A cross-sectional study of walking, balance and upper limb assessment scales in people with cervical dystonia.

Cervical dystonia (CD) is a neurological movement disorder causing the neck to move involuntarily away from the neutral position. CD is a network disorder, involving multiple brain areas and, therefore, may impair movement in parts of the body other than the neck. This study used clinical assessments to investigate walking, balance and upper limb function (UL) in people with CD; the reliability of scoring these assessments and examined for relationship between CD severity, usual exercise and clinical assessments. We conducted a prospective observational cohort study of participants with isolated, focal, idiopathic CD. Participants were assessed by experienced physiotherapists and completed three questionnaires and eight clinical assessments of fear of falling, balance confidence, walking, balance, UL function and usual exercise. Results were compared to published data from healthy adults and other neurological populations. Twenty-two people with mild to moderate CD participated. Fear of falling, gross UL function and usual exercise were worse in people with CD compared with healthy adults, while walking, balance and distal UL function were similar to healthy populations. All assessments were reliably performed by physiotherapists, and we found no correlations between the severity of dystonia or usual exercise and performance on the physical assessments. Routine performance of clinical assessment of walking and balance are likely not required in people with mild to moderate CD; however, fear of falling and gross upper limb function should be assessed to determine any problems which may be amenable to therapy.

Validation of Fear of Falling and Balance Confidence Assessment Scales in Persons With Dystonia.

BACKGROUND AND PURPOSE: Falls are problematic for people living with neurological disorders and a fear of falling can impact on actual falls. Fear of falling is commonly assessed using the Falls Self-Efficacy Scale International (FES-I) or the Activities-specific Balance Confidence (ABC) Scale. These scales can predict risk of falling. We aimed to validate the FES-I and the ABC in persons with dystonia. METHODS: We conducted an online survey of people with dystonia, collecting information on demographics, 6-month falls history, dystonia disability, and the FES-I and ABC scales. Scales were validated for structural validity and internal consistency. We also examined goodness-of-fit, convergent validity, and predictive validity, and determined cutoff scores for predicting falls risk. RESULTS: Survey responses (n = 122) showed that both FES-I and ABC scales have high internal validity and convergent validity with the Functional Disability Questionnaire in persons with dystonia. Each scale examines a single factor, fear of falling (FES-I) and balance confidence (ABC). At least one fall was reported by 39% of participants; the cutoff value for falls risk was found to be 29.5 and 71.3 for the FES-I and the ABC respectively. DISCUSSION AND CONCLUSIONS: The FES-I and the ABC scales are valid scales to examine fear of falling and balance confidence in persons with dystonia. Fear of falling is high and balance confidence is low and both are worse in those with dystonia who have previously fallen.Video Abstract available for more insights from the authors (see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A182).

Four cases of orthostatic myoclonus.

Orthostatic unsteadiness (unsteadiness on standing) is a relatively common symptom and can have neurological or non-neurological causes. Glass et al. have recently described a syndrome presenting with unsteadiness or leg jerking during standing or gait initiation difficulty which they have termed orthostatic myoclonus (OM). OM is a disabling syndrome but potentially treatable. It may develop on the background of neurodegenerative disease; other causes include pro-myoclonic drugs such as tricyclic antidepressants. In order to increase awareness of this syndrome, we report four patients with electrophysiologically confirmed OM who were referred to the movement disorder unit for lower limb tremor studies. All four patients presented with unsteadiness on standing. There were no signs suggestive of neurodegenerative disease and three of the patients had a provisional diagnosis of orthostatic tremor. The diagnosis of OM was supported by a surface electromyography showing 9-16Hz, non-rhythmic muscle bursts with burst duration of 50-100ms during standing. OM is unrecognised by many physicians as a cause of orthostatic intolerance. The most common syndrome with which OM may be confused is orthostatic tremor. A correct diagnosis is important as it may respond to treatment with clonazepam, gabapentin or piracetam.

A multicentre, randomized, double-blinded, placebo-controlled Phase III study to investigate EXtending the time for Thrombolysis in Emergency Neurological Deficits (EXTEND).

BACKGROUND AND HYPOTHESIS: Thrombolytic therapy with tissue plasminogen activator is effective for acute ischaemic stroke within 4·5 h of onset. Patients who wake up with stroke are generally ineligible for stroke thrombolysis. We hypothesized that ischaemic stroke patients with significant penumbral mismatch on either magnetic resonance imaging or computer tomography at three- (or 4·5 depending on local guidelines) to nine-hours from stroke onset, or patients with wake-up stroke within nine-hours from midpoint of sleep duration, would have improved clinical outcomes when given tissue plasminogen activator compared to placebo. STUDY DESIGN: EXtending the time for Thrombolysis in Emergency Neurological Deficits is an investigator-driven, Phase III, randomized, multicentre, double-blind, placebo-controlled study. Ischaemic stroke patients presenting after the three- or 4·5-h treatment window for tissue plasminogen activator and within nine-hours of stroke onset or with wake-up stroke within nine-hours from the midpoint of sleep duration, who fulfil clinical (National Institutes of Health Stroke Score ≥4-26 and prestroke modified Rankin Scale <2) will undergo magnetic resonance imaging or computer tomography. Patients who also meet imaging criteria (infarct core volume <70 ml, perfusion lesion : infarct core mismatch ratio >1·2, and absolute mismatch >10 ml) will be randomized to either tissue plasminogen activator or placebo. STUDY OUTCOME: The primary outcome measure will be modified Rankin Scale 0-1 at day 90. Clinical secondary outcomes include categorical shift in modified Rankin Scale at 90 days, reduction in the National Institutes of Health Stroke Score by 8 or more points or reaching 0-1 at day 90, recurrent stroke, or death. Imaging secondary outcomes will include symptomatic intracranial haemorrhage, reperfusion and or recanalization at 24 h and infarct growth at day 90.

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.

A unifying explanation of primary generalized seizures through nonlinear brain modeling and bifurcation analysis.

The aim of this paper is to explain critical features of the human primary generalized epilepsies by investigating the dynamical bifurcations of a nonlinear model of the brain's mean field dynamics. The model treats the cortex as a medium for the propagation of waves of electrical activity, incorporating key physiological processes such as propagation delays, membrane physiology, and corticothalamic feedback. Previous analyses have demonstrated its descriptive validity in a wide range of healthy states and yielded specific predictions with regards to seizure phenomena. We show that mapping the structure of the nonlinear bifurcation set predicts a number of crucial dynamic processes, including the onset of periodic and chaotic dynamics as well as multistability. Quantitative study of electrophysiological data supports the validity of these predictions. Hence, we argue that the core electrophysiological and cognitive differences between tonic-clonic and absence seizures are predicted and interrelated by the global bifurcation diagram of the model's dynamics. The present study is the first to present a unifying explanation of these generalized seizures using the bifurcation analysis of a dynamical model of the brain.

Progression of structural neuropathology in preclinical Huntington's disease: a tensor based morphometry study.

BACKGROUND AND OBJECTIVES: Regional cerebral atrophy occurs in carriers of the Huntington's disease (HD) gene mutation before clinical diagnosis is possible. The current inability to reliably measure progression of pathology in this preclinical phase impedes development of therapies to delay clinical onset. We hypothesised that longitudinal statistical imaging would detect progression of structural pathology in preclinical carriers of the HD gene mutation, in the absence of measurable clinical change. METHODS: Thirty subjects (17 preclinical mutation positive, 13 mutation negative) underwent serial clinical and magnetic resonance imaging (MRI) assessments over an interval of 2 years. Statistically significant changes in regional grey and white matter volume on MRI were analysed using tensor based morphometry (TBM). This technique derives a voxel-wise estimation of regional tissue volume change from the deformation field required to warp a subject's early to late T1 images. RESULTS: Over 2 years, there was progressive regional grey matter atrophy in mutation-positive relative to negative subjects, without significant clinical progression of disease. Significant grey matter volume loss was limited to bilateral putamen and globus pallidus externa (GPe), left caudate nucleus, and left ventral midbrain in the region of the substantia nigra. CONCLUSIONS: While these results are consistent with previous cross sectional pathologic and morphometric studies, significant progression of atrophy in HD before the onset of significant clinical decline is now demonstrable with longitudinal statistical imaging. Such measures could be used to assess the efficacy of potential disease modifying drugs in slowing the progression of pathology before confirmed clinical onset of HD.

Huntington's disease: clinical correlates of disability and progression.

OBJECTIVE: To define the phenotypic variation in a large population of patients with Huntington disease (HD) and to identity clinical features that predict disability and the rate of disease progression. METHODS: The authors analyzed data on 1,026 patients, followed for a median of 2.7 years, using a mixed effects model. The factors studied included the age at onset, the major clinical feature at onset, the severity of motor and cognitive impairment, and the level of disability. RESULTS: The mean age at onset was 41.5 (range 8 to 83) years, and patients were enrolled at all stages of disease. Younger onset was associated with more dystonia, less chorea, and a faster rate of motor, cognitive, and functional progression. The rate of progression was not related to the major clinical feature at onset or the sex of the affected parent. Disability correlated with the motor score (excluding chorea and dystonia) and the symbol-digit modalities test. Weight loss correlated with severe chorea. CONCLUSIONS: The rate of progression of HD was significantly more rapid with a younger age at onset. Therefore, CAG repeat length may be an important determinant of not only the age at onset, but also the rate of disease progression. Chorea was associated with weight loss, but chorea and dystonia were not major determinants of disability.

The distribution of structural neuropathology in pre-clinical Huntington's disease.

Putative neuroprotective agents in Huntington's disease may have particular application before brain pathology becomes manifest clinically. If these agents were to be tested in clinical trials, a reliable marker of the burden and rate of progression of pathological change in the pre-clinical group would be needed. The present study investigates whether the Huntington's disease genotype is associated with regional differences in brain structure, particularly differences that could not be predicted from clinical or neuropsychological assessment. A secondary aim is to seek indirect evidence of pathological progression in the form of changes in local tissue volume with age, specific to the Huntington's disease genotype. Formal motor examination, neuropsychological assessment, and T(1)-weighted cerebral MRI were performed in 34 subjects who had undergone predictive genetic testing for Huntington's disease. Clinical and cognitive testing were performed blinded to gene status. A linear discriminant analysis revealed the combination of test scores (the 'optimal clinical score') which best differentiated 18 subjects carrying the Huntington's disease gene mutation (the 'gene-positive' group). Voxel-based morphometry (VBM) was used to identify regions of significant main effect of Huntington's disease gene status on grey and white matter volume and regions of significant interaction of gene status with age. In the gene-positive group, there was significant reduction in grey matter volume in the left striatum, bilateral insula, dorsal midbrain and bilateral intra-parietal sulcus relative to 'gene-negative' controls. There was a significant reduction of periventricular white matter volume with age bilaterally in the gene-positive relative to the gene-negative group. Changes remained significant when controlled for differences in optimal clinical score between subjects. This study provides evidence of distributed grey matter pathology and progressive white matter atrophy with age before clinical onset of Huntington's disease. This suggests that VBM may be useful in monitoring cross-sectional and longitudinal changes in brain structure in pre-clinical Huntington's disease and for determining the efficacy of neuroprotective agents.

The current use of botulinum toxin.

Botulinum toxin is the most potent neurotoxin known, and has been in clinical use since the late 1970s. The toxin inhibits the release of acetylcholine from nerve terminals by inhibiting transport of the synaptic vesicles, thus causing functional denervation lasting up to 6 months. Our understanding of the mechanism of action of the toxin and the spectrum of diseases treatable with this agent continues to increase. Efficacy has been demonstrated in hemifacial spasm, dystonia, spasticity, hyperhidrosis and other conditions. Alternative serotypes are used in some centres, generally after the development of immunoresistance to the standard toxin (serotype A), and are likely to be in routine use in the near future. This paper reviews the history, pharmacology and current uses of botulinum toxin.