Clinical and genetic keys to cerebellar ataxia due to FGF14 GAA expansions.

BACKGROUND: SCA27B caused by FGF14 intronic heterozygous GAA expansions with at least 250 repeats accounts for 10-60% of cases with unresolved cerebellar ataxia. We aimed to assess the size and frequency of FGF14 expanded alleles in individuals with cerebellar ataxia as compared with controls and to characterize genetic and clinical variability. METHODS: We sized this repeat in 1876 individuals from France sampled for research purposes in this cross-sectional study: 845 index cases with cerebellar ataxia and 324 affected relatives, 475 controls, as well as 119 cases with spastic paraplegia, and 113 with familial essential tremor. FINDINGS: A higher frequency of expanded allele carriers in index cases with ataxia was significant only above 300 GAA repeats (10.1%, n = 85) compared with controls (1.1%, n = 5) (p < 0.0001) whereas GAA250-299 alleles were detected in 1.7% of both groups. Eight of 14 index cases with GAA250-299 repeats had other causal pathogenic variants (4/14) and/or discordance of co-segregation (5/14), arguing against GAA causality. We compared the clinical signs in 127 GAA≥300 carriers to cases with non-expanded GAA ataxia resulting in defining a key phenotype triad: onset after 45 years, downbeat nystagmus, episodic ataxic features including diplopia; and a frequent absence of dysarthria. All maternally transmitted alleles above 100 GAA were unstable with a median expansion of +18 repeats per generation (r2 = 0.44; p < 0.0001). In comparison, paternally transmitted alleles above 100 GAA mostly decreased in size (-15 GAA (r2 = 0.63; p < 0.0001)), resulting in the transmission bias observed in SCA27B pedigrees. INTERPRETATION: SCA27B diagnosis must consider both the phenotype and GAA expansion size. In carriers of GAA250-299 repeats, the absence of documented familial transmission and a presentation deviating from the key SCA27B phenotype, should prompt the search for an alternative cause. Affected fathers have a reduced risk of having affected children, which has potential implications for genetic counseling. FUNDING: This work was supported by the Fondation pour la Recherche Médicale, grant number 13338 to JLM, the Association Connaître les Syndrome Cérébelleux - France (to GS) and by the European Union's Horizon 2020 research and innovation program under grant agreement No 779257 ("SOLVE-RD" to GS). DP holds a Fellowship award from the Canadian Institutes of Health Research (CIHR). SK received a grant (01GM1905C) from the Federal Ministry of Education and Research, Germany, through the TreatHSP network. This work was supported by the Australian Government National Health and Medical Research Council grants (GNT2001513 and MRFF2007677) to MB and PJL.

Trial of Botulinum Toxin for Isolated or Essential Head Tremor.

BACKGROUND: Local injections of botulinum toxin type A have been used to treat essential head tremor but have not been extensively studied in randomized trials. METHODS: In a multicenter, double-blind, randomized trial, we assigned, in a 1:1 ratio, adult patients with essential or isolated head tremor to receive botulinum toxin type A or placebo. Botulinum toxin or placebo was injected under electromyographic guidance into each splenius capitis muscle on the day of randomization (day 0) and during week 12. The primary outcome was improvement by at least 2 points on the Clinical Global Impression of Change (CGI) scale at week 6 after the second injection (week 18 after randomization). The CGI scale was used to record the patient's assessment of the degree of improvement or worsening of head tremor since baseline; scores range from 3 (very much improved) to -3 (very much worse). Secondary outcomes included changes in tremor characteristics from baseline to weeks 6, 12, and 24. RESULTS: A total of 120 patients were enrolled; 3 patients were excluded during screening, and 117 patients were randomly assigned to receive botulinum toxin (62 patients) or placebo (55 patients) and were included in the intention-to-treat analysis. Twelve patients in the botulinum toxin group and 2 patients in the placebo group did not receive injections during week 12. The primary outcome - improvement by at least 2 points on the CGI scale at week 18 - was met by 31% of the patients in the botulinum toxin group as compared with 9% of those in the placebo group (relative risk, 3.37; 95% confidence interval, 1.35 to 8.42; P = 0.009). Analyses of secondary outcomes at 6 and 12 weeks but not at 24 weeks were generally supportive of the primary-outcome analysis. Adverse events occurred in approximately half the patients in the botulinum toxin group and included head and neck pain, posterior cervical weakness, and dysphagia. CONCLUSIONS: Injection of botulinum toxin into each splenius capitis muscle on day 0 and during week 12 was more effective than placebo in reducing the severity of isolated or essential head tremor at 18 weeks but not at 24 weeks, when the effects of injection might be expected to wane, and was associated with adverse events. (Funded by the French Ministry of Health; Btx-HT ClinicalTrials.gov number, NCT02555982.).

Assessment of axial rotation movement in cervical dystonia using cone-beam computed tomography.

BACKGROUND: Cervical dystonia is a neurological disorder characterized by involuntary muscle contractions and abnormal postures of the head and neck. Botulinum neurotoxin injection is the first-line treatment. Imaging determination of the cervical segments involved (lower or upper according to the torticollis-torticaput [COL-CAP] Classification) is an aid in determining the muscles to be injected. We aimed to clarify the impact of dystonia on posture and rotational movement of cervical vertebrae in the transverse plane. METHODS: A comparative study was conducted in a movement disorders department. Ten people with cervical dystonia and 10 matched healthy subjects (without cervical dystonia) were recruited. 3-D images of posture and cervical range of motion in axial rotation in the sitting position were recorded by using a cone-beam CT scanner. Range of rotational motion of the upper cervical spine from the occipital bone to fourth cervical vertebra was measured and compared between the two groups. FINDINGS: The head posture analysis showed that the total cervical spine position was more significantly distant from the neutral position for people with dystonia than healthy subjects (p = 0.007). The rotational range of motion of the cervical spine was significantly lower in cervical dystonia participants than in healthy subjects for the total (p = 0.026) and for upper cervical spine (p = 0.004). INTERPRETATION: We demonstrated, by means of cone-beam CT, that the disorganization of movements due to cervical dystonia affected the upper cervical spine and mostly the atlantoaxial joint. The involvement of rotator muscles at this cervical level should be considered more in treatments.

Fixel-Based Analysis Reveals Whole-Brain White Matter Abnormalities in Cervical Dystonia.

BACKGROUND: Cervical dystonia (CD) is a form of isolated focal dystonia typically associated to abnormal head, neck, and shoulder movements and postures. The complexity of the clinical presentation limits the investigation of its pathophysiological mechanisms, and the neural networks associated to specific motor manifestations are still the object of debate. OBJECTIVES: We investigated the morphometric properties of white matter fibers in CD and explored the networks associated with motor symptoms, while regressing out nonmotor scores. METHODS: Nineteen patients affected by CD and 21 healthy controls underwent diffusion-weighted magnetic resonance imaging. We performed fixel-based analysis, a novel method evaluating fiber orientation within specific fiber bundles, and compared fiber morphometric properties between groups. Moreover, we correlated fiber morphometry with the severity of motor symptoms in patients. RESULTS: Compared to controls, patients exhibited decreased white matter fibers in the right striatum. Motor symptom severity negatively correlated with white matter fibers passing through inferior parietal areas and the head representation area of the motor cortex. CONCLUSIONS: Abnormal white matter integrity at the basal ganglia level may affect several functional networks involved, for instance, in motor preparation and execution, visuomotor coordination, and multimodal integration. This may result in progressive maladaptive plasticity, culminating in overt symptoms of dystonia. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Quantification of Head Tremors in Medical Conditions: A Comparison of Analyses Using a 2D Video Camera and a 3D Wireless Inertial Motion Unit.

This study compares two methods to quantify the amplitude and frequency of head movements in patients with head tremor: one based on video-based motion analysis, and the other using a miniature wireless inertial magnetic motion unit (IMMU). Concomitant with the clinical assessment of head tremor severity, head linear displacements in the frontal plane and head angular displacements in three dimensions were obtained simultaneously in forty-nine patients using one video camera and an IMMU in three experimental conditions while sitting (at rest, counting backward, and with arms extended). Head tremor amplitude was quantified along/around each axis, and head tremor frequency was analyzed in the frequency and time-frequency domains. Correlation analysis investigated the association between the clinical severity of head tremor and head linear and angular displacements. Our results showed better sensitivity of the IMMU compared to a 2D video camera to detect changes of tremor amplitude according to examination conditions, and better agreement with clinical measures. The frequency of head tremor calculated from video data in the frequency domain was higher than that obtained using time-frequency analysis and those calculated from the IMMU data. This study provides strong experimental evidence in favor of using an IMMU to quantify the amplitude and time-frequency oscillatory features of head tremor, especially in medical conditions.

Somatotopy of cervical dystonia in motor-cerebellar networks: Evidence from resting state fMRI.

INTRODUCTION: Cervical dystonia is the most frequent form of isolated focal dystonia. It is often associated with a dysfunction in brain networks, mostly affecting the basal ganglia, the cerebellum, and the somatosensory cortex. However, it is unclear if such a dysfunction is somato-specific to the brain areas containing the representation of the affected body part, and may thereby account for the focal expression of cervical dystonia. In this study, we investigated resting state functional connectivity in the areas within the motor cortex and the cerebellum containing affected and non-affected body representations in cervical dystonia patients. METHODS: Eighteen patients affected by cervical dystonia and 21 healthy controls had resting state fMRI. The functional connectivity between the motor cortex and the cerebellum, as well as their corresponding measures of gray matter volume and cortical thickness, were compared between groups. We performed seed-based analyses, selecting the different body representation areas in the precentral gyrus as seed regions, and all cerebellar areas as target regions. RESULTS: Compared to controls, patients exhibited increased functional connectivity between the bilateral trunk representation area of the motor cortex and the cerebellar vermis 6 and 7b, respectively. These functional abnormalities did not correlate with structural changes or symptom severity. CONCLUSIONS: Our findings indicate that the abnormal function of the motor network is somato-specific to the areas encompassing the neck representation. Functional abnormalities in discrete relevant areas of the motor network could thus contribute to the focal expression of CD.

Incobotulinum toxin A in Parkinson's disease with foot dystonia: A double blind randomized trial.

INTRODUCTION: Plantar flexion of toe dystonia is very painful and leads to difficulties in walking. The objective of this study was to investigate the effect of incobotulinum toxin A (Xeomin) in the treatment of this type of dystonia in parkinsonian patients, using a randomized, double blind, placebo-controlled trial. METHODS: 45 parkinsonian patients with painful dystonic plantar flexion of toes were injected either with incobotulinum toxin A (Btx group), or with placebo in two muscle targets: the Flexor digitorum longus and the Flexor digitorum brevis. Three groups were compared: the first group received placebo in the Flexor digitorum longus and 100UI of Btx in the Flexor digitorum brevis (n = 16); the second group received 100 UI of Btx in the Flexor digitorum longus and placebo in the Flexor digitorum brevis (n = 13); and the third group, 2 injections of placebo (n = 16). The patients were injected in the same way twice with an interval of 3 months. The primary endpoint was measured six weeks after injections with the Clinical Global Impression (CGI) of change. Dystonia severity and associated pain were also assessed. RESULTS: Mean CGI was improved in the Btx group compared to the placebo group (P = 0.039). A significant reduction of pain and dystonia severity were observed in patients treated with Btx compared to baseline but no improvement was noted when compared to placebo group. No difference of efficacy was highlighted between the two injection sites. CONCLUSIONS: Btx injections are effective for improving clinical state of parkinsonian patients with plantar flexion of toe dystonia.

Does dystonic muscle activity affect sense of effort in cervical dystonia?

BACKGROUND: Focal dystonia has been associated with deficient processing of sense of effort cues. However, corresponding studies are lacking in cervical dystonia (CD). We hypothesized that dystonic muscle activity would perturb neck force control based on sense of effort cues. METHODS: Neck extension force control was investigated in 18 CD patients with different clinical features (7 with and 11 without retrocollis) and in 19 control subjects. Subjects performed force-matching and force-maintaining tasks at 5% and 20% of maximum voluntary contraction (MVC). Three task conditions were tested: i) with visual force feedback, ii) without visual feedback (requiring use of sense of effort), iii) without visual feedback, but with neck extensor muscle vibration (modifying muscle afferent cues). Trapezius muscle activity was recorded using electromyography (EMG). RESULTS: CD patients did not differ in task performance from healthy subjects when using visual feedback (ANOVA, p>0.7). In contrast, when relying on sense of effort cues (without visual feedback, 5% MVC), force control was impaired in patients without retrocollis (p = 0.006), but not in patients with retrocollis (p>0.2). Compared to controls, muscle vibration without visual feedback significantly affected performance in patients with retrocollis (p<0.001), but not in patients without retrocollis. Extensor EMG during rest, included as covariate in ANOVA, explained these group differences. CONCLUSION: This study shows that muscle afferent feedback biases sense of effort cues when controlling neck forces in patients with CD. The bias acts on peripheral or central sense of effort cues depending on whether the task involves dystonic muscles. This may explain why patients with retrocollis more accurately matched isometric neck extension forces. This highlights the need to consider clinical features (pattern of dystonic muscles) when evaluating sensorimotor integration in CD.

Baseline Features Influencing the Effectiveness of Retraining Therapy for Writer's Cramp.

Background: The effectiveness of retraining therapy (RT) for writer's cramp is difficult to predict and its determinants are unknown. Methods: We examined factors potentially predicting improved legibility after RT in patients with writer's cramp (WC). We reviewed the files of 693 WC patients treated with RT from 1995 to 2009. Standardized assessments were made both at baseline and after 2 months of RT in 305 patients. The effect of RT on legibility was evaluated by using the handwriting subscore of the Burke-Fahn-Marsden (BFM) disability scale. Initial and final handwriting samples were blindly scored in random order. Associations between WC patterns and changes in legibility were identified by uni- and multivariable analyses. Results: Legibility improved by ≥1 point in the BFM handwriting subscore in 93 patients (31%). WC patients who improved were more likely to have synergic dystonic patterns involving the wrist and forearm (60% vs. 40%; P = 0.03) and less likely to have flexion of fingers F3 to F5 (19% vs. 81%; P = 0.017). Outcome was not related to gender, age, or dystonia duration. Our results confirm that retraining therapy could improve legibility in patients with writer's cramp. Conclusions: The pattern of writer's cramp can help to identify patients who are most likely to benefit from retraining therapy, regardless of age, gender, and disease duration.

Diffusion abnormalities in the primary sensorimotor pathways in writer's cramp.

OBJECTIVE: To determine whether there are diffusion abnormalities along the fibers connecting sensorimotor regions, including the primary sensorimotor areas and the striatum, in patients with writer's cramp using voxel-based diffusion analysis and fiber tracking. Recent studies have shown structural changes in these regions in writer's cramp. DESIGN: Patient and control group comparison. SETTING: Referral center for movement disorders. PARTICIPANTS: Twenty-six right-handed patients with writer's cramp and 26 right-handed healthy control subjects matched for sex and age. INTERVENTIONS: Clinical motor evaluations. MAIN OUTCOME MEASURES: Fractional anisotropy changes and results of fiber tracking in writer's cramp. RESULTS: Diffusion-tensor imaging revealed increased fractional anisotropy bilaterally in the white matter of the posterior limb of the internal capsule and adjacent structures in the patients with writer's cramp. Fiber tracking demonstrated that fractional anisotropy changes involve fiber tracts connecting the primary sensorimotor areas with subcortical structures. CONCLUSIONS: Diffusion abnormalities are present in fiber tracts connecting the primary sensorimotor areas with subcortical structures in writer's cramp. These abnormalities strengthen the role of the corticosubcortical pathways in the pathophysiologic mechanisms of writer's cramp.

Myoclonus or tremor in orthostatism: an under-recognized cause of unsteadiness in Parkinson's disease.

Patients with Parkinson's disease (PD) often complain of unsteadiness. This can occur as the result of various neurological dysfunctions, including changes in postural adjustments, loss of postural reflexes, axial akinesia and rigidity, freezing and/or postural hypotension. In some cases these symptoms remain unexplained, and rare cases of unsteadiness have been attributed to tremor on standing. To delineate this condition, we investigated 11 consecutive PD patients with unexplained unsteadiness because of tremor on standing, seen in our department over a 6-year period. All the patients had detailed clinical and electrophysiological investigations based on surface polygraphic electromyographic recordings. Four patients had fast orthostatic tremor (13-18 Hz), one had intermediate orthostatic tremor (8-9 Hz), and three had slow orthostatic tremor (4-6 Hz). The remaining 3 patients had orthostatic myoclonus, a condition that has not previously been reported in PD. Patients with fast tremor improved on clonazepam. Patients with slow tremor and myoclonus improved on levodopa and sometimes benefited further when clonazepam was added. These observations show the usefulness of neurophysiological investigations for diagnosing and treating unexplained unsteadiness in Parkinson's disease.

Rett syndrome: an overlooked diagnosis in women with stereotypic hand movements, psychomotor retardation, Parkinsonism, and dystonia?

Rett syndrome is an X-linked neurodevelopmental disorder resulting in profound psychomotor retardation. It is usually diagnosed by a pediatrician or pediatric neurologist. Adult neurologists may, therefore, overlook the possibility of Rett syndrome in women with psychomotor retardation of unknown etiology. We report the case of a woman diagnosed with Rett syndrome at age 49 years. This report emphasizes the diagnostic value of movement disorders, including hand stereotypies, Parkinsonism, and dystonia, in adults with Rett syndrome.

Lack of inhibitory interaction between somatosensory afferent inputs and intracortical inhibitory interneurons in focal hand dystonia.

We looked for an impaired interaction in the primary motor cortex between intracortical inhibitory circuits and circuits fed by somatosensory inputs in patients with writer's cramp. Short-interval intracortical inhibition (sICI) to wrist extensor carpi radialis muscle (ECR) was conditioned by stimulation of antagonist muscle afferents and sICI to first dorsal interosseus (FDI) muscle by homotopic cutaneous afferents stimulation. sICI was assessed at rest and during a tonic contraction of the target muscle. Eighteen patients with writer's cramp (10 having a wrist dystonic posture in flexion during writing and 8 in extension) were compared to 14 control subjects. Peripheral inputs decreased sICI in control subjects. This decrease was lost in patients in both FDI and ECR, regardless of the wrist dystonic posture. By contrast, contraction-induced depression of sICI appeared dependant on the dystonic status of the muscle: depression of sICI to ECR was abolished in patients with wrist dystonic posture in flexion, but not in patients with dystonic posture in extension, sICI even giving way to motor-evoked potential facilitation. Loss of interaction between interneurons mediating sICI and peripheral inputs probably belongs to the initial abnormalities underlying dystonia. Lack of peripherally induced sICI modulation may oppose wrist and/or hand muscles synergies.