Andrew P. Duker

The Modified Bradykinesia Rating Scale for Parkinson’s Disease: Reliability and Comparison with Kinematic Measures

Bradykinesia encompasses slowness, decreased movement amplitude, and dysrhythmia. Unified Parkinsons Disease Rating Scale–based bradykinesia‐related items require that clinicians condense abnormalities in speed, amplitude, fatiguing, hesitations, and arrests into a single score. The objective of this study was to evaluate the reliability of a modified bradykinesia rating scale, which separately assesses speed, amplitude, and rhythm and its correlation with kinematic measures from motion sensors. Fifty patients with Parkinsons disease performed Unified Parkinsons Disease Rating Scale–directed finger tapping, hand grasping, and pronation–supination while wearing motion sensors. Videos were rated blindly and independently by 4 clinicians. The modified bradykinesia rating scale and Unified Parkinsons Disease Rating Scale demonstrated similar inter‐ and intrarater reliability. Raters placed greater weight on amplitude than on speed or rhythm when assigning a Unified Parkinsons Disease Rating Scale score. Modified bradykinesia rating scale scores for speed, amplitude, and rhythm correlated highly with quantitative kinematic variables. The modified bradykinesia rating scale separately captures bradykinesia components with interrater and intrarater reliability similar to that of the Unified Parkinsons Disease Rating Scale. Kinematic sensors can accurately quantify speed, amplitude, and rhythm to aid in the development and evaluation of novel therapies in Parkinsons disease.

At-home training with closed-loop augmented-reality cueing device for improving gait in patients with Parkinson disease

Shuffling and freezing while walking can impair function in patients with Parkinson disease (PD). Open-loop devices that provide fixed-velocity visual or auditory cues can improve gait but may be unreliable or exacerbate freezing of gait in some patients. We examined the efficacy of a closed-loop, accelerometer-driven, wearable, visual-auditory cueing device in 13 patients with PD with off-state gait impairment at baseline and after 2 weeks of twice daily (30 minute duration) at-home use. We measured gait velocity, stride length, and cadence using a validated electronic gait-analysis system. Subjects underwent standard motor assessment and completed a self-administered Freezing of Gait Questionnaire (FOGQ) (range 0-24; lower is better). After training, device use enhanced walking velocity (61.6 ± 20.1 cm/s to 72.6 ± 26.5 cm/s, p = 0.006) and stride length (74.3 ± 16.4 cm to 84.0 ± 18.5 cm, p = 0.004). Upon device removal, walking velocity (64.5 ± 21.4 cm/s to 75.4 ± 21.5 cm/s, p < 0.001) and stride length (79.0 ± 20.3 cm to 88.8 ± 17.7 cm, p = 0.003) exhibited a greater magnitude of change, suggesting immediate residual benefits. Also upon device removal, nearly 70 percent of subjects improved by at least 20 percent in either walking velocity, stride length, or both. An overall improvement in gait was measured by the FOGQ (14.2 ±1.9 to 12.4 ± 2.5, p = 0.02). Although issues related to compliance and response variability render a definitive interpretation of study outcome difficult, devices using closed-loop sensory feedback appear to be effective and desirable nonpharmacologic interventions to improve walking in selected individuals with PD.

Differential response of speed, amplitude, and rhythm to dopaminergic medications in Parkinson's disease.

Although movement impairment in Parkinsons disease includes slowness (bradykinesia), decreased amplitude (hypokinesia), and dysrhythmia, clinicians are instructed to rate them in a combined 0–4 severity scale using the Unified Parkinsons Disease Rating Scale motor subscale. The objective was to evaluate whether bradykinesia, hypokinesia, and dysrhythmia are associated with differential motor impairment and response to dopaminergic medications in patients with Parkinsons disease. Eighty five Parkinsons disease patients performed finger‐tapping (item 23), hand‐grasping (item 24), and pronation–supination (item 25) tasks OFF and ON medication while wearing motion sensors on the most affected hand. Speed, amplitude, and rhythm were rated using the Modified Bradykinesia Rating Scale. Quantitative variables representing speed (root mean square angular velocity), amplitude (excursion angle), and rhythm (coefficient of variation) were extracted from kinematic data. Fatigue was measured as decrements in speed and amplitude during the last 5 seconds compared with the first 5 seconds of movement. Amplitude impairments were worse and more prevalent than speed or rhythm impairments across all tasks (P < .001); however, in the ON state, speed scores improved exclusively by clinical (P < 10−6) and predominantly by quantitative (P < .05) measures. Motor scores from OFF to ON improved in subjects who were strictly bradykinetic (P < .01) and both bradykinetic and hypokinetic (P < 10−6), but not in those strictly hypokinetic. Fatigue in speed and amplitude was not improved by medication. Hypokinesia is more prevalent than bradykinesia, but dopaminergic medications predominantly improve the latter. Parkinsons disease patients may show different degrees of impairment in these movement components, which deserve separate measurement in research studies.

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.

Methylphenidate for gait impairment in Parkinson disease: A randomized clinical trial

Background: There is a paucity of therapies for gait impairment in Parkinson disease (PD). Open-label studies have suggested improved gait after treatment with methylphenidate (MPD). Objective: To evaluate the efficacy of MPD for the treatment of gait impairment in PD. Methods: Twenty-seven subjects with PD and moderate gait impairment were screened for this 6-month placebo-controlled, double-blind study. Subjects were randomly assigned to MPD (maximum, up to 80 mg/day) or placebo for 12 weeks and crossed over after a 3-week washout. The primary outcome measure was change in a gait composite score (stride length + velocity) between groups at 4 and 12 weeks. Secondary outcome measures included changes in motor function, as measured by the Unified Parkinsons Disease Rating Scale (UPDRS), Freezing of Gait Questionnaire (FOGQ), number of gait-diary freezing episodes, and measures of depression, sleepiness, and quality of life. Three-factor repeated-measures analysis of variance was used to measure changes between groups. Results: Twenty-three eligible subjects with PD were randomized and 17 completed the trial. There was no change in the gait composite score or treatment or time effect for any of the variables. Treatment effect was not modified by state or study visit. Although there was a trend for reduced frequency of freezing and shuffling per diary, the FOGQ and UPDRS scores worsened in the MPD group compared to placebo. There was a marginal improvement in some measures of depression. Conclusions: MPD did not improve gait and tended to worsen measures of motor function, sleepiness, and quality of life. Classification of evidence: This study provides Class III evidence for the lack of benefit of MPD on PD-associated gait impairment. Clinical trial registration: NCT00526630.

Deep brain stimulation of the ventral intermediate nucleus of the thalamus in medically refractory orthostatic tremor: preliminary observations.

Orthostatic tremor (OT) is a disabling movement disorder associated with postural and gait impairment in the elderly. Medical therapy often yields insufficient benefit. We report the clinical and electrophysiological data on two patients with medication‐refractory OT treated with deep brain stimulation of the ventral intermediate thalamic nucleus (Vim DBS). Patient 1 underwent bilateral deep brain stimulation (DBS) and Patient 2 unilateral Vim DBS following 28 and 30 years of disease duration, respectively. Both patients showed increased latency to symptom onset after rising from a seated position, improved tolerance for prolonged standing, and slower crescendo of tremor severity when remaining upright. Postoperative evaluation demonstrated decreased amplitude of electromyographic activity with persistence of well‐defined oscillatory behavior showing strong coherence at 15 Hz between all muscles tested in the upper and lower limbs. Postural sway was unchanged. Clinical benefits have been sustained for over 18 months in Patient 1, and receded after 3 months in Patient 2. These findings support the consideration of bilateral Vim DBS implantation as a therapeutic option in patients with medically refractory OT. Further efficacy studies on chronic stimulation to disrupt the abnormal oscillatory activity in this disorder are warranted.

Psychogenic Facial Movement Disorders: Clinical Features and Associated Conditions

The facial phenotype of psychogenic movement disorders has not been fully characterized. Seven tertiary‐referral movement disorders centers using a standardized data collection on a computerized database performed a retrospective chart review of psychogenic movement disorders involving the face. Patients with organic forms of facial dystonia or any medical or neurological disorder known to affect facial muscles were excluded. Sixty‐one patients fulfilled the inclusion criteria for psychogenic facial movement disorders (91.8% females; age: 37.0 ± 11.3 years). Phasic or tonic muscular spasms resembling dystonia were documented in all patients most commonly involving the lips (60.7%), followed by eyelids (50.8%), perinasal region (16.4%), and forehead (9.8%). The most common pattern consisted of tonic, sustained, lateral, and/or downward protrusion of one side of the lower lip with ipsilateral jaw deviation (84.3%). Ipsi‐ or contralateral blepharospasm and excessive platysma contraction occurred in isolation or combined with fixed lip dystonia (60.7%). Spasms were reported as painful in 24.6% of cases. Symptom onset was abrupt in most cases (80.3%), with at least 1 precipitating psychological stress or trauma identified in 57.4%. Associated body regions involved included upper limbs (29.5%), neck (16.4%), lower limbs (16.4%), and trunk (4.9%). There were fluctuations in severity and spontaneous exacerbations and remissions (60%). Prevalent comorbidities included depression (38.0%) and tension headache (26.4%). Fixed jaw and/or lip deviation is a characteristic pattern of psychogenic facial movement disorders, occurring in isolation or in combination with other psychogenic movement disorders or other psychogenic features.

Dopamine agonists and pathologic behaviors.

The dopamine agonists ropinirole and pramipexole exhibit highly specific affinity for the cerebral dopamine D3 receptor. Use of these medications in Parkinsons disease has been complicated by the emergence of pathologic behavioral patterns such as hypersexuality, pathologic gambling, excessive hobbying, and other circumscribed obsessive-compulsive disorders of impulse control in people having no history of such disorders. These behavioral changes typically remit following discontinuation of the medication, further demonstrating a causal relationship. Expression of the D3 receptor is particularly rich within the limbic system, where it plays an important role in modulating the physiologic and emotional experience of novelty, reward, and risk assessment. Converging neuroanatomical, physiological, and behavioral science data suggest the high D3 affinity of these medications as the basis for these behavioral changes. These observations suggest the D3 receptor as a therapeutic target for obsessive-compulsive disorder and substance abuse, and improved understanding of D3 receptor function may aid drug design of future atypical antipsychotics.

Lower-body parkinsonism: reconsidering the threshold for external lumbar drainage

Background An 80-year-old man with a 60 pack-year smoking habit, hypertension, and hypercholesterolemia presented to a movement disorders clinic with a 30-month history of step-wise progression of gait, balance, and memory impairment. He had experienced multiple falls and two hospitalizations for sudden-onset freezing of gait.Investigations Neurological examination, brain MRI, neuropsychological evaluation, gait analysis, continuous external lumbar drainage of cerebrospinal fluid, and post-mortem neuropathological studies.Diagnosis Vascular parkinsonism was diagnosed on the basis of the patients history and imaging findings; however, post-mortem neuropathology was consistent with a diagnosis of normal pressure hydrocephalus and did not support that of vascular parkinsonism.Treatment Ventriculoperitoneal shunt placement superseded tighter control of vascular risk factors, as judged by the patients response to continuous lumbar drainage.

Gluten-related neurologic dysfunction.

The term gluten-related disorders (GRD) encompasses a spectrum of systemic autoimmune diseases with diverse manifestations. GRD are characterized by abnormal immunological responsiveness to ingested gluten in genetically susceptible individuals. Celiac disease (CD) or gluten-sensitive enteropathy is only one of a number of GRD. Extraintestinal manifestations include dermatitis herpetiformis (DH) and neurologic dysfunction. Furthermore it is only recently that the concept of extraintestinal manifestations without enteropathy has become accepted. In this chapter we review the spectrum of neurologic manifestations in GRD, discuss recent advances in their diagnosis, and look at their possible pathophysiologic mechanisms.