Which disease features run in essential tremor families?:A systematic review

Essential tremor is a common and highly heritable movement disorder. It is largely unknown, however, to what extent family members share overlapping symptoms. Such knowledge would be useful, as it may lead to the definition of familial essential tremor phenotypes, which will aid the ongoing search for genotypes. Also, this information can be used by clinicians in patient counselling. Therefore, we conducted a systematic review to provide an overview of the evidence on which essential tremor features run in families, to assess the literature's strengths and weaknesses, and to provide recommendations for future studies. PubMed was searched resulting in 460 titles: sixteen articles ultimately proved fit for inclusion. The results are represented in line with the Axis 1 classification of tremor as published in the latest Consensus Statement. In summary, we found varying levels of positive evidence for familial aggregation of age at onset, disease progression, alcohol responsiveness, parkinsonism and dystonia. Evidence on midline tremor was conflicting. The evidence on familial clustering was negative for cerebellar signs and action tremor asymmetry. Although the level of evidence is modest, it seems that some disease features are indeed familial, while other features are not. We discuss complicating factors, such as state-vs-trait dependency of characteristics, the place of familial dystonia, and the development of diagnostic criteria for essential tremor over time. In the future, comprehensive replication studies are needed, with the addition of several characteristics that have not been investigated so far, as the next step towards discovery of essential tremor phenotypes

Shared demographics and comorbidities in different functional motor disorders

Introduction: Functional motor disorders are often delineated according to the dominant motor symptom. In a large cohort, we aimed to find if there were differences in demographics, mode of onset, pain, fatigue, depression and anxiety and levels of physical functioning, quality of life and social adjustment between patients with different dominant motor symptoms. Methods: Baseline data from the Self-Help and Education on the Internet for Functional Motor Disorders Trial was used. Patients were divided into dominant motor symptom groups based on the diagnosis of the referring neurologist. Data on the above topics were collected by means of an online questionnaire and compared between groups using parametric and nonparametric statistics. Results: In 160 patients a dominant motor symptom could be determined, 31 had tremor, 45 myoclonus, 23 dystonia, 30 paresis, 31 gait disorder. No statistical differences between groups were detected for demographics, mode of onset and severity of pain, fatigue, depression and anxiety. Physical functioning was worse in the gait disorder group (median 20, IQR 25) compared to tremor (50 (55), p = 0.002) and myoclonus (50 (52), p = 0.001). Work and social adjustment was less impaired in the myoclonus group (median 20, IQR 18) compared to gait disorder (median 30, IQR18, p < 0.001) and paresis (28, IQR 10, p = 0.001). Self-report showed large overlap in motor symptoms. Conclusion: No differences were detected between groups of functional motor symptoms, regarding demographics, mode of onset, depression, anxiety, pain and fatigue. The large overlap in symptoms contributes to the hypothesis of shared underlying mechanisms of functional motor disorders

The auditory startle response in relation to outcome in functional movement disorders

Background: The auditory startle reflex (ASR) is enlarged in patients with functional movement disorders (FMD). Objectives: To study whether the ASR relates to symptom reduction in FMD patients, who participated in a placebo controlled double blind treatment trial with Botulinum Neurotoxin (BoNT). Methods: Response to treatment in the BoNT study was assessed using the Clinical Global Impression - Improvement scale (CGI-I). The electromyography (EMG) muscle activity of 7 muscles following 110 dB tones was measured in 14 FMD patients before and after one-year treatment and compared to 11 matched controls. The early and a late (behaviorally affected) component of the ASR and the sympathetic skin response (SSR) were assessed. Results: 10 of 14 patients (71.4%) showed symptom improvement, which was believed to be mainly caused by placebo effects. The early total response probability of the ASR at baseline tended to be larger in patients compared to controls (p = 0.08), but normalized at follow-up (p = 0.84). The late total response probability was larger in patients vs. controls at baseline (p < 0.05), a trend that still was present at follow-up (p = 0.08). The SSR was higher in patients vs. controls at baseline (p < 0.01), and normalized at follow-up (p = 0.71). Conclusions: On a group level 71.4% of the patients showed clinical symptom improvement after treatment. The early part of the ASR, most likely reflecting anxiety and hyperarousal, normalized in line with the clinical improvement. Interestingly, the augmented late component of the ASR remained enlarged suggesting persistent altered behavioral processing in functional patients despite motor improvement

The prognosis of functional limb weakness, a 14-year case-control study

Reliable data on the prognosis of functional motor disorder are scarce, as existing studies of the prognosis of functional motor disorder are nearly all retrospective, small and uncontrolled. In this study we used a prospectively recruited, controlled cohort design to assess misdiagnosis, mortality and symptomatic and health outcome in patients with functional limb weakness compared to neurological disease and healthy control subjects. We also carried out an exploratory analysis for baseline factors predicting outcome. One hundred and seven patients with functional limb weakness, 46 neurological and 38 healthy control subjects from our previously studied prospective cohort were traced for follow-up after an average of 14 years. Misdiagnosis was determined in a consensus meeting using information from records, patients and their GPs. Numbers and causes of death were collected via death certificates. Outcome of limb weakness, physical and psychiatric symptoms, disability/quality of life and illness perception were recorded with self-rated questionnaires. Outcome measures were compared within and between groups. Seventy-six patients (71%) with functional limb weakness, 31 (67%) neurological and 23 (61%) healthy controls were included in follow-up. Misdiagnosis was found in one patient in the functional limb weakness group (1%) and in one neurological control (2%). Eleven patients with functional limb weakness, eight neurological control subjects and one healthy control subject had died. Weakness had completely remitted in 20% of patients in the functional limb weakness group and in 18% of the neurological controls (P = 0.785) and improved in a larger proportion of functional limb weakness patients (P = 0.011). Outcomes were comparable between patient groups, and worse than the healthy control group. No baseline factors were independent predictors of outcome, although somatization disorder, general health, pain and total symptoms at baseline were univariably correlated to outcome. This study is the largest and longest follow-up study of functional limb weakness. Misdiagnosis in functional limb weakness is rare after long-term follow-up. The disorder is associated with a higher mortality rate than expected, and symptoms are persistent and disabling. It appears difficult to predict outcome based on common baseline variables. These data should help inform clinicians to provide a more realistic outlook of the outcome and emphasize the importance of active and targeted therapy

Test Arrangement of Small-scale Shear Tests of Composite Slabs

AbstractComposite slab consists of the layer of concrete above the trapezoidal sheeting. The sheeting serves as a lost formwork as well as a tension bearing member after the hardening of concrete. The interaction between the sheeting and the concrete is necessary for composite action and can be ensured by prepressed embossments in the sheeting. According to nowadays codes, full scale bending tests are required in the design of the new sheeting of this type of composite slabs. An alternative longitudinal shear tests of a small part of the slab have already been derived by many authors. However, the testing arrangement is not unified. The results of the shear tests can be influenced by the magnitude and the way of application of the clamping force, the loading speed, the interface conditions and others. This paper presents a proposal of the testing arrangement and the recommendations for the testing procedure of small-scale shear tests. The recommendations are posted based on the results of several series of performed laboratory tests

Myoclonus-dystonia : distinctive motor and non-motor phenotype from other dystonia syndromes

Background: myoclonus-dystonia (M-D) due to a pathogenic variant of SGCE is an autosomal dominant inherited movement disorder. Apart from motor symptoms, psychiatric disorders are highly prevalent in patients with MD. Previous studies suggest, but never tested directly, that the type of psychiatric disorder differs between dystonia syndromes, probably related to disease specific pathology. Little is known about other non-motor symptoms (NMS) in M.D. Here, we systematically study NMS in M-D in direct comparison to other types of dystonia and healthy controls. Methods: Standardized questionnaires were used to assess type and severity of psychiatric co-morbidity, sleep problems, fatigue and quality of life. Results of M-D patients with a pathogenic variant of SGCE were compared to results of idiopathic cervical dystonia (CD) patients, dopa-responsive dystonia (DRD) patients with a pathogenic variant of GCH1 and controls. Results: We included 164 participants: 41 M-D, 51 CD, 19 DRD patients, 53 controls. Dystonia patients (M-D, CD and DRD) had an increased prevalence of psychiatric disorders compared to controls (56-74% vs. 29%). In M-D we found a significantly increased prevalence of obsessive-compulsive disorder (OCD) and psychosis compared to CD and DRD. All dystonia patients had more sleep problems (49-68% vs. 36%) and fatigue (42-73% vs. 15%) than controls. Compared to other dystonia subtypes, M-D patients reported less excessive daytime sleepiness and fatigue. Conclusion: Psychiatric comorbidity is frequent in all dystonia types, but OCD and psychosis are more common in M-D patients. Further research is necessary to elucidate underlying pathways

Pentameric repeat expansions:cortical myoclonus or cortical tremor?

Functional Genomics of Muscle, Nerve and Brain Disorder

Developmental neurobiology of cerebellar and Basal Ganglia connections

BACKGROUND: The high prevalence of mixed phenotypes of Early Onset Ataxia (EOA) with comorbid dystonia has shifted the pathogenetic concept from the cerebellum towards the interconnected cerebellar motor network. This paper on EOA with comorbid dystonia (EOA-dystonia) explores the conceptual relationship between the motor phenotype and the cortico-basal-ganglia-ponto-cerebellar network. METHODS: In EOA-dystonia, we reviewed anatomic-, genetic- and biochemical-studies on the comorbidity between ataxia and dystonia. RESULTS: In a clinical EOA cohort, the prevalence of dystonia was over 60%. Both human and animal studies converge on the underlying role for the cortico-basal-ganglia-ponto-cerebellar network. Genetic -clinical and -in silico network studies reveal underlying biological pathways for energy production and neural signal transduction. CONCLUSIONS: EOA-dystonia phenotypes are attributable to the cortico-basal-ganglia-ponto-cerebellar network, instead of to the cerebellum, alone. The underlying anatomic and pathogenetic pathways have clinical implications for our understanding of the heterogeneous phenotype, neuro-metabolic and genetic testing and potentially also for new treatment strategies, including neuro-modulation

Axial jerks: a clinical spectrum ranging from propriospinal to psychogenic myoclonus

Propriospinal myoclonus (PSM) is a rare disorder with repetitive flexor, arrhythmic jerks of the trunk, hips and knees. Its generation is presumed to relay in the spinal cord. We report a case series of 35 consecutive patients with jerks of the trunk referred as possible PSM to a tertiary referral center for movement disorders. We review classical PSM features as well as psychogenic and tic characteristics. In our case series, secondary PSM was diagnosed in one patient only. 34 patients showed features suggestive of a psychogenic origin of axial jerks. Diagnosis of psychogenic axial jerks was based on clinical clues without additional investigations (n = 8), inconsistent findings at polymyography (n = 15), regular eye blinking preceding jerks (n = 2), or the presence of a Bereitschaftspotential (BP) (n = 9). In addition, several tic characteristics were noted. Almost all patients referred with possible PSM in our tertiary referral clinic had characteristics suggesting a psychogenic origin even in the presence of a classic polymyography pattern or in the absence of a BP. Clinical overlap with adult-onset tics seems to exist

Driving Performance in Patients With Idiopathic Cervical Dystonia; A Driving Simulator Pilot Study

Objective: To explore driving performance and driving safety in patients with cervical dystonia (CD) on a simulated lane tracking, intersections and highway ride and to compare it to healthy controls. Design: This study was performed as an explorative between groups comparison. Participants: Ten CD patients with idiopathic CD, 30 years or older, stable on botulinum toxin treatment for over a year, holding a valid driver's license and being an active driver were compared with 10 healthy controls, matched for age and gender. Main outcome measures: Driving performance and safety, measured by various outcomes from the simulator, such as the standard deviation of the lateral position on the road, rule violations, percentage of line crossings, gap distance, and number of collisions. Fatigue and driving effort were measured with the Borg CR-10 scale and self-perceived fitness to drive was assessed with Fitness to Drive Screening. Results: Except for a higher percentage of line crossings on the right side of the road by controls (median percentage 2.30, range 0.00-37.00 vs. 0.00, range 0.00-9.20, p = 0.043), no differences were found in driving performance and driving safety during the simulator rides. Fatigue levels were significantly higher in CD patients just before (p = 0.005) and after (p = 0.033) the lane tracking ride (patients median fatigue levels before 1.5 (range 0.00-6.00) and after 1.5 (range 0.00-7.00) vs. controls median fatigue levels before and after 0.00 (no range). No significant differences were found on self-perceived fitness to drive. Conclusion: In patients with CD there were no indications that driving performance or driving safety were significant different from healthy controls in a simulator. Patients reported higher levels of fatigue both before and after driving compared to controls in accordance with the non-motor symptoms known in CD