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To differentiate arytenoid subluxation and vocal fold paralysis by CT cine mode scanning combined with three-dimensional (3D) reconstruction image.Seventy-six patients with suspected vocal fold dyskinesia were collected. All patients were examined being asked to inhale deeply and then make "Yi" sound continuously during CT scanning with cine mode. The optimal maximum opening and minimum closing phases of glottis were selected and 3D reconstruction images were performed. The length of vocal fold, the width of glottis, and the subglottal convergence angle, anteversion angle, elevation angle, valgus angle, and varus angle of cricoarytenoid joints were measured. Vocal fold deformation was divided into three types: type I, type II, and type III. Kappa test was used to compare the consistency between CT diagnosis and clinical diagnosis. Single-factor analysis of variance was used to analyze the statistical differences among arytenoid subluxation, vocal fold paralysis, and normal vocal fold.There was high consistency between CT diagnosis and clinical diagnosis (k = 0.731, P0.05), as well as significant differences in the opening width of glottis between type I and type III, the valgus and varus angles of cricoarytenoid joints between type I and type II or type III, and the subglottal convergence angles among the three types of vocal fold deformation.CT scanning with cine mode combined with 3D reconstruction can display the changes of larynx structures in vocal fold dyskinesia, and can be used for the differential diagnosis of arytenoid cartilage subluxation and vocal fold paralysis.

A 76-year-old man was admitted to the hospital with acute onset of involuntary movements of the left side of his body. His neurological examination revealed he was oriented only to himself, and aforementioned movements of his left arm and leg. CT head demonstrated old infarcts in his right aspect of his pons and basal ganglia. Cerebrospinal fluid analysis was unremarkable. He initially had a normal blood glucose with an elevated anion gap and elevated creatine kinase. Brain MRI showed a small lacunar-type ischaemic infarct within the anteromedial aspect of the right cerebral peduncle, which localised to his haemiballism. To prevent worsening rhabdomyolysis associated with his haemiballism, the primary team initiated both tetrabenazine and diazepam. His movements improved after 1 week of medication therapy. This report discusses a thorough workup for this movement disorder and when to intervene for this distressing condition.

A 6-month-old girl presented to hospital via ambulance with a decreased conscious level (initial Glasgow Coma Scale of 3) and an abnormal breathing pattern described as diaphragmatic flutter. She then developed abnormal movements and continued to have episodes of fluctuating conscious levels so was transferred to a tertiary hospital paediatric intensive care unit for further investigation. During her 16-day stay in hospital, she continued to experience discrete episodes of drowsiness, bradycardia, unusual breathing patterns and abnormal movements which were associated with agitation, tachycardia, hypertension and insomnia. The patient underwent extensive investigation for her symptoms and, after some delay in waiting for initial results before considering a urine drug screen, she was ultimately found to have lisdexamfetamine and clonidine in her urine drug screen. Her symptoms subsequently resolved after her mother’s visits were restricted.

Background Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is characterized by biphasic seizures and white matter lesions with reduced diffusion, which are often accompanied by involuntary movements. The neurological outcomes of AESD vary from normal to mild or severe sequelae, including intellectual disability, paralysis, and epilepsy. The present study aimed to clarify the prognostic factors of AESD, including involuntary movements. Methods We enrolled 29 patients with AESD admitted to Tottori University Hospital from 1991 to 2020 and retrospectively analyzed their clinical data. Neurological outcomes were assessed by the Pediatric Cerebral Performance Category score and cerebral paralysis as neurological sequelae. Results Of the 29 patients, 12 had favorable outcomes and 17 had unfavorable outcomes. Univariate analysis revealed that the presence of underlying diseases, a decline in Glasgow Coma Scale (GCS) score 12–24 h after early seizures, and involuntary movements were associated with unfavorable outcomes. In multivariate analysis, a decline in GCS score and involuntary movements were associated with unfavorable outcomes. The sensitivities and specificities of underlying diseases, a decline of ≥ 3 points in GCS score 12–24 h after early seizures, and involuntary movements for unfavorable outcomes were 53% and 92%, 92% and 65%, and 59% and 92%, respectively. Conclusions The appearance of involuntary movements may be associated with unfavorable outcomes of AESD. The prognostic factors identified herein are comparable with previously known prognostic factors of consciousness disturbances after early seizures.

Background Abnormal glutamatergic neurotransmission in the primary motor cortex (M1) contributes to Parkinson's disease (PD) pathophysiology and is related to l -dopa-induced dyskinesia (LID). We previously showed that short-term treatment with safinamide, a monoamine oxidase type-B inhibitor with anti-glutamatergic properties, improves abnormally enhanced short-interval intracortical facilitation (SICF) in PD patients. Objective To examine whether a long-term SICF modulation has beneficial effects on clinical measures, including LID severity, and whether these changes parallel improvement in cortical plasticity mechanisms in PD. Methods We tested SICF in patients with and without LID before (S0) and after short- (14 days - S1) and long-term (12 months - S2) treatment with safinamide 100 mg/day. Possible changes in M1 plasticity were assessed using intermittent theta-burst stimulation (iTBS). Finally, we correlated safinamide-related neurophysiological changes with modifications in clinical scores. Results SICF was enhanced at S0, and prominently in patients with LID. Safinamide normalized SICF at S1, and this effect persisted at S2. Impaired iTBS-induced plasticity was present at S0 and safinamide restored this alteration at S2. There was a significant correlation between the degree of SICF and the amount of iTBS-induced plasticity at S0 and S2. In patients with LID, the degree of SICF at S0 and S2 correlated with long-term changes in LID severity. Conclusions Altered SICF contributes to M1 plasticity impairment in PD. Both SICF and M1 plasticity improve after long-term treatment with safinamide. The abnormality in SICF-related glutamatergic circuits plays a role in LID pathophysiology, and its long-term modulation may prevent LID worsening over time.

Background: Impulsive compulsive behaviors (ICBs) can affect a significant number of Parkinson’s disease (PD) patients. Objective: We have studied brain samples from a brain bank of PD patients who received apomorphine via continuous infusion in life to assess the prevalence and outcome of ICBs. Methods: A search on the Queen Square Brain Bank (QSBB) database for cases donated from 2005 to 2016 with a pathological diagnosis of idiopathic PD was conducted. Notes of all donors who used apomorphine via continuous infusion for at least three months were reviewed. Clinical and demographic data were collected, as well as detailed information on treatment, prevalence and outcomes of ICBs. Results: 193 PD cases, 124 males and 69 females, with an average age at disease onset of 60.2 years and average disease duration of 17.2 years were reviewed. Dementia occurred in nearly half of the sample, depression in one quarter, and dyskinesias in a little over 40%. The prevalence of ICBs was 14.5%. Twenty-four individuals used apomorphine infusion for more than three months. Patients on apomorphine had younger age at disease onset, longer disease duration, and higher prevalence of dyskinesias. The prevalence of de novo ICB cases among patients on apomorphine was 8.3%. Apomorphine infusion was used for an average of 63.1 months on an average maximum dose of 79.5 mg per day. Ten patients remained on apomorphine until death. Conclusions: Apomorphine can be used as an alternative treatment for patients with previous ICBs as it has low risk of triggering recurrence of ICBs. RESUMO Antecedentes: Comportamentos impulsivo-compulsivos (CICs) podem acometer uma parcela significativa de indivíduos com doença de Parkinson (DP). Objetivo: Nós estudamos amostras de tecido cerebral de uma população de pacientes com DP de um banco de cérebros que receberam apomorfina por infusão contínua em vida, com a finalidade de avaliar a prevalência e o desfecho dos CICs. Métodos: Uma pesquisa no banco de dados do Banco de Cérebros de Queen Square foi conduzida à procura de doações recebidas entre 2005 e 2016 com diagnóstico anatomopatológico de DP idiopática. Os prontuários de todos os doadores que usaram apomorfina por infusão contínua por um período mínimo de três meses foram revisados. Dados clínicos e demográficos foram coletados, assim como informações detalhadas sobre o tratamento, prevalência e desfecho dos CICs. Resultados: 193 casos de DP, 124 do sexo masculino e 69 do sexo feminino, com idade média de início da doença de 60,2 anos e tempo médio de duração da doença de 17,2 anos, foram revisados. Aproximadamente metade dos casos apresentaram demência, um quarto depressão, e um pouco mais de 40% discinesias. A prevalência de CICs foi 14,5%. Vinte e quatro indivíduos usaram infusão de apomorfina por mais de três meses. Os pacientes que usaram apomorfina apresentaram DP mais cedo, maior duração da doença, e uma maior prevalência de discinesias. A prevalência de novos casos de CICs entre pacientes usando apomorfina foi de 8,3%. Infusão de apomorfina foi usada em média por 63,1 meses a um dose máxima média de 79,5 mg por dia. Dez pacientes permaneceram usando apomorfina até o óbito. Conclusões: Apomorfina pode ser usada como opção de tratamento alternativo para pacientes que apresentarem CICs no passado considerando seu baixo risco de causar recorrência de CICs.

Introduction In 2009, we described a possible founder effect of autosomal dominant Segawa disease in Cordoba (Spain) due to mutation c.265C>T (p. Q89*) in the GCH1 gene. We present a retrospective multicentre study aimed at improving our knowledge of Segawa disease in Spain and providing a detailed phenotypic-genotypic description of patients. Methods Clinical-genetic information were obtained from standardized questionnaires that were completed by the neurologists attending children and/or adults from 16 Spanish hospitals. Results Eighty subjects belonging to 24 pedigrees had heterozygous mutations in GCH1. Seven genetic variants have been described only in our cohort of patients, 5 of which are novel mutations. Five families not previously described with p. Q89* were detected in Andalusia due to a possible founder effect. The median latency to diagnosis was 5 years (IQR 0–16). The most frequent signs and/or symptoms were lower limb dystonia (38/56, 67.8%, p = 0.008) and diurnal fluctuations (38/56, 67.8%, p = 0.008). Diurnal fluctuations were not present in the phenotypes other than dystonia. Fifty-three of 56 symptomatic patients were treated with a levodopa/decarboxylase inhibitor for (mean ± SD) 12.4 ± 8.12 years, with 81% at doses lower than 350 mg/day (≤5 mg/kg/d in children). Eleven of 53 (20%) patients had non-responsive symptoms that affected daily life activities. Dyskinesias (4 subjects) were the most prominent adverse effects. Conclusion This study identifies 5 novel mutations and supports the hypothesis of a founder effect of p. Q89* in Andalusia. New insights are provided for the phenotypes and long-term treatment responses, which may improve early recognition and therapeutic management.

Parkinson’s disease (PD) is the second most common neurodegenerative disease and a prime target of cell therapies. In fact, aborted fetal tissue has been used as donor material for such therapies since the 1980s. These cell therapies, however, suffer from several problems, such as a short supply of donor materials, quality instability of the tissues, and ethical restrictions. The advancement of stem cell technologies has enabled the production of donor cells from pluripotent stem cells with unlimited scale, stable quality, and less ethical problems. Several research groups have established protocols to induce dopamine neural progenitors from pluripotent stem cells in a clinically compatible manner and confirmed efficacy and safety in non-clinical studies. Based on the results from these non-clinical studies, several clinical trials of pluripotent stem cell-based therapies for PD have begun. In the context of immune rejection, there are several modes of stem cell-based therapies: autologous transplantation, allogeneic transplantation without human leukocyte antigen-matching, and allogeneic transplantation with matching. In this mini-review, several practical points of stem cell-based therapies for PD are discussed.

Introduction With the levodopa threshold effect for dyskinesia observed, threshold dosage of levodopa was identified in the general Parkinson's disease (PD) population. While early-onset PD (EOPD) and late-onset PD (LOPD) differ in the pathogenesis and clinical manifestations, threshold dosage of levodopa for individualized treatment remains unestablished. The objective of this study was to propose threshold dosage of levodopa in EOPD and LOPD patients, respectively. Methods Data on demographic and clinical and treatment measures were collected in 539 PD patients. Patients were divided into different onset groups using 50 as the cut-off age. We used univariable and multivariable analysis to screen for risk factors for dyskinesia. Receiver operating characteristic curve was used to determine the levodopa threshold dosages for dyskinesia. Results The prevalence of dyskinesia was 47.7% (53/111) in the EOPD group and 24.1% (103/428) in the LOPD group. Risk factors identified for dyskinesia include high levodopa daily dose and levodopa responsiveness for EOPD patients and high levodopa daily dose, long levodopa treatment duration, low body weight, use of entacapone, and high Hoehn-Yahr stage in off state for LOPD patients. The daily levodopa threshold dosages were 400 mg or 5.9 mg/kg for EOPD and 450 mg or 7.2 mg/kg for LOPD. Conclusion EOPD patients had lower levodopa threshold dosage comparing with LOPD patients. Treatment of EOPD requires stricter levodopa dose control to delay the onset of dyskinesia.

Functional neurological disorders differ from malingering/factitious disorders and are diagnosed based solely on careful history taking and neurological evaluation. Some clinical characteristics, including distractibility, entrainability, and variability are important to identify the positive physical signs that indicate functional alterations. Thorough investigations are not essential to exclude organic pathologies, whereas electrophysiological and radiological findings are sometimes useful. Neurologists play an important role when they explain the diagnosis to the patient. The explanation itself may be therapeutic, when delivered successfully and may help patients to understand the nature and mechanisms underlying their movement disorder. A multidisciplinary team approach, including coordination between rehabilitation therapists and psychotherapists may produce positive treatment outcomes, particularly in movement disorder centers. In this article, we discuss some functional neurological disorders, including those in patients with functional movement disorders (involuntary movements) together with video presentations.

BACKGROUND Functional movement disorder (FMD), a conversion disorder characterized by involuntary movements, is difficult to treat. METHODS We aimed to assess the effects of anodal transcranial direct current stimulation (tDCS) and yoga in FMD patients (n=5). TDCS of the right temporoparietal junction, a brain region relevant in the sense of self-agency, was conducted. Subjects underwent both sham and anodal tDCS with a washout period of 3 weeks. Yoga was used as a mode of exercise, as well as in conjunction with stimulation to sustain potential changes in neural plasticity. RESULTS A total of 5 subjects completed the study [mean age: 52 (SE: 4) y, disease duration: 5 (SE: 1.6) y], undergoing both sham and anodal tDCS. Anodal tDCS does not appear to be superior to sham tDCS in alleviating symptoms and disability, but combining tDCS and yoga appears to lead to mild improvement noted on clinical observation, based on the change in the efficacy index of Clinical Global Impression found in 4 subjects. CONCLUSION Our study results suggest that anodal tDCS is not superior to sham tDCS in alleviating subjective symptoms and disability in FMD. However, interpretation of these results is limited due to the small number of stimulation sessions and number of subjects. Future studies using more frequent stimulation sessions are needed to further determine whether anodal tDCS may have a therapeutic effect in this patient group compared with sham tDCS.

Background: Motor complications are a consequence of the chronic dopaminergic treatment of Parkinson’s disease (PD) and include levodopa-induced dyskinesia (LIDs) and motor fluctuations (MF). Currently, evidence is on lacking whether patients with GBA-associated PD differ in their risk of developing motor complications compared to the general PD population. Objective: To evaluate the association of GBA carrier status with the development of LIDS and MFs from early PD. Methods: Motor complications were recorded prospectively in 884 patients with PD from four longitudinal cohorts using part IV of the UPDRS or MDS-UPDRS. Subjects were followed for up to 11 years and the associations of GBA mutations with the development of motor complications were assessed using parametric accelerated failure time models. Results: In 439 patients from Europe, GBA mutations were detected in 53 (12.1%) patients and a total of 168 cases of LIDs and 258 cases of MF were observed. GBA carrier status was not associated with the time to develop LIDs (HR 0.78, 95%CI 0.47 to 1.26, p = 0.30) or MF (HR 1.19, 95%CI 0.84 to 1.70, p = 0.33). In the American cohorts, GBA mutations were detected in 36 (8.1%) patients and GBA carrier status was also not associated with the progression to LIDs (HR 1.08, 95%CI 0.55 to 2.14, p = 0.82) or MF (HR 1.22, 95%CI 0.74 to 2.04, p = 0.43). Conclusion: This study does not provide evidence that GBA-carrier status is associated with a higher risk of developing motor complications. Publication of studies with null results is vital to develop an accurate summary of the clinical features that impact patients with GBA-associated PD. publishedVersion

Introduction The non-motor symptoms (NMSs) of Parkinson's disease (PD) significantly impact the patient's health-related quality of life. This subanalysis of the J-FIRST study evaluated the effect of istradefylline, a selective adenosine A2A receptor antagonist, on NMSs in istradefylline-naive Japanese patients with PD. Methods Patients with PD and ≥1 NMS and ‘wearing-off’ with their current antiparkinsonian treatment were observed for up to 52 weeks. The effect of istradefylline on NMSs was measured in terms of changes in the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part 1 total, individual sub-items scores and the 8 item PD questionnaire (PDQ-8) estimated by the marginal structural model. Results Overall, 732 patients were istradefylline-naive prior to the study, of whom 171 were treated with istradefylline for ≥8 weeks during the observation period (istradefylline-treated patients). At baseline, istradefylline-treated patients were more likely to have a dyskinesia (49.7% vs 40.8%) and received a significantly higher daily dose of levodopa (462.8 mg vs 413.0 mg) than those who did not receive istradefylline (n = 561). MDS-UPDRS Part 1 total score at the end of the 52-week observational period slightly increased in patients who received istradefylline and those who did not (0.49 ± 0.41 vs 0.07 ± 0.20; P = 0.36). There were no statistically significant differences between the two groups of patients in terms of changes in the MDS-UPDRS Part 1 total score or any sub-items, or in the PDQ-8 total score. Conclusion NMSs remained generally controlled in istradefylline-treated Japanese patients with PD who exhibited wearing-off with their current antiparkinsonian treatment. Istradefylline could be a feasible treatment option for patients with advanced PD, without worsening existing NMSs.

1. Kristi S. Wood, MD, MSc* 2. Laura J. Perretta, MD† 3. John S. Blanco, MD‡ 4. Ericalyn Kasdorf, MD§ 1. *Division of Orthopaedic Surgery, Queen’s University, Kingston Health Sciences Centre, Kingston, ON, Canada 2. †Division of Neonatology, Maria Fareri Children’s Hospital at Westchester Medical Center, Valhalla, NY 3. ‡Department of Orthopedic Surgery, Hospital for Special Surgery, New York, NY 4. §Division of Newborn Medicine, New York Presbyterian-Weill Cornell Medical Center, New York, NY A term girl presents with concern of focal seizure activity on postnatal day 1. Her parents observed rhythmic twitching of the left lower extremity that did not cease when the extremity was held and was not suppressible. A video recording obtained at approximately 12 hours of life demonstrated more than 30 seconds of sustained myoclonic jerks and fasciculation of the quadriceps area (Video). It was reported that similar movements of the left lower extremity were previously noted a few times, starting at approximately 2 hours of age during a diaper change, but these self-resolved episodes lasted only a few seconds. After the longer documented episode, the patient was transferred to our institution for evaluation in the NICU. Video 1. Click here to view the video. Lower extremity movements as recorded by the parents on the day of birth. This patient was born via scheduled cesarean delivery for breech presentation, with Apgar scores of 8 and 9 at 1 and 5 minutes after birth, respectively. Obstetric history is notable only for frank breech positioning on all ultrasonographic images. Her physical examination findings are normal aside from external rotation of the bilateral hips with positive bilateral Barlow maneuvers. Laboratory assessment for potential infection shows a white blood cell count of 14,100/µL (14.1 × 109/L) with 8% bands, an immature to total neutrophil ratio of 0.1 (reference range

Polymorphisms of the catechol-O-methyl transferase (COMT) or monoamine oxidase B (MAO-B) genes may affect the occurrence of dyskinesia in Parkinson’s disease (PD) patients. However, the findings are inconsistent. Thus, we performed a meta-analysis to assess whether COMT and MAO-B genetic variants are associated with an increased incidence of levodopa-induced dyskinesia (LID) in PD patients. A literature search of PubMed, Embase, and Cochrane Library was conducted to identify relevant studies published up to January 2021. The strength of the association between the polymorphisms and LID susceptibility was estimated by odds ratio (OR) and associated 95% confidence interval (CI). The pooled ORs were assessed in different genetic models. Ten studies involving 2385 PD patients were included in the meta-analysis. Analysis of pooled ORs and 95% CIs suggested that the AA genotype of COMT(rs4680) was associated with LID (OR = 1.39, 95%CI: 1.02–1.89, P = 0.039) in the recessive model, and this correlation was more obvious in Brazilian samples in the analysis stratified by ethnicity. For the AG genotype of MAO-B(rs1799836), the pooled OR was 1.66 (95% CI: 1.04–2.65, P = 0.03) in patients with LID versus those without LID in the heterozygote model. Our meta-analysis implicates the AA genotype of the COMT rs4680 polymorphism as potentially increasing the risk of LID in a recessive genetic model for PD patients. Furthermore, the AG genotype of the MAO-B rs1799836 polymorphism may influence the prevalence of LID in PD patients in the heterozygote model. However, further well-designed studies with larger PD patient cohorts are required to validate these results after adjusting for confounding factors.

Objective To examine specific symptom progression patterns and possible disease staging in Parkinson disease clinical subtypes. Methods We recently identified Parkinson disease clinical subtypes based on comprehensive behavioral evaluations, “Motor Only,” “Psychiatric & Motor,” and “Cognitive & Motor,” which differed in dementia and mortality rates. Parkinson disease participants (“Motor Only”: n = 61, “Psychiatric & Motor”: n = 17, “Cognitive & Motor”: n = 70) and controls (n = 55) completed longitudinal, comprehensive motor, cognitive, and psychiatric evaluations (average follow‐up = 4.6 years). Hierarchical linear modeling examined group differences in symptom progression. A three‐way interaction among time, group, and symptom duration (or baseline age, separately) was incorporated to examine disease stages. Results All three subtypes increased in motor dysfunction compared to controls. The “Motor Only” subtype did not show significant cognitive or psychiatric changes compared to the other two subtypes. The “Cognitive & Motor” subtype’s cognitive dysfunction at baseline further declined compared to the other two subtypes, while also increasing in psychiatric symptoms. The “Psychiatric & Motor” subtype’s elevated psychiatric symptoms at baseline remained steady or improved over time, with mild, steady decline in cognition. The pattern of behavioral changes and analyses for disease staging yielded no evidence for sequential disease stages. Interpretation Parkinson disease clinical subtypes progress in clear, temporally distinct patterns from one another, particularly in cognitive and psychiatric features. This highlights the importance of comprehensive clinical examinations as the order of symptom presentation impacts clinical prognosis.

BACKGROUND There are limited data regarding the effectiveness of levodopa-carbidopa intestinal gel (LCIG) for dyskinesia. OBJECTIVE Compare the effectiveness of LCIG versus oral optimized medical treatment (OMT) for dyskinesia in patients with advanced Parkinson's disease (PD) using the Unified Dyskinesia Rating Scale (UDysRS). METHODS This phase 3b, open-label, multicenter, 12-week, interventional study (NCT02799381) randomized 63 LCIG naive patients with advanced PD (UDysRS ≥30) to LCIG (N = 30) or OMT (N = 33) treatment. Dyskinesia impact was assessed at baseline through week 12 using the UDysRS. PD-related motor and non-motor symptoms, and quality of life (QoL) were also assessed. RESULTS Dyskinesias measured by UDysRS were significantly reduced in the LCIG group (n = 24; -17.37 ± 2.79) compared with the OMT group (n = 26; -2.33 ± 2.56) after 12 weeks (-15.05 ± 3.20; 95% CI, -21.47 to -8.63; P

The aim of this study was to describe atypical dyskinesias (AtypDs) occurring during treatment with antipsychotic drugs (APDs). AtypDs are dyskinesias showing either an unusual temporal relationship between onset of treatment and start of the adverse drug reaction (ADR) or an unusual presentation of clinical symptoms.Data on the utilisation of APDs and reports of severe APD-induced AtypDs were collected using data from the observational pharmacovigilance programme - 'Arzneimittelsicherheit in der Psychiatrie (English: drug safety in psychiatry)' (AMSP) - from 1993 to 2016.A total of 495,615 patients were monitored, of which 333,175 were treated with APDs. Sixty-seven cases (0.020%) of severe AtypDs under treatment with APDs were registered. The diagnoses of schizophrenic disorders as well as organic mental disorders were related to significantly higher rates of AtypDs. Second-generation antipsychotic drugs (SGAs) showed slightly higher rates of AtypDs (0.024%) than high-potency (0.011%) or low-potency first-generation antipsychotic drugs (FGAs; 0.006%). In 41 cases (61.2%), two or more drugs were found to cause AtypDs.Our study indicates that AtypDs are rare ADRs. SGAs may have a higher risk for the occurrence of AtypDs than FGAs. Clinicians should be aware of this ADR and patients should be monitored and examined carefully.

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare genetic disorder characterized by deficient synthesis of dopamine and serotonin. It presents in early infancy, and causes severe developmental disability and lifelong motor, behavioral, and autonomic symptoms including oculogyric crises (OGC), sleep disorder, and mood disturbance. We investigated the safety and efficacy of delivery of a viral vector expressing AADC (AAV2-hAADC) to the midbrain in children with AADC deficiency (ClinicalTrials.gov Identifier NCT02852213). Seven (7) children, aged 4–9 years underwent convection-enhanced delivery (CED) of AAV2-hAADC to the bilateral substantia nigra (SN) and ventral tegmental area (VTA) (total infusion volume: 80 µL per hemisphere) in 2 dose cohorts: 1.3 × 1011 vg (n = 3), and 4.2 × 1011 vg (n = 4). Primary aims were to demonstrate the safety of the procedure and document biomarker evidence of restoration of brain AADC activity. Secondary aims were to assess clinical improvement in symptoms and motor function. Direct bilateral infusion of AAV2-hAADC was safe, well-tolerated and achieved target coverage of 98% and 70% of the SN and VTA, respectively. Dopamine metabolism was increased in all subjects and FDOPA uptake was enhanced within the midbrain and the striatum. OGC resolved completely in 6 of 7 subjects by Month 3 post-surgery. Twelve (12) months after surgery, 6/7 subjects gained normal head control and 4/7 could sit independently. At 18 months, 2 subjects could walk with 2-hand support. Both the primary and secondary endpoints of the study were met. Midbrain gene delivery in children with AADC deficiency is feasible and safe, and leads to clinical improvements in symptoms and motor function., Aromatic L-amino acid decarboxylase deficiency (AADC) is a rare neurodevelopmental disorder. Here the authors describe a clinical trial of MR-guided delivery of AAV2-AADC for the treatment of AADC.

Management of motor symptoms in Parkinson's Disease(PD) relies on subjective information provided by patients, the quality of which can be affected by many factors.Objective data collected during daily life could complement this information and improve management of motor symptoms.To assess the usefulness of the Personal KinetiGraph (PKG) in characterizing the intensity and timing of motor symptoms in PD patients.Retrospective study of all PD patients followed at a tertiary academic movement disorders center assessed by PKG between December 1, 2016 and October 30, 2018. PKG was worn for 7 days prior to the clinical visit. We compared the information obtained from the interview and the clinical visit, and assessed the impact of the PKG on treatment decision making.170 PKG results were reviewed. PKG complemented patient input in 82.9%(141/170) and led to medication changes in 71%(100/141) of the complemented inputs. PKG contributed the least to correcting or complementing patients' input when patients self-reported as undertreated (22%) and the most when patient were unable to answer all questions regarding motor response to individual doses (100%) (Fisher, p 0.0001). The majority of patient undergoing 3 or 4 PKG encounters did not reach a controlled state as defined by PKG until the 3rd or 4th encounter, suggesting that repeated use of the PKG might be needed to help optimize motor control as therapy changes done after one encounter might not be enough.PKG might be useful in supplementing patient-provided information for accurate assessment and treatment plan.

Introduction Functional brain imaging has shown alterations in the basal ganglia, cortex and cerebellum in Parkinson's disease patients. However, few functional imaging studies have tested how these changes evolve over time. Our study aimed to test the longitudinal progression of movement-related functional activity in Parkinson's disease patients. Methods At baseline, 48 Parkinson's disease patients and 16 healthy controls underwent structural and functional magnetic resonance imaging during a joystick motor task. Patients had repeated imaging after 18-months (n = 42) and 36-months (n = 32). T-tests compared functional responses between Parkinson's disease patients and controls, and linear mixed effects models examined longitudinal differences within Parkinson's disease. Correlations of motor-activity with bradykinesia, rigidity and tremor were undertaken. All contrasts used whole-brain analyses, thresholded at Z > 3.1 with a cluster-wise P Results Baseline activation was significantly greater in patients than controls across contralateral parietal and occipital regions, ipsilateral precentral gyrus and thalamus. Longitudinally, patients showed significant increases in cerebellar activity at successive visits following baseline. Task-related activity also increased in the contralateral motor, parietal and temporal areas at 36 months compared to baseline, however this was reduced when controlling for motor task performance. Conclusion We have shown that there are changes over time in the blood-activation level dependent response of patients with Parkinson's disease undertaking a simple motor task. These changes are observed primarily in the ipsilateral cerebellum and may be compensatory in nature.

Background Mavoglurant (AFQ056), a selective metabotropic glutamate receptor 5 (mGluR5) inhibitor, was tested for t levodopa-induced dyskinesia (LID) in patients with Parkinson’s Disease (PD). However, clinical trials showed inconsistent results regarding the efficacy of mavoglurant in treating LID in patients with Parkinson's disease (PD). Methods A computer literature search of PubMed, Scopus, Web of science, and Cochrane CENTRAL was conducted until March 2021. We selected relevant randomized controlled trials comparing mavoglurant to placebo. Study data were extracted and pooled as mean difference (MD) in the meta-analysis model. Results Six RCTs were included in this meta-analysis with a total of 485 patients. Mavoglurant was not significantly superior to placebo in terms of the “off-time” (MD −0.27 h, 95% CI −0.65 to 0.11), “on time” (MD 0.29 h, 95% CI −0.09 to 0.66), Lang-Fahn activities of daily living dyskinesia scale (MD −0.95, 95% CI −1.98 to 0.07), UPDRS-III (MD −0.51, 95% CI −1.66 to 0.65), or UPDRS-IV (MD −0.41, 95% CI −0.85 to 0.03). However, the pooled modified abnormal involuntary movement scale favored the mavoglurant group than the placebo group (MD −2.53, 95% CI −4.23 to −0.82). Conclusions This meta-analysis provides level one evidence that mavoglurant is not effective in treating the LID in patients with PD.

Introduction: The subthalamic nucleus (STN) is known to be involved in the pathophysiology of Parkinson´s disease and by reducing its abnormal activity, normal output of basal ganglia can be restored along with improvement in PD cardinal motor features. Deep brain stimulation of the STN is currently the main surgical procedure for PD with motor complications, but lesioning can be an alternative.Areas covered: Here, the authors systematically review the current evidence regarding subthalamotomy both with radiofrequency and, more recently, with focused ultrasound (FUS) for the treatment of PD.Expert opinion: Unilateral subthalamotomy for the treatment of PD motor features can be considered a viable option in asymmetric patients, particularly with FUS which allows a minimally invasive safe and effective ablation of the STN. Risk of inducing dyskinesia (i.e., hemichorea/ballism) may be strikingly reduced when lesions enlarge dorsally to impinge on pallidothalamic fibers.

Adenylyl cyclase 5 (ADCY5)-related phenotypes comprise an expanding disease continuum, but much remains to be understood about the underlying pathogenic mechanisms of the disease. ADCY5-related disease comprises a spectrum of hyperkinetic disorders involving chorea, myoclonus, and/or dystonia, often with paroxysmal exacerbations. Hypotonia, developmental delay, and intellectual disability may be present. The causative gene encodes adenylyl cyclase, the enzyme responsible for the conversion of adenosine triphosphate (ATP) to cyclic adenosine-3',5'-monophosphate (cAMP). cAMP is a second messenger that exerts a wide variety of effects via several intracellular signaling pathways. ADCY5 is the most commonly expressed isoform of adenylyl cyclase in medium spiny neurons (MSNs) of the striatum, and it integrates and controls dopaminergic signaling. Through cAMP pathway, ADCY5 is a key regulator of the cortical and thalamic signaling that control initiation of voluntary movements and prevention of involuntary movements. Gain-of-function mutations in ADCY5 have been recently linked to a rare genetic disorder called ADCY5-related dyskinesia, where dysregulation of the cAMP pathway leads to reduced inhibitory activity and involuntary hyperkinetic movements. Here, we present an update on the neurobiology of ADCY5, together with a detailed overview of the reported clinical phenotypes and genotypes. Although a range of therapeutic approaches has been trialed, there are currently no disease-modifying treatments. Improved in vitro and in vivo laboratory models will no doubt increase our understanding of the pathogenesis of this rare genetic movement disorder, which will improve diagnosis, and also facilitate the development of precision medicine approaches for this, and other forms of hyperkinesia. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background. In 2008, the Movement Disorders Society published the Unified Dyskinesia Rating Scale (UDysRS). This has become the established tool for assessing the severity and disability associated with dyskinesia in patients with Parkinson’s Disease (PD). We translated and validated the Polish version of the UDysRS, explored its dimensionality, and compared it to the Spanish version, which is the Reference Standard for UDysRS translations. Material and methods. The UDysRS was translated into Polish by a team led by JS and GO. The back-translation, completed by colleagues fluent in both Polish and English who were not involved in the original translation, was reviewed and approved by the Executive Committee of the MDS Rating Scales Programme. Then the translated version of the UDysRS underwent cognitive pretesting, and the translation was modified based on the results. The approved version was considered to be the Official Working Document of the Polish UDysRS and was tested on 250 Polish PD patients recruited at movement disorder centres. Data was compared to the Reference Standard used for validating UDysRS translations. Results. The overall factor structure of the Polish version was consistent with that of the Reference Standard version, as evidenced by the high Confirmatory Fit Index score (CFI = 0.98). The Polish UDysRS was thus confirmed to share a common factor structure with the Reference Standard. Conclusions. The Official Polish UDysRS translation is recommended for use in clinical and research settings. Worldwide use of uniform rating measures offers a common ground to study similarities and differences in disease manifestations and progression across cultures.

Purpose Dyskinesia-hyperpyrexia syndrome (DHS) is a rare but life-threatening disease. The clinical manifestations of this syndrome overlap substantially with Parkinson hyperpyrexia syndrome and serotonin syndrome and are often confused by clinicians. The purpose of this review was to enable clinicians to recognize this syndrome and thereby reach a correct diagnosis and provide optimal treatments to improve prognosis in clinical practice. Methods Using the methodology described in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, we conducted a literature search of the PubMed, Embase, and MEDLINE databases using keywords in titles and abstracts of published literature. Quality assessment was performed using the modified Newcastle-Ottawa scale. Results A total of 11 patients obtained from nine publications were included in this systematic review. All of the cases occurred in patients with advanced Parkinson's disease (PD) of long disease duration. High ambient temperature was the most common trigger of this syndrome. Hyperpyrexia and dyskinesias were present in all cases. The consciousness disturbances of this syndrome included confusion, hallucination, and lethargy or stupor. Autonomic dysfunction (except for hyperpyrexia) is uncommon in DHS, and only two patients presented with tachycardia. The treatment of this syndrome included supportive interventions (including rehydration, anti-pyretic and anti-infection treatments, and maintaining electrolyte balance), dopaminergic drug reduction and sedation. Two patients died due to DHS. Conclusions We summarized the triggers, clinical features, and treatments of all reported dyskinesia-hyperpyrexia syndrome cases, proposed guiding diagnostic criteria, and established a flow chart to guide diagnoses to quickly identify these three syndromes in clinical practice.

Background: Parkinson’s disease (PD) is a neurodegenerative condition with a diverse and complex pattern of motor and non-motor symptoms which change over time with disease duration. Objective: The aims of the present study were to discover what symptoms matter most to people with the condition and to examine how these priorities change with disease duration. Methods: A simple free-text online survey (using SmartSurvey) was developed by Parkinson’s UK, which asked participants to identify up to three aspects of the condition they would most like to see improvement in. Results: 790 people participated reporting 2,295 issues related to PD which were grouped into 24 broad symptom domains. Of these, 1,358 (59.1%) were categorised as motor symptoms, 859 (37.4%) as non-motor issues and 78 (3.4%) as medication problems. This study reveals how certain features of PD become more or less important to patients as the condition progresses. Non-motor symptoms were highly cited from the very earliest stages of PD. Problems with walking, balance and falls, speech problems, freezing and dyskinesia become increasingly important as the condition progresses whereas tremor, stiffness and psychological health become decreasingly important as the condition progresses. Conclusions: The data suggest that the priorities of people affected by PD for improving life are personal and change with duration of the condition. These findings have implications for developing person-centred management and care, as well as for directing future research to improve quality of life.

Muscles' trigger points can induce scapular dyskinesia (SD) which interferes with overhead athletes' professional training. We aimed to evaluate effects of dry needling (DN) alone and plus manual therapy (MT) on pain and function of overhead athletes with SD. 40 overhead athletes (15 male, 25 female) aged 18-45 with at least 3 points Numeric Rating Scale (NRS) pain intensity during training were recruited and randomly allocated to the treatment group: MT followed by DN on trigger points of Subscapularis, Pectoralis minor, Serratus anterior, upper and lower Trapezius muscles; or the control group: MT alone. The effect of shoulder trigger points DN plus MT with MT alone on pain, function, Pain Pressure Threshold (PPT) and SD in athletes with SD were compared. Both the examiner and the therapist were blinded to group assignment. Both groups were analyzed. Pain, disability and SD were improved in treatment group (P < .05). On the other hand, when only MT was applied, despite reduction in pain and disability (P < .001), scapular slide only improved in hands on waist position. Comparing the differences between groups showed a substantial reduction in pain (P < .001) and disability (P = .02) with significant improvement in scapular dyskinesia in treatment group (P = .02). Moreover, PPT significantly increased in the control group (P = .004). No adverse effects reported by the participants during this study. DN is an easy and applicable method that can synergistically reduce pain, disability and dyskinesia when it is combined with manual techniques to treat shoulder dysfunctions.

[Purpose] To determine whether the development of levodopa-induced dyskinesia (LID) in Parkinson disease (PD) specifically relates to dopaminergic depletion in sensorimotor-related subregions of the striatum., [Methods] Our primary study sample consisted of 185 locally recruited PD patients, of which 73 (40%) developed LID. Retrospective 123I-FP-CIT SPECT data were used to quantify the specific dopamine transporter (DAT) binding ratio within distinct functionally defined striatal subregions related to limbic, executive, and sensorimotor systems. Regional DAT levels were contrasted between patients who developed LID (PD + LID) and those who did not (PD-LID) using analysis of covariance models controlled for demographic and clinical features. For validation of the findings and assessment of the evolution of LID-associated DAT changes from an early disease stage, we also studied serial 123I-FP-CIT SPECT data from 343 de novo PD patients enrolled in the Parkinson Progression Marker’s Initiative using mixed linear model analysis., [Results] Compared with PD-LID, DAT level reductions in PD + LID patients were most pronounced in the sensorimotor striatal subregion (F = 5.99, P = 0.016) and also significant in the executive-related subregion (F = 5.30, P = 0.023). In the Parkinson Progression Marker’s Initiative cohort, DAT levels in PD + LID (n = 161, 47%) were only significantly reduced compared with PD-LID in the sensorimotor striatal subregion (t = −2.05, P = 0.041), and this difference was already present at baseline and remained largely constant over time., [Conclusion] Measuring DAT depletion in functionally defined sensorimotor-related striatal regions of interest may provide a more sensitive tool to detect LID-associated dopaminergic changes at an early disease stage and could improve individual prognosis of this common clinical complication in PD.

CONTEXT: Spinal-generated movement disorders are a complex group of medical conditions, frequently misdiagnosed, originating in the spinal cord or from combined peripheral and central nervous system involvement. In this case report, we describe a novel form of position-dependent dyskinesia due to severe craniocervical malformation. FINDINGS: An 83-year-old woman with basilar invagination at the C2 vertebra above the line of Chamberlain, occipitocervical lordosis, platybasia with a short clivus, ankylosis of the C1–C2 complex and fusion of the C1 arch developed an unusual pattern of position-dependent left arm dyskinesia triggered by bending her neck forward with simultaneous contact of the flexed elbow with a flat surface. Symptoms did not improve with anticonvulsants and she progressed and died suddenly. CONCLUSION/CLINICAL RELEVANCE: A newly described form of position-dependent arm dyskinesia can be associated with severe craniocervical malformation.

Objective:To determine the demographic pattern of juvenile-onset parkinsonism (JP, Materials and Methods:We conducted a 2-year, pan-India, multicenter collaborative study to analyze clinical patterns of JP, YOPD, and EOPD. All patients under follow-up of movement disorders specialists and meeting United Kingdom (UK) Brain Bank criteria for PD were included.Results:A total of 668 subjects (M:F 455:213) were recruited with a mean age at onset of 38.7 ± 8.1 years. The mean duration of symptoms at the time of study was 8 ± 6 years. Fifteen percent had a family history of PD and 13% had consanguinity. JP had the highest consanguinity rate (53%). YOPD and JP cases had a higher prevalence of consanguinity, dystonia, and gait and balance issues compared to those with EOPD. In relation to nonmotor symptoms, panic attacks and depression were more common in YOPD and sleep-related issues more common in EOPD subjects. Overall, dyskinesias were documented in 32.8%. YOPD subjects had a higher frequency of dyskinesia than EOPD subjects (39.9% vs. 25.5%), but they were first noted later in the disease course (5.7 vs. 4.4 years).Conclusion:This large cohort shows differing clinical patterns in JP, YOPD, and EOPD cases. We propose that cutoffs of

Background Scapular focused exercise interventions are frequently used to treat individuals with shoulder pain. However, evidence for changes in scapular motion after intervention is limited. Objective To compare the effects of scapular movement training versus standardized exercises for individuals with shoulder pain. Methods This will be a single-blinded randomized controlled trial. Sixty-four individuals with shoulder pain for at least 3 months, scapular dyskinesis, and a positive scapular assistance test will be randomly allocated to one of two groups: Scapular Movement Training (group 1) and Standardized Exercises (group 2). Group 1 will receive education about scapular position and movement, and be trained to modify the scapular movement pattern. Group 2 will perform stretching and strengthening exercises. Both groups will be treated twice a week for eight weeks. Three-dimensional scapular kinematics and muscle activity of the serratus anterior and upper, middle, and lower trapezius during elevation and lowering of the arm will be assessed at baseline and after 8 weeks of treatment. Pain intensity, function, fear avoidance beliefs, and kinesiophobia will be assessed at baseline and after 4 and 8 weeks of treatment, and 4 weeks after the end of treatment. Conclusions The results of this study may contribute to a better understanding of the efficacy of scapular focused treatments for individuals with shoulder pain. Clinical trial registration: NCT03528499

Autoimmune encephalitis (AIE) constitutes an important treatable cause of movement disorders. We aimed to highlight the spectrum of movement disorder and other salient features of AIE patients diagnosed at our tertiary care centre and describe their clinical symptoms, diagnostic approach, treatment, and outcome. We evaluated 11 patients who presented with movement disorder in association with AIE at our centre. Various abnormal movements observed were tremor, dyskinesias, stereotypy, dystonia, ataxia, asterixis, myoclonus, and parkinsonism. Antibodies were detected against NMDAR (n = 3), LGI-1 (n = 2), GAD-65 (n = 1), CASPR-2 (n = 1), Sox-1 (n = 1), Yo (n = 1), and thyroid peroxidase (n = 1). One patient was diagnosed with opsoclonus myoclonus syndrome associated with the suspected neuroblastic tumour. Six patients responded well to first-line immunotherapy (intravenous immunoglobulins or steroid or both). Three patients with anti-NMDAR antibodies received second-line therapy consisting of rituximab. Movement disorder is one of the most consistent features of AIE. Understanding of the ever-expanding spectrum of antibodies associated with movement disorders helps in the early diagnosis and better management of patients of autoimmune movement disorder.

Functional movement disorders are commonly seen in neurology services and may coexist with other neurological diseases. This combination is known as "functional overlay" and an increasing interest on this topic has emerged in the past decade as the field of functional neurological disorders has moved forward. Some neurological diseases may be more prone to develop "functional overlay" than others, and within the field of movement disorders, most studies have focused on patients with Parkinson's disease. This review comprehensively summarizes the current body of knowledge on this topic and provides an expert opinion to equip clinicians with a pragmatic approach to recognize functional movement disorders in patients with Parkinson's disease, to communicate the diagnosis and to become familiar with potential therapies in this complex clinical scenario. Potential underlying mechanisms and risk factors that may play a role in increasing the vulnerability of Parkinson's disease patients to develop functional movement disorder comorbidity are also discussed within the framework of modern neurobiological theories of brain functioning.

Introduction: Tardive dyskinesia (TD) is a hyperkinetic movement disorder that arises as a complication of exposure to dopamine receptor blocking agents. Vesicular monoamine transporter type 2 (VMAT2) inhibitors reduce dyskinesia by decreasing transport of monoamines, including dopamine, into presynaptic vesicles, leaving unpackaged dopamine to be metabolized by monoamine oxidase. Deutetrabenazine was adapted from an earlier VMAT2 inhibitor, tetrabenazine, by substituting three deuterium isotopes in place of three hydrogen isotopes at the site of metabolic degradation to improve upon the pharmacokinetics of the parent compound. Areas covered: The authors reviewed the pivotal trials examining the safety and efficacy of deutetrabenazine, as well as long-term data from an open-label extension. Also reviewed were posters and oral presentations, as well as information from the product label and the United States Food and Drug Administration. Expert opinion: Deutetrabenazine is effective at decreasing dyskinesia in TD, but drug selection and cost-effectiveness between existing VMAT2 inhibitors are evolving areas of study. Other areas of investigation include novel anti-dyskinetic agents and use of deep brain stimulation.

Background: Scapular dyskinesis has been considered a risk factor for athletic shoulder injury; however, findings in the prospective literature have demonstrated mixed results. Purpose: To determine if scapular dyskinesis increases the risk of shoulder injury in athletes. Study Design: Meta-analysis. Methods: A systematic search was conducted on the MEDLINE, CINAHL Plus, SPORTDiscus, and Embase databases to identify prospective studies examining scapular dyskinesis and shoulder injury risk in athletes. Studies were included if they assessed participants using a dynamic scapular assessment at baseline and monitored for the development of shoulder injury. Data from the studies were subject to meta-analysis using the Mantel-Haenszel method to produce a pooled risk ratio. Results: Seven studies were eligible for inclusion, resulting in 212 shoulder injuries observed across 923 athletes. Scapular dyskinesis was present in 46% of participants, and these athletes had an injury rate of 25%. The presence of scapular dyskinesis displayed a trend to increase the risk of shoulder injury, but this was not statistically significant (risk ratio, 1.07; 95% CI, 0.85-1.34; P = .59). Conclusion: Scapular dyskinesis was not significantly associated with the development of shoulder injury in athletes. Registration: CRD42019133089 (PROSPERO).

Excessive theta (θ) frequency oscillation and synchronization in the basal ganglia (BG) has been reported in elderly parkinsonian patients and animal models of levodopa (L-dopa)-induced dyskinesia (LID), particularly the θ oscillation recorded during periods when L-dopa is withdrawn (the off L-dopa state). To gain insight into processes underlying this activity, we explored the relationship between primary motor cortex (M1) oscillatory activity and BG output in LID. We recorded local field potentials in the substantia nigra pars reticulata (SNr) and M1 of awake, inattentive resting rats before and after L-dopa priming in Sham control, Parkinson disease model, and LID model groups. We found that chronic L-dopa increased θ synchronization and information flow between the SNr and M1 in off L-dopa state LID rats, with a SNr-to-M1 flow directionality. Compared with the on state, θ oscillational activity (θ synchronization and information flow) during the off state were more closely associated with abnormal involuntary movements. Our findings indicate that θ oscillation in M1 may be consequent to abnormal synchronous discharges in the BG and support the notion that M1 θ oscillation may participate in the induction of dyskinesia.

Background Scapular dyskinesis (SD) has been associated with shoulder soft-tissue tightness as well scapular muscle strength and/or activation deficits. Inadequate development of the trapezius muscle (trapezius dysplasia) is a relatively rare condition inconsistently associated with shoulder dysfunction. Case description a 24-year old male complaining of left scapular area pain associated with SD and scapular muscle weakness was noted to present with a smaller ipsilateral lower trapezius (LT). Further inquiry including electromyography, rehabilitative ultrasound imaging (RUSI) and magnetic resonance imaging ruled out nerve palsy and demonstrated a hypoplastic left LT. This led to a greater emphasis on serratus anterior (SA) training along with the addition of neuromuscular electrical stimulation of the LT. Outcomes Following 12 sessions over a 5-month period the patient reported no pain or functional deficits, and was able to resume all recreational activities. The patient’s subjective shoulder value increased from 55% to 80%, and LT strength was markedly improved. Discussion Scapular muscle dysplasia may represent a less recognized cause of SD. A more thorough inspection of scapular muscle shape and orientation, possibly augmented by RUSI may be indicated in patients presenting with SD. Neuromuscular electrical stimulation is a potentially useful modality for addressing scapular muscle activation and strength deficits and future research into its efficacy under these circumstances may be warranted.

Idiopathic rapid eye movement sleep behaviour disorder (RBD) is now recognized as an early manifestation of α-synucleinopathies. Increasing experimental studies demonstrate that manipulative lesion or inactivation of the neurons within the sublaterodorsal tegmental nucleus (also known as the subcoeruleus nucleus in humans) can induce RBD-like behaviours in animals. As current RBD animal models are not established on the basis of α-synucleinopathy, they do not represent the pathological substrate of idiopathic RBD and thus cannot model the phenoconversion to Parkinson’s disease. The purpose of this study was therefore to establish an α-synucleinopathy-based RBD animal model with the potential to convert to parkinsonian disorder. To this end, we first determined the functional neuroanatomical location of the sublaterodorsal tegmental nucleus in wild-type C57BL/6J mice and then validated its function by recapitulating RBD-like behaviours based on this determined nucleus. Next, we injected preformed α-synuclein fibrils into the sublaterodorsal tegmental nucleus and performed regular polysomnographic recordings and parkinsonian behavioural and histopathological studies in these mice. As a result, we recapitulated RBD-like behaviours in the mice and further showed that the α-synucleinopathy and neuron degeneration identified within the sublaterodorsal tegmental nucleus acted as the neuropathological substrates. Subsequent parkinsonian behavioural studies indicated that the α-synucleinopathy-based RBD mouse model were not stationary, but could further progress to display parkinsonian locomotor dysfunction, depression-like disorder, olfactory dysfunction and gastrointestinal dysmotility. Corresponding to that, we determined α-synuclein pathology in the substantia nigra pars compacta, olfactory bulb, enteral neuroplexus and dorsal motor nucleus of vagus nerve, which could underlie the parkinsonian manifestations in mice. In conclusion, we established a novel α-synucleinopathy-based RBD mouse model and further demonstrated the phenoconversion of RBD to Parkinson’s disease in this animal model.