neuronal network also referred to as “the brain in the gut” because of its similarities to the CNS. We have recently shown that the ENS can be readily analyzed using routine colonic biopsies. This led us to propose that the ENS could represent a unique window to assess the neuropathology in living patients with PD. In this perspective, we discuss current evidence which indicates that the presence of ENS pathology may by exploited to improve our understanding and management of PD and likely other neurodegenerative disorders.

The Management of Tics

A tic is a stereotyped repetitive involuntary movement or sound, frequently preceded by premonitory sensations or urges. Most tic disorders are genetic or idiopathic in nature, possibly due to a developmental failure of inhibitory function within frontal‐subcortical circuits modulating volitional movements. Currently available oral medications can reduce the severity of tics, but rarely eliminate them. Botulinum toxin injections can be effective if there are a few particularly disabling motor tics. Deep brain stimulation has been reported to be an effective treatment for the most severe cases, but remains unproven. A comprehensive evaluation accounting for secondary causes, psychosocial factors, and comorbid neuropsychiatric conditions is essential to successful treatment of tic disorders.

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

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

The syndrome of delayed post-hypoxic leukoencephalopathy

Delayed post-hypoxic leukoencephalopathy (DPHL) is a demyelinating syndrome characterized by acute onset of neuropsychiatric symptoms days to weeks following apparent recovery from coma after a period of prolonged cerebral hypo-oxygenation. It is diagnosed, after excluding other potential causes of delirium, with a clinical history of carbon monoxide poisoning, narcotic overdose, myocardial infarction, or another global cerebral hypoxic event. The diagnosis can be supported by neuroimaging evidence of diffuse hemispheric demyelination sparing cerebellar and brainstem tracts, or by an elevated cerebrospinal fluid myelin basic protein. Standard or hyperbaric oxygen following CO poisoning may reduce the likelihood of DPHL or other neurologic sequelae. Bed rest and avoidance of stressful procedures for the first 10 days following any prolonged hypoxic event may also lower the risk. Gradual recovery over a 3 to 12 month period is common, but impaired attention or executive function, parkinsonism, or corticospinal tract signs can persist. Stimulants, amantadine or levodopa may be considered for lasting cognitive or parkinsonian symptoms. Anticipation and recognition of DPHL should lead to earlier and more appropriate utilization of health care services.

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 Parkinsons 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.

A U.S. survey of patients with Parkinson's disease: Satisfaction with medical care and support groups

Relatively little is known about patient satisfaction with Parkinsons disease (PD) care and the use of support groups in the United States. We surveyed members of the Muhammad Ali Parkinsons Disease Registry to assess satisfaction with medical care and to evaluate support group use. Satisfaction was measured on a 5‐point Likert scale, with high satisfaction defined as a four or five. We used multiple logistic regression to identify factors associated with high satisfaction and support group use. The response rate was 38% (726 of 1923). Most (57%) expressed high satisfaction with PD care. Individuals were most satisfied with the time their provider spent with them (61%) and PD education (56%) but least satisfied with prognostic information (35%) and information about non‐drug interventions (28%). Patients seeing a PD specialist were three times more satisfied with their care than those seeing a general neurologist (OR = 3.00, 95% CI: 1.92–4.71; P < 0.0001). Support group use is common, and 61% of survey respondents had attended one at any point. Caucasian race (OR = 2.85, 95% CI: 1.45–5.61), PD duration (OR = 1.05 per year, CI: 1.01–1.10), and PD specialist care (OR = 1.80, CI: 1.16–2.77) were associated with greater support group attendance. Overall, 49% reported high satisfaction with their support group. The greatest concerns were specific needs not being addressed (15%) and insufficient expertise within the group (14%). Most individuals with Parkinsons disease expressed high levels of satisfaction, especially with specialist care. Specialty care and improved education, in the clinic or through support groups, may enhance satisfaction and health care quality.

Progressive multifocal leucoencephalopathy associated with lupus and methotrexate overdose

Progressive multifocal leucoencephalopathy (PML) is a CNS infection of oligodendrocytes by JC virus, which rarely occurs in lupus, and can be mistaken for antiphospholipid antibody syndrome or neuropsychiatric systemic lupus erythematosus (NSLE). This case of PML in a patient with systemic lupus erythematosus on supra-therapeutic doses of methotrexate emphasises that CNS infection is an important diagnostic consideration before empiric treatment with immunosuppresants for NSLE.

Environmental and occupational risk factors for progressive supranuclear palsy: Case-control study

The cause of progressive supranuclear palsy (PSP) is largely unknown. Based on evidence for impaired mitochondrial activity in PSP, we hypothesized that the disease may be related to exposure to environmental toxins, some of which are mitochondrial inhibitors.

Neurobehavioral aspects, pathophysiology, and management of Tourette syndrome.

PURPOSE OF REVIEW This update summarizes progress in understanding Tourette syndrome clinical characteristics, etiology, and treatment over the past year. RECENT FINDINGS Premonitory sensory phenomena were found to have important impacts on Tourette syndrome quality of life. A rare genetic form of Tourette syndrome due to L-histidine-decarboxylase mutation, with similar features in human and rodent, has inspired new research on functional anatomy of Tourette syndrome. In response to new data, treatment guidelines have been revised to include behavioral therapy as first-line treatment. Novel dopamine receptor antagonists aripiprazole and ecopipam have shown potential efficacy - as well as tolerability concerns. Recent work has suggested efficacy and tolerability of topiramate and fluphenazine, but more rigorous studies are needed to further understand their role in Tourette syndrome management. Recent consensus guidelines explain when deep brain stimulation can be considered for severe refractory cases under a multidisciplinary team. SUMMARY More research is needed to identify better tolerated treatments for, to understand pathophysiology or functional anatomy of, and to predict or influence longitudinal outcome of Tourette syndrome.

Tourette’s Disorder

Opinion statementTourette’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.