Paroxysmal movement disorders.

Paroxysmal movement disorders include two groups of intermittent neurologic disorders: paroxysmal dyskinesia, in which episodes of involuntary hyperkinetic movements (mainly chorea and/or dystonia) occur with preserved consciousness, and episodic ataxias, which are characterized by discrete attacks of cerebellar dysfunction, sometimes associated with progressive ataxia. Since episodic ataxias are individually discussed in Chapter 8 of this volume, we herein provide a deep overview of phenotypic, genetic, pathophysiologic, diagnostic, and treatment aspects of paroxysmal dyskinesia, following the trigger-based nomenclature which distinguishes paroxysmal kinesigenic dyskinesia, paroxysmal nonkinesigenic dyskinesia, and paroxysmal exercise-induced dyskinesia. Emerging paroxysmal dyskinesia not fulfilling the criteria for the above-mentioned subtypes will also be discussed. Phenotypic and genotypic overlap among paroxysmal movement disorders, epilepsy, and migraine have progressively emerged, thus shedding light on a shared pathophysiologic framework. Advances in our understanding of the pathomechanisms underlying paroxysmal movement disorders, which involve dysfunctions of ion channels, proteins associated with the vesical synaptic cycle machinery, and proteins involved in neuronal energy metabolism, point toward a discrete number of converging pathophysiologic pathways and may lay foundations for developing target-specific therapies.

Sydenham's Chorea in Children with Acute Rheumatic Fever: An Echocardiographic Survey of Pediatric Patients in Northwestern Iran.

Background: Although infrequent, Sydenham's chorea (SC) may occur as a result of injury to the basal ganglia in children with acute rheumatic fever (ARF) secondary to group A Streptococcal infection. Certain hallmarks of SC, such as movement disorders, could be utilized as a predictive marker for carditis. The present study aimed to investigate neurologic and cardiologic symptoms in children with suspected SC after ARF. Methods: All children aged 5-16 who were admitted at Shahid Madani Pediatric Hospital (Tabriz, Iran), with an initial diagnosis of ARF and SC between 2009 and 2022 were included for echocardiographic assessment and prospective follow-up within 6 and 12 months after the start point. The pattern and severity of valvulopathy, as well as the prevalence of Jones criteria for rheumatic fever, were used to assess the effect. The collected data were analyzed using SPSS Statistics software (version 22.0) using Chi square and Fisher's exact tests. P<0.05 was considered statistically significant. Results: The study enrolled 85 children, 36 girls and 49 boys, with a mean age of 9.7±2.7. On the first echocardiography, 42.4% of patients had mitral valve regurgitation (MR), with a predominance of female patients (P=0.04). Of those diagnosed with SC (12 girls and 6 boys), 66.7% showed cardiac involvement, with a higher prevalence of MR in both sexes (P=0.04). The pattern of cardiac involvement after 6 months was significantly different between the groups (P=0.04). However, no such difference was observed during the one-year follow-up (P=0.07). Female sex was found to have a significant relationship with SC localization (P=0.01). Conclusion: In addition to its neurological manifestations, SC can be associated with clinical or subclinical cardiac valve dysfunction that might last for more than a year. In addition to attempting early detection and appropriate management, a precise cardiac and neurologic assessment during admission and follow-up is recommended.A preprint version of this manuscript is available at DOI: 10.21203/rs.3.rs-772662/v1 (https://www.researchsquare.com/article/rs-772662/v1).

[Analysis of clinical characteristics and variant of NKX2-1 gene in a Chinese boy with Brain-Lung-Thyroid syndrome].

OBJECTIVE: To carry out clinical and genetic analysis for a child featuring Brain-Lung-Thyroid syndrome (BLTS). METHODS: A child who had presented at the Children's Hospital Affiliated to Shandong University on May 27, 2022 was selected as the study subject. Clinical data was collected. Trio-whole exome sequencing (Trio-WES) was carried out for the child and his parents, and candidate variant was verified by Sanger sequencing and bioinformatic analysis. The child was given individualized treatment following the diagnosis. RESULTS: The child, a two-year-and-seven-month-old boy, had presented with global developmental delay, ataxia and hypothyroidism. WES revealed that he has harbored a heterozygous c.674C>T variant of the NKX2-1 gene, based on which he was diagnosed with BLTS. CT scan revealed interstitial and parenchymal inflammation in his lungs, which was reduced by budesonide aerosol inhalation. CONCLUSION: Discovery of the novel c.674C>T variant has enriched the mutational spectrum of the NKX2-1 gene. Budesonide aerosol may be used to treat lung inflammation associated with BLTS.

Profiling deutetrabenazine extended-release tablets for tardive dyskinesia and chorea associated with Huntington's disease.

INTRODUCTION: Tardive dyskinesia (TD) and Huntington's disease (HD)-associated chorea are persistent and disabling hyperkinetic disorders that can be treated with vesicular monoamine transporter type 2 (VMAT2) inhibitors, including the recently approved once-daily (QD) formulation of deutetrabenazine (DTBZ ER). While its efficacy and safety profile have not been directly investigated, currently available data confirms bioequivalence and similar bioavailability to the twice-daily formulation (DTBZ BID). AREAS COVERED: The authors briefly review the pivotal trials establishing efficacy of DTBZ for TD and HD-associated chorea, the pharmacokinetic data for bioequivalence between QD and BID dosing of DTBZ, as well as dose proportionality evidence, titration recommendations, and safety profile for DTBZ ER. EXPERT OPINION: Long-term data show that DTBZ is efficacious and well tolerated for the treatment of TD and HD-associated chorea. DTBZ ER likely demonstrates therapeutic equivalence with no new safety signals. Due to the lack of comparative clinical trial data, no evidence-based recommendation about choice of VMAT2 inhibitor or switching between VMAT2 inhibitors can be made about best practice. Ultimately, QD dosing may offer the chance of improved medication adherence, an important consideration in patients with complex treatment regimens and/or patients with cognitive decline.

Insights from European Reference Network for rare neurological disorders study surveys on diagnosis, treatment, and management of NKX2-1-related disorders.

BACKGROUND: NKX2-1-related disorder (NKX2-1-RD) is a rare disease characterized by a triad of primary hypothyroidism, neonatal respiratory distress, and neurological features, including chorea. OBJECTIVE: This study aimed to identify discrepancies in the management of NKX2-1-RD among European Union (EU) specialists. METHODS: The ERN-RND Chorea & Huntington disease group designed a survey to conduct a cross-sectional multicenter study on the management of NKX2-1-RD. Descriptive analysis was performed, and total responses are presented for each item. RESULTS: The study involved 23 experts from 13 EU countries with experience in evaluating hyperkinetic patients with NKX2-1-RD: 11 were adult specialists, and 12 were pediatric specialists. NKX2-1-RD diagnosis was made at different ages, with the most common initial symptoms being hypotonia and/or motor developmental delay (reported by 11 experts) and chorea (reported by 8 experts). Chorea involved various body parts and showed improvement as reported by 9 experts, stabilization by 12 experts, and worsening by 2 experts with age. The pharmacological treatment of chorea varied widely among the experts. Misdiagnosis was reported by 14 experts. NKX2-1 pathogenic variants or deletions were confirmed in >75 % of patients (reported by 12 experts). Pulmonary and endocrinology evaluations were requested by 7 and 12 experts, respectively. The management of psychiatric comorbidities also varied among the different experts. CONCLUSIONS: This study highlights the need for a clinical practice guideline for the management of NKX2-1-RD to ensure that patients across the EU receive consistent and appropriate care. Such a guideline would benefit both doctors and healthcare practitioners.

Late-onset Chorea with a Rare but Identifiable Cause.

Chorea is a very commonly encountered movement disorder; it has various etiologies, and it can have autoimmune, vascular, degenerative, or paraneoplastic etiology. Our patient had acute onset chorea and a strong history of smoking, which made us suspect first vascular followed by paraneoplastic cause. After ruling out common vascular and metabolic causes, his whole body positron emission tomography (PET) scan revealed a mass in the right upper lobe, a biopsy revealed a small cell carcinoma lung and a paraneoplastic panel showed antibodies positive for collapsin response mediator protein 5 antigen (CRMP-5/CV2); the patient was started on immunomodulation, chemotherapy with the variable response, he succumbed to a cardiac event after treatment.

Crossed-reflex in antiphospholipid chorea.

Chorea is a hyperkinetic movement disorder associated with various underlyingconditions, including autoimmune diseases such as antiphospholipid syndrome (APS). APS can manifest with a wide range of neurological symptoms, including chorea. We present a case of a 77-year-old man with subacute generalized chorea secondary to primary APS. Notably, the patient exhibited a left patellar crossed-reflex, a phenomenon rarely documented in chorea cases, the pathophysiology of which has not yet been elucidated. In summary, this case challenges the traditional demographics of antiphospholipid syndrome (APS) by suggesting a potential link between APS and late-age patients. It emphasizes the importance of considering APS in late-onset chorea cases.

Hyperkinetic and Hypokinetic Movement Disorders in SSPE: A Systematic Review of Case Reports and Case Series.

Background: Subacute Sclerosing Panencephalitis (SSPE) typically presents with periodic myoclonus; however, a spectrum of movement disorders including dystonia, chorea, tremor, and parkinsonism have also been described. This review aims to evaluate the array of movement disorders in SSPE, correlating them with neuroimaging findings, disease stages, and patient outcomes. Methods: A comprehensive review of published case reports and case series was conducted on patients with SSPE exhibiting movement disorders other than periodic myoclonus. PRISMA guidelines were followed, and the protocol was registered with PROSPERO (2023 CRD42023434650). A comprehensive search of multiple databases yielded 37 reports detailing 39 patients. Dyken's criteria were used for SSPE diagnosis, and the International Movement Disorders Society definitions were applied to categorize movement disorders. Results: The majority of patients were male, with an average age of 13.8 years. Approximately, 80% lacked a reliable vaccination history, and 39% had prior measles infections. Dystonia was the most common movement disorder (49%), followed by parkinsonism and choreoathetosis. Rapid disease progression was noted in 64% of cases, with a disease duration of ≤6 months in 72%. Neuroimaging showed T2/FLAIR MR hyperintensities, primarily periventricular, with 26% affecting the basal ganglia/thalamus. Brain biopsies revealed inflammatory and neurodegenerative changes. Over half of the patients (56%) reached an akinetic mute state or died. Conclusion: SSPE is associated with diverse movement disorders, predominantly hyperkinetic. The prevalence of dystonia suggests basal ganglia dysfunction.

Atypical Presentations of Huntington Disease-like 2 in South African Individuals.

BACKGROUND: Huntington disease-like 2 (HDL2) is a neurodegenerative disorder, affecting only individuals of African ancestry. Full penetrance occurs in individuals with 40 repeats or more. OBJECTIVE: To describe the phenotypic variability of HDL2 in a group of mixed ancestry individuals from South Africa. METHODS: Eight patients were assessed with analysis of repeat size and magnetic resonance brain imaging. We applied the Unified Huntington's Disease Rating Scale (UHDRS), but in deceased patients (4), this was estimated from video material. RESULTS: Cognitive domains were more severely affected than motor; UHDRS motor scores were notable for bradykinesia, and to a slightly lesser extent, for rigidity and dystonia; a single patient had marked chorea. Repeat lengths ranged from 45 to 63 (median, 52). CONCLUSION: This South African group of mixed ancestry HDL2 individuals presented with severe cognitive and behavioral impairments, with lesser degrees or absence of chorea. This presentation is possibly related to large repeat sizes.

Movement Disorders in Patients with Subacute Sclerosing Panencephalitis: A Systematic Review.

BACKGROUND: Subacute sclerosing panencephalitis (SSPE) is a complication of measles, occurring after a latency of 4-10 years. It continues to occur in developing countries although resurgence is being reported from developed countries. Characteristic features include progressive neuropsychiatric issues, myoclonus, seizures, movement disorders and visual impairment. Electroencephalography (EEG) typically shows periodic generalized discharges, and elevated CSF anti-measles antibodies are diagnostic. Movement disorders are being increasingly recognized as part of the clinical spectrum, and range from hyperkinetic (chorea, dystonia, tremor, tics) to hypokinetic (parkinsonism) disorders and ataxia. OBJECTIVES: This article aims to comprehensively review the spectrum of movement disorders associated with SSPE. METHODS: A literature search was conducted in PubMed and EMBASE databases in December 2023 and articles were identified for review. RESULTS: Movement disorders reported in SSPE included hyperkinetic (chorea, dystonia, tremor and tics), hypokinetic (parkinsonism), ataxia and extraocular movement disorders. Myoclonus, a core clinical feature, was the most frequent "abnormal movement." Movement disorders were observed in all clinical stages, and could also be a presenting feature, even sans myoclonus. Hyperkinetic movement disorders were more common than hypokinetic movement disorders. An evolution of movement disorders was observed, with ataxia, chorea and dystonia occurring earlier, and parkinsonism later in the disease. Neuroradiological correlates of movement disorders remained unclear. CONCLUSION: A wide spectrum of movement disorders was observed throughout the clinical stages of SSPE. Most data were derived from case reports and small case series. Multicentric longitudinal studies are required to better delineate the spectrum and evolution of movement disorders in SSPE.

Hemichorea-hemiballismus due to diabetic striatopathy a serious complication of uncontrolled diabetes.

We report the case of a man in his mid-80s with diabetes mellitus who presented to the emergency department with a 1-day history of right-sided choreiform movements and falls. Laboratory tests revealed blood glucose of 597 mg/dL. Non-contrast CT imaging of his head demonstrated a faint hyperdensity involving the left lentiform nucleus and brain MRI showed a hyperintensity in the left basal ganglia on T1-weighted images. These lesions are typical of diabetic striatopathy. Symptoms of hemichorea/hemiballismus did not resolve with glycaemic control and several pharmacological agents were tried with eventual improvement with risperidone. He was discharged to a rehabilitation facility and had mild persistent arm chorea at 6-month follow-up.

A Novel Missense Variant in the NKX2-1 Homeodomain Prevents Transcriptional Rescue by TAZ.

Background: Brain-lung-thyroid syndrome (BLTS) is caused by NKX2-1 haploinsufficiency, resulting in chorea/choreoathetosis, respiratory problems, and hypothyroidism. Genes interacting with NKX2-1 mutants influence its phenotypic variability. We report a novel NKX2-1 missense variant and the modifier function of TAZ/WWTR1 in BLTS. Methods: A child with BLTS underwent next-generation sequencing panel testing for thyroid disorders. His family was genotyped for NKX2-1 variants and screened for germline mosaicism. Mutant NKX2-1 was generated, and transactivation assays were performed on three NKX2-1 target gene promoters. DNA binding capacity and protein-protein interaction were analyzed. Results: The patient had severe BLTS and carried a novel missense variant c.632A>G (p.N211S) in NKX2-1, which failed to bind to specific DNA promoters, reducing their transactivation. TAZ cotransfection did not significantly increase transcription of these genes, although the variant retained its ability to bind to TAZ. Conclusions: We identify a novel pathogenic NKX2-1 variant that causes severe BLTS and is inherited through germline mosaicism. The mutant lacks DNA-binding capacity, impairing transactivation and suggesting that NKX2-1 binding to DNA is essential for TAZ-mediated transcriptional rescue.

Dancing Out of Step: A Case of Tuberculous Meningitis Presenting as Childhood Chorea.

Background: Acute to subacute pediatric movement disorders require prompt diagnosis to identify potentially treatable diseases. Case Report: We present a 6-year-old male with a three-week history of generalized chorea transitioning to predominantly right-sided hemichorea and then to left hemiplegia. Discussion: We review the mechanisms in tuberculous meningitis underlying his movement abnormalities.

Adult-onset acute rheumatic fever with chorea and carditis.

Rheumatic fever is a major cause of cardiovascular morbidity and mortality in low-income and middle-income countries, and it usually occurs at a young age. Adult-onset acute rheumatic fever is a rare condition and usually represents a recurrence of childhood-onset disease. We report a case of an elderly man presenting with rheumatic carditis and rheumatic chorea subsequently diagnosed with adult-onset rheumatic fever.