Victor S.C. Fung

Phenomenology and classification of dystonia: A consensus update

This report describes the consensus outcome of an international panel consisting of investigators with years of experience in this field that reviewed the definition and classification of dystonia. Agreement was obtained based on a consensus development methodology during 3 in‐person meetings and manuscript review by mail. Dystonia is defined as a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both. Dystonic movements are typically patterned and twisting, and may be tremulous. Dystonia is often initiated or worsened by voluntary action and associated with overflow muscle activation. Dystonia is classified along 2 axes: clinical characteristics, including age at onset, body distribution, temporal pattern and associated features (additional movement disorders or neurological features); and etiology, which includes nervous system pathology and inheritance. The clinical characteristics fall into several specific dystonia syndromes that help to guide diagnosis and treatment. We provide here a new general definition of dystonia and propose a new classification. We encourage clinicians and researchers to use these innovative definition and classification and test them in the clinical setting on a variety of patients with dystonia.

A Double-Blind, Placebo-Controlled Study to Assess the Mitochondria-Targeted Antioxidant MitoQ as a Disease-Modifying Therapy in Parkinson's Disease

Multiple lines of evidence point to mitochondrial oxidative stress as a potential pathogenic cause for Parkinsons disease (PD). MitoQ is a powerful mitochondrial antioxidant. It is absorbed orally and concentrates within mitochondria where it has been shown to protect against oxidative damage. We enrolled 128 newly diagnosed untreated patients with PD in a double‐blind study of two doses of MitoQ compared with placebo to explore the hypothesis that, over 12 months, MitoQ would slow the progression of PD as measured by clinical scores, particularly the Unified Parkinson Disease Rating Scale. We showed no difference between MitoQ and placebo on any measure of PD progression. MitoQ does not slow the progression of PD, and this finding should be taken into account when considering the oxidative stress hypothesis for the pathogenesis of PD.

Clinical and physiological assessments for elucidating falls risk in Parkinson's disease†

The study aims were to devise (1) a fall risk screen for people with PD using routine clinical measures and (2) an explanatory (physiological) fall risk assessment for guiding fall prevention interventions. One hundred thirteen people with PD (age 66 ± 95% CI 1.6 years) underwent clinical assessments and quantitative tests of sway, gait, strength, reaction time, and lower limb sensation. Participants were then followed up for 12 months to determine fall incidence. In the follow‐up year, 51 participants (45%) fell one or more times whereas 62 participants (55%) did not fall. Multivariate analyses of routine clinical measures revealed that a fall in the past year, abnormal axial posture, cognitive impairment, and freezing of gait were independent risk factors for falls and predicted 38/51 fallers (75%) and 45/62 non‐fallers (73%). A multivariate model combining clinical and physiological measures that elucidate the pathophysiology of falls identified abnormal posture, freezing of gait, frontal impairment, poor leaning balance, and leg weakness as independent risk factors. This model correctly classified 39/51 fallers (77%) and 51/62 non‐fallers (82%). Patients with PD at risk of falls can be identified accurately with routine clinical assessments and quantitative physiological tests. Many of the risk factors identified are amenable to targeted intervention.

The effects of an exercise program on fall risk factors in people with Parkinson's disease: a randomized controlled trial

This randomized controlled trial with blinded assessment aimed to determine the effect of a 6‐month minimally supervised exercise program on fall risk factors in people with Parkinsons disease (PD). Forty‐eight participants with PD who had fallen or were at risk of falling were randomized into exercise or control groups. The exercise group attended a monthly exercise class and exercised at home three times weekly. The intervention targeted leg muscle strength, balance, and freezing. The primary outcome measure was a PD falls risk score. The exercise group had no major adverse events and showed a greater improvement than the control group in the falls risk score, which was not statistically significant (between group mean difference = −7%, 95% CI −20 to 5, P = 0.26). There were statistically significant improvements in the exercise group compared with the control group for two secondary outcomes: Freezing of Gait Questionnaire (P = 0.03) and timed sit‐to‐stand (P = 0.03). There were statistically nonsignificant trends toward greater improvements in the exercise group for measures of muscle strength, walking, and fear of falling, but not for the measures of standing balance. Further investigation of theimpact of exercise on falls in people with PD is warranted.

Walking speed, cadence and step length are selected to optimize the stability of head and pelvis accelerations

The aim of this study was to evaluate the hypothesis that an individual’s preferred or usual walking speed, step length and cadence optimize the stability of head and pelvic accelerations in vertical (V), anterior–posterior (AP) and medio-lateral (ML) planes when walking. Acceleration patterns of the head and pelvis were recorded in ten healthy young adults as they walked on a level surface in three separate experiments: (1) walking at five different speeds, ranging from very slow to very fast; (2) walking in time to a metronome set at five different cadences, ranging from 33 to 167% of subjects’ usual cadence; and (3) walking at five different step lengths varying from very short to very long while keeping in time with a metronome set at cadences 67, 100 and 125% of usual cadence. The results indicated that acceleration patterns in the V and AP planes were most stable when subjects walked at their usual cadence and step length. In the ML plane, stability was suboptimal, but still adequate, with the usual cadence and step length. The findings suggest that healthy young people walk in a manner that maximizes V and AP stability while maintaining adequate, though suboptimal ML stability.

Pathogenic effects of novel mutations in the P‐type ATPase ATP13A2 (PARK9) causing Kufor‐Rakeb syndrome, a form of early‐onset parkinsonism

Kufor‐Rakeb syndrome (KRS) is a rare form of autosomal recessive juvenile or early‐onset, levodopa responsive parkinsonism and has been associated with mutations in ATP13A2(also known as PARK9), a lysosomal type 5 P‐type ATPase. Recently, we identified novel compound heterozygous mutations, c.3176T>G (p.L1059R) and c.3253delC (p.L1085WfsX1088) in ATP13A2 of two siblings affected with KRS. When overexpressed, wild‐type ATP13A2 localized to Lysotracker‐positive and LAMP2‐positive lysosomes while both truncating and missense mutated ATP13A2 were retained in the endoplasmic reticulum (ER). Both mutant proteins were degraded by the proteasomal but not the lysosomal pathways. In addition, ATP13A2 mRNA with c.3253delC was degraded by nonsense‐mediated mRNA decay (NMD), which was protected by cycloheximide treatment. To validate our findings in a biologically relevant setting, we used patient‐derived human olfactory neurosphere cultures and fibroblasts and demonstrated persistent ER stress by detecting upregulation of unfolded protein response‐related genes in the patient‐derived cells. We also confirmed NMD degraded ATP13A2 c.3253delC mRNA in the cells. These findings indicate that these novel ATP13A2 mutations are indeed pathogenic and support the notion that mislocalization of the mutant ATP13A2, resultant ER stress, alterations in the proteasomal pathways and premature degradation of mutant ATP13A2 mRNA contribute to the aetiology of KRS.Hum Mutat 32:1–9, 2011.

Postmortem analysis of bilateral subthalamic electrode implants in Parkinson's disease

This is the second neuropathological report detailing bilateral electrodes targeting the subthalamic nucleus (STN) in idiopathic Parkinsons disease (PD). The patient presented with unilateral tremor‐dominant parkinsonism. Bilateral STN stimulation was carried out 7 years later due to significant disease progression and severe motor fluctuations. The patient exhibited bilateral improvements in rigidity and bradykinesia both intraoperatively and postoperatively. The patient died 2 months later from aspiration pneumonia. Neuropathological examination confirmed both the diagnosis of PD and the electrode placements. The tip of the left electrode was located medially and posteriorly in the left STN and the tip of the right electrode entered the base of the thalamus/zona incerta immediately above the right STN. Tissue changes associated with the subthalamic electrode tracts included mild cell loss, astrogliosis, and some tissue vacuolation. Our postmortem analysis indicates little tissue damage associated with STN stimulation for PD.

Myoclonus-dystonia: significance of large SGCE deletions.

Myoclonus‐dystonia (M‐D) is an autosomal‐dominant movement disorder caused by mutations in SGCE. We investigated the frequency and type of SGCE mutations with emphasis on gene dosage alterations and explored the associated phenotypes. We tested 35 M‐D index patients by multiplex ligation‐dependent probe amplification (MLPA) and genomic sequencing. Mutations were found in 26% (9/35) of the cases, all but three with definite M‐D. Two heterozygous deletions of the entire SGCE gene and flanking DNA and a heterozygous deletion of exon 2 only were detected, accounting for 33% (3/9) of the mutations found. Both large deletions contained COL1A2 and were additionally associated with joint problems. Further, we discovered one novel small deletion (c.771_772delAT, p.C258X) and four recurrent point mutations (c.289C>T, p.R97X; c.304C>T, p.R102X; c.709C>T, p.R237X; c.1114C>T, p.R372X). A Medline search identified 22 articles on SGCE mutational screening. Sixty‐four unrelated M‐D patients were described with 41 different mutations. No genotype–phenotype association was found, except in patients with deletions encompassing additional genes. In conclusion, a rigorous clinical preselection of patients and careful accounting for non‐motor signs should precede mutational tests. Gene dosage studies should be included in routine SGCE genetic testing.

Levodopa-carbidopa intestinal gel in advanced Parkinson's disease: Final 12-month, open-label results

Motor complications in Parkinsons disease (PD) are associated with long‐term oral levodopa treatment and linked to pulsatile dopaminergic stimulation. l‐dopa‐carbidopa intestinal gel (LCIG) is delivered continuously by percutaneous endoscopic gastrojejunostomy tube (PEG‐J), which reduces l‐dopa‐plasma–level fluctuations and can translate to reduced motor complications. We present final results of the largest international, prospective, 54‐week, open‐label LCIG study. PD patients with severe motor fluctuations (>3 h/day “off” time) despite optimized therapy received LCIG monotherapy. Additional PD medications were allowed >28 days post‐LCIG initiation. Safety was the primary endpoint measured through adverse events (AEs), device complications, and number of completers. Secondary endpoints included diary‐assessed off time, “on” time with/without troublesome dyskinesia, UPDRS, and health‐related quality‐of‐life (HRQoL) outcomes. Of 354 enrolled patients, 324 (91.5%) received PEG‐J and 272 (76.8%) completed the study. Most AEs were mild/moderate and transient; complication of device insertion (34.9%) was the most common. Twenty‐seven (7.6%) patients withdrew because of AEs. Serious AEs occurred in 105 (32.4%), most commonly complication of device insertion (6.5%). Mean daily off time decreased by 4.4 h/65.6% (P < 0.001). On time without troublesome dyskinesia increased by 4.8 h/62.9% (P < 0.001); on time with troublesome dyskinesia decreased by 0.4 h/22.5% (P = 0.023). Improvements persisted from week 4 through study completion. UPDRS and HRQoL outcomes were also improved throughout. In the advanced PD population, LCIGs safety profile consisted primarily of AEs associated with the device/procedure, l‐dopa/carbidopa, and advanced PD. LCIG was generally well tolerated and demonstrated clinically significant improvements in motor function, daily activities, and HRQoL sustained over 54 weeks.

Exercise for falls prevention in Parkinson disease: A randomized controlled trial

Objective: To determine whether falls can be prevented with minimally supervised exercise targeting potentially remediable fall risk factors, i.e., poor balance, reduced leg muscle strength, and freezing of gait, in people with Parkinson disease. Methods: Two hundred thirty-one people with Parkinson disease were randomized into exercise or usual-care control groups. Exercises were practiced for 40 to 60 minutes, 3 times weekly for 6 months. Primary outcomes were fall rates and proportion of fallers during the intervention period. Secondary outcomes were physical (balance, mobility, freezing of gait, habitual physical activity), psychological (fear of falling, affect), and quality-of-life measures. Results: There was no significant difference between groups in the rate of falls (incidence rate ratio [IRR] = 0.73, 95% confidence interval [CI] 0.45–1.17, p = 0.18) or proportion of fallers (p = 0.45). Preplanned subgroup analysis revealed a significant interaction for disease severity (p < 0.001). In the lower disease severity subgroup, there were fewer falls in the exercise group compared with controls (IRR = 0.31, 95% CI 0.15–0.62, p < 0.001), while in the higher disease severity subgroup, there was a trend toward more falls in the exercise group (IRR = 1.61, 95% CI 0.86–3.03, p = 0.13). Postintervention, the exercise group scored significantly (p < 0.05) better than controls on the Short Physical Performance Battery, sit-to-stand, fear of falling, affect, and quality of life, after adjusting for baseline performance. Conclusions: An exercise program targeting balance, leg strength, and freezing of gait did not reduce falls but improved physical and psychological health. Falls were reduced in people with milder disease but not in those with more severe Parkinson disease. Classification of evidence: This study provides Class III evidence that for patients with Parkinson disease, a minimally supervised exercise program does not reduce fall risk. This study lacked the precision to exclude a moderate reduction or modest increase in fall risk from exercise. Trial registration: Australian New Zealand Clinical Trials Registry (ACTRN12608000303347).