Non-Motor Symptoms and Quality of Life in Patients with PRRT2-Related Paroxysmal Kinesigenic Dyskinesia.

Background: Monoallelic pathogenic variants of PRRT2 often result in paroxysmal kinesigenic dyskinesia (PKD). Little is known about health-related quality of life (HrQoL), non-motor manifestations, self-esteem, and stigma in patients with PKD. Objectives: We investigated non-motor symptoms and how they related to HrQoL in a genetically homogeneous group of PRRT2-PKD patients. We paid special attention to perceived stigmatization and self-esteem. Methods: We prospectively enrolled 21 consecutive PKD patients with a pathogenic variant of PRRT2, and 21 healthy controls matched for age and sex. They were evaluated with dedicated standardized tests for non-motor symptoms, HrQoL, anxiety, depression, stigma, self-esteem, sleep, fatigue, pain, and psychological well-being. Results: Patients reported an alteration of the physical aspects of HrQoL, regardless of the presence of residual paroxysmal episodes. Non-motor manifestations were frequent, and were an important determinant of the alteration of HrQoL. In addition, patients perceived a higher level of stigmatization which positively correlated with a delay in diagnosis (ρ = 0.615, P = 0.003) and the fear of being judged (ρ = 0.452, P = 0.04), but not with the presence of paroxysmal episodes (ρ = 0.203, P = 0.379). Conclusions: Our findings have important implications for care givers concerning patient management and medical education about paroxysmal dyskinesia. PRRT2-PKD patients should be screened for non-motor disorders in routine care. A long history of misdiagnosis may play a role in the high level of perceived stigmatization. Improving knowledge about diagnostic clues suggestive of PKD is mandatory.

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.

Cerebellum Dysfunction in Patients With PRRT2-Related Paroxysmal Dyskinesia.

BACKGROUND AND OBJECTIVES: The main culprit gene for paroxysmal kinesigenic dyskinesia, characterized by brief and recurrent attacks of involuntary movements, is PRRT2. The location of the primary dysfunction associated with paroxysmal dyskinesia remains a matter of debate and may vary depending on the etiology. While striatal dysfunction has often been implicated in these patients, evidence from preclinical models indicates that the cerebellum could also play a role. We aimed to investigate the role of the cerebellum in the pathogenesis of PRRT2-related dyskinesia in humans. METHODS: We enrolled 22 consecutive right-handed patients with paroxysmal kinesigenic dyskinesia with a pathogenic variant of PRRT2 and their matched controls. Participants underwent a multimodal neuroimaging protocol. We recorded anatomic and diffusion-weighted MRI, as well as resting-state fMRI, during which we tested the aftereffects of sham and repetitive transcranial magnetic stimulation applied to the cerebellum on endogenous brain activity. We quantified the structural integrity of gray matter using voxel-based morphometry, the structural integrity of white matter using fixel-based analysis, and the strength and direction of functional cerebellar connections using spectral dynamic causal modeling. RESULTS: Patients with PRRT2 had decreased gray matter volume in the cerebellar lobule VI and in the medial prefrontal cortex, microstructural alterations of white matter in the cerebellum and along the tracts connecting the cerebellum to the striatum and the cortical motor areas, and dysfunction of cerebellar motor pathways to the striatum and the cortical motor areas, as well as abnormal communication between the associative cerebellum (Crus I) and the medial prefrontal cortex. Cerebellar stimulation modulated communication within the motor and associative cerebellar networks and tended to restore this communication to the level observed in healthy controls. DISCUSSION: Patients with PRRT2-related dyskinesia have converging structural alterations of the motor cerebellum and related pathways with a dysfunction of cerebellar output toward the cerebello-thalamo-striato-cortical network. We hypothesize that abnormal cerebellar output is the primary dysfunction in patients with a PRRT2 pathogenic variant, resulting in striatal dysregulation and paroxysmal dyskinesia. More broadly, striatal dysfunction in paroxysmal dyskinesia might be secondary to aberrant cerebellar output transmitted by thalamic relays in certain disorders. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov identifier: NCT03481491.

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.

Sleep in ADCY5-Related Dyskinesia: Prolonged Awakenings Caused by Abnormal Movements.

STUDY OBJECTIVES: ADCY5 mutations cause early-onset hyperkinetic movement disorders comprising diurnal and nocturnal paroxysmal dyskinesia, and patient-reported sleep fragmentation. We aimed to characterize all movements occurring during sleep and in the transition from sleep to awakening, to ascertain if there is a primary sleep disorder, or if the sleep disturbance is rather a consequence of the dyskinesia. METHODS: Using video polysomnography, we evaluated the nocturnal motor events and abnormal movements in 7 patients with ADCY5-related dyskinesia and compared their sleep measures with those of 14 age- and sex-matched healthy controls. RESULTS: We observed an increased occurrence of abnormal movements during wake periods compared to sleep in patients with ADCY5-related dyskinesia. While asleep, abnormal movements occurred more frequently during stage N2 and REM sleep, in contrast with stage N3 sleep. Abnormal movements were also more frequent during morning awakenings compared to wake periods before falling asleep. The pattern of the nocturnal abnormal movements mirrored those observed during waking hours. Compared to controls, patients with ADCY5-related dyskinesia had lower sleep efficiencies due to prolonged awakenings secondary to the abnormal movements, but no other differences in sleep measures. Notably, sleep onset latency was short and devoid of violent abnormal movements. CONCLUSIONS: In this series of patients with ADCY5-related dyskinesia, nocturnal paroxysmal dyskinesia were not associated with drowsiness or delayed sleep onset, but emerged during nighttime awakenings with subsequent delayed sleep, whereas sleep architecture was normal.

Visual assessment of diffusion weighted imaging infarct volume lacks accuracy and reliability.

PURPOSE: The DAWN trial (Diffusion weighted imaging or CT perfusion Assessment with clinical mismatch in the triage of Wake-up and late presenting strokes undergoing Neurointervention with Trevo) has demonstrated the benefits of thrombectomy in patients with unknown or late onset strokes, using automated software (RAPID) for measurement of infarct volume. Because RAPID is not available in all centers, we aimed to assess the accuracy and repeatability of visual infarct volume estimation by clinicians and the consequences for thrombectomy decisions based on the DAWN criteria. MATERIALS AND METHODS: 18 physicians, who routinely depend on MRI for acute stroke imaging, assessed 32 MR scans selected from a prospective databaseover two independent sessions. Raters were asked to visually estimate the diffusion weighted imaging (DWI) infarct volume for each case. Sensitivity, specificity, and accuracy of the estimated volumes were compared with the available RAPID measurements for various volume cut-off points. Thrombectomy decisions based on DAWN criteria with RAPID measurements and raters' visual estimates were compared. Inter-rater and intra-rater agreement was measured using kappa statistics. RESULTS: The mean accuracy of raters was <90% for all volume cut-points. Inter-rater agreement was below substantial for each DWI infarct volume cut-off points. Intra-rater agreement was substantial for 55-83% of raters, depending on the selected cut-off points. Applying DAWN criteria with visual estimates instead of RAPID measurements led to 19% erroneous thrombectomy decisions, and showed a lack of reproducibility. CONCLUSION: The visual assessment of DWI infarct volume lacks accuracy and repeatability, and could lead to a significant number of erroneous decisions when applying the DAWN criteria.