Long-term follow-up of pallidal deep brain stimulation for craniocervical dystonia: is the globus pallidus internus the best target?

OBJECTIVE: Craniocervical dystonia (CCD) is a common type of segmental dystonia, which is a disabling disease that has been frequently misdiagnosed. Blepharospasm or cervical dystonia is the most usual symptom initially. Although deep brain stimulation (DBS) of the globus pallidus internus (GPi) has been widely used for treating CCD, its clinical outcome has been primarily evaluated in small-scale studies. This research examines the sustained clinical effectiveness of DBS of the GPi in individuals diagnosed with CCD. METHODS: The authors report 24 patients (14 women, 10 men) with refractory CCD who underwent DBS of the GPi between 2016 and 2023. The severity and disability of the dystonia were evaluated using the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS). The BFMDRS scores were collected preoperatively, 6 months postoperatively, and at the most recent follow-up visit. RESULTS: The mean age at onset was 52.0 ± 11.0 years (range 33-71 years) and the mean disease duration was 63.3 ± 73.3 months (range 7-360 months) (values for continuous variables are expressed as the mean ± SD). The mean follow-up period was 37.5 ± 23.5 months (range 6-84 months). The mean total BFMDRS motor scores at the 3 different time points were 13.3 ± 9.4 preoperatively, 5.0 ± 4.7 (55.3% improvement, p < 0.001) at 6 months, and 4.5 ± 3.6 (56.6% improvement, p < 0.001) at last follow-up. The outcomes were deemed poor in 6 individuals. CONCLUSIONS: Inferences drawn from the findings suggest that DBS of the GPi has long-lasting effectiveness and certain limitations in managing refractory CCD. The expected stability of the clinical outcome is not achieved. Patients with specific types of dystonia might consider targets other than GPi for a more precise therapy.

Actigraph-based quantification of sleep in children with dystonia undergoing deep brain stimulation.

OBJECTIVE: Dystonia is among the most common pediatric movement disorders and can manifest with a range of debilitating symptoms, including sleep disruptions. The duration and quality of sleep are strongly associated with quality of life in these individuals and could serve as biomarkers of dystonia severity and the efficacy of interventions such as deep brain stimulation (DBS). Thus, this study investigated sleep duration and its relationship to disease severity and DBS response in pediatric dystonia. METHODS: Actigraphs (wearable three-axis accelerometers) were used to record multiday sleep data in 22 children with dystonia, including 6 patients before and after DBS implantation, and age- and sex- matched healthy controls. Data were preprocessed, and metrics of sleep duration and quality were extracted. Repeated-measures statistical analyses were used. RESULTS: Children with dystonia slept less than typically developing children (p = 0.009), and shorter sleep duration showed trending correlation with worse dystonia severity (r = -0.421, p = 0.073). Of 4 patients who underwent DBS and had good-quality data, 1 demonstrated significantly improved sleep (p < 0.001) postoperatively. Reduction in dystonia severity strongly correlated with increased sleep duration after DBS implantation (r = -0.965, p = 0.035). CONCLUSIONS: Sleep disturbances are an underrecognized marker of pediatric dystonia severity, as well as the effectiveness of interventions such as DBS. They can serve as objective biomarkers of disease burden and symptom progression after treatment.

[Phenotypic and genotypic spectrum of KMT2B dystonia. Description of three Colombian patients]. / Espectro fenotípico y genotípico de la distonía causada por el gen KMT2B. Descripción de tres casos colombianos.

INTRODUCTION: KMT2B-related dystonia is a childhood-onset movement disorder characterized by focal dystonia of the lower extremities progressing to generalized dystonia with predominant cervical, cranial, and laryngeal involvement. So far, fewer than 100 variants have been reported, the vast majority being de novo mutations. The presenting frame of KMT2B dystonia, with dysmorphology features and other complex neurologic symptoms shows the spectrum of KMT2B dystonia as a probable syndromic disease, rather than an isolated early-onset dystonia, which has been the classic view of the condition. CASE REPORTS: We report three patients who presented regression in their neurodevelopment, focal dystonia of the lower limbs with subsequent generalization, in whom two de novo variants were reported in the KMT2B gene, with a mean age of presentation lower than the average reported worldwide. CONCLUSIONS: We describe the largest local series of patients with KMT2B dystonia in Colombia (to our knowledge), which allows us to expand the genotype-phenotype relationship of this genetic dystonia. Although many affected individuals follow a similar disease course, it is important to determine clinical features that may be associated such as neurodevelopmental regression.

TITLE: Espectro fenotípico y genotípico de la distonía causada por el gen KMT2B. Descripción de tres casos colombianos.Introducción. La distonía relacionada con KMT2B es un trastorno del movimiento hipercinético, de inicio en la infancia, caracterizado inicialmente por distonía focal de las extremidades inferiores que progresa a una distonía generalizada con mayor afectación cervical, craneal y laríngea. Hasta el momento se han descrito aproximadamente 100 variantes causantes de enfermedad, y la mayoría son de novo. La presentación clínica de la distonía con hallazgos fenotípicos comunes en los pacientes, asociada a frecuente afectación del neurodesarrollo, afectación intelectual y otros trastornos del movimiento, hace pensar más en el espectro KMT2B como una condición sindrómica, más que en una distonía aislada de inicio temprano, como clásicamente se ha clasificado. Casos clínicos. Se presenta el caso de tres pacientes con regresión del neurodesarrollo, distonía focal de los miembros inferiores con posterior generalización, en quienes se identificaron tres variantes en el gen KMT2B, en dos de los casos de novo (en una de ellas se desconoce la segregación), y dos de ellas comunicadas por primera vez en la bibliografía. La edad media de presentación fue menor a la edad promedio notificada a nivel mundial. Conclusiones. Describimos una serie de pacientes colombianos con distonía DYT-KMT2B (la más grande en nuestro conocimiento a nivel local), lo que nos permite ampliar la relación genotipo-fenotipo de esta distonía genética. Si bien múltiples individuos afectados siguen un curso de enfermedad similar, es importante determinar las características clínicas que pueden estar asociadas, como la regresión del neurodesarrollo y su potencial clasificación como distonía compleja. Describimos, además, dos nuevas variantes asociadas al fenotipo.

Deep brain stimulation for pediatric pantothenate kinase-associated neurodegeneration with status dystonicus: A case report and literature review.

BACKGROUND: Pantothenate kinase-associated neurodegeneration (PKAN) is a type of inherited metabolic disorder caused by mutation in the PANK2 gene. The metabolic disorder mainly affects the basal ganglia region and eventually manifests as dystonia. For patients of dystonia, their dystonic symptom may progress to life-threatening emergency--status dystonicus. OBJECTIVE: We described a case of a child with PKAN who had developed status dystonicus and was successfully treated with deep brain stimulation (DBS). Based on this rare condition, we analysed the clinical features of PKAN with status dystonicus and reviewed the reasonable management process of this condition. CONCLUSION: This case confirmed the rationality of choosing DBS for the treatment of status dystonicus. Meanwhile, we found that children with classic PKAN have a cluster of risk factors for developing status dystonicus. Once children diagnosed with similar neurodegenerative diseases are under status dystonicus, DBS can be active considered because it has showed high control rate of this emergent condition.

Pyruvate dehydrogenase-E1α deficiency presenting as generalized dystonia: A genetic diagnosis with important clinical implications.

Pyruvate dehydrogenase complex (PDC) deficiency is a genetic mitochondrial disease mostly associated with severe lactic acidosis, rapid progression of neurological symptoms and death during childhood. We present a 33-year-old male with PDC deficiency caused by a Val262Leu mutation in PDHA1gene. He demonstrated generalized dystonia affecting trunk and upper extremities and paraparesis as the most significant features, with onset of symptoms at age 8. Brain MRI showed bilaterally increased signal within the globus pallidus, typical of Leigh syndrome. A periodic lactate increase in serum and cerebrospinal fluid was detected. We describe a case of pyruvate dehydrogenase deficiency being diagnosed only 25 years after the onset of symptoms and highlight PDHC deficiency as a possible cause of treatable dystonia in childhood, which may respond well to thiamine and levodopa treatment.

The integrated stress response pathway and neuromodulator signaling in the brain: lessons learned from dystonia.

The integrated stress response (ISR) is a highly conserved biochemical pathway involved in maintaining proteostasis and cell health in the face of diverse stressors. In this Review, we discuss a relatively noncanonical role for the ISR in neuromodulatory neurons and its implications for synaptic plasticity, learning, and memory. Beyond its roles in stress response, the ISR has been extensively studied in the brain, where it potently influences learning and memory, and in the process of synaptic plasticity, which is a substrate for adaptive behavior. Recent findings demonstrate that some neuromodulatory neuron types engage the ISR in an "always-on" mode, rather than the more canonical "on-demand" response to transient perturbations. Atypical demand for the ISR in neuromodulatory neurons introduces an additional mechanism to consider when investigating ISR effects on synaptic plasticity, learning, and memory. This basic science discovery emerged from a consideration of how the ISR might be contributing to human disease. To highlight how, in scientific discovery, the route from starting point to outcomes can often be circuitous and full of surprise, we begin by describing our group's initial introduction to the ISR, which arose from a desire to understand causes for a rare movement disorder, dystonia. Ultimately, the unexpected connection led to a deeper understanding of its fundamental role in the biology of neuromodulatory neurons, learning, and memory.

Effects of onabotulinum toxin type A injections in patients with Meige's syndrome.

BACKGROUND: Meige's syndrome is a type of facial dystonia characterized by the simultaneous occurrence of blepharospasm and oromandibular dystonia. Although botulinum toxin type A (OBTA) injections are the standard treatment, evidence of their effectiveness and safety in this scenario is still lacking. OBJECTIVE: Our research aimed to evaluate the improvement and occurrence of side effects following injections of onabotulinum toxin type A (OBTA) in patients with Meige's syndrome. METHODS: Patients with Meige's syndrome undergoing botulinum toxin injections were enrolled in this study. We assessed dystonia intensity before and 14 days after OBTA injection using the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) to measure the response of symptoms in the eyes (blepharospasm) and mouth (oromandibular dystonia). Other variables, such as dosage, side effects, and demographic data, were also recorded. RESULTS: The study included 41 participants, with a mean age of 67.7 years and a female-to-male ratio of 3.5:1. The mean BFMDRS score before the injections was 8.89, and after 14 days, it was 2.88. The most reported side effect was ptosis, with a 7.3% incidence. OBTA significantly reduced dystonia severity (p < 0.0001). The clinical response for the blepharospasm component was superior to the oromandibular dystonia component. CONCLUSION: Our results support that OBTA seems to be an effective and safe therapeutic option for treating Meige's syndrome. The effect of OBTA was more pronounced in the treatment of blepharospasm than in oromandibular dystonia.

ANTECEDENTES: A síndrome de Meige (SM) é caracterizada pela ocorrência concomitante de blefarospasmo e distonia oromandibular. Embora a toxina onabotulínica do tipo A (TBA) seja o tratamento de escolha, há uma falta de evidências sobre sua eficácia e segurança nesse cenário. OBJETIVO: O objetivo do nosso estudo foi avaliar os efeitos obtidos com a aplicação de TBA em pacientes com SM. MéTODOS: Pacientes com SM que realizam aplicação de TBA foram convidados a participar desse estudo. Os participantes foram questionados sobre a intensidade da distonia antes e 14 dias após a injeção de TBA, utilizando a Escala de Distonia de Burke-Fahn-Marsden (EDBFM) para mensurar a resposta obtida em cada segmento. Outras variáveis, como dose, ocorrência de efeitos colaterais e dados demográficos, também foram registradas. RESULTADOS: O estudo contou com 41 participantes (idade média de 67,7; razão de 3,5 pacientes do sexo feminino para cada participante do sexo masculino). O escore médio na EDBFM antes das aplicações de TBA era 8,89, e, após 14 dias, 2,88. O efeito colateral mais reportado foi ptose (7.3%). A TBA foi capaz de reduzir a severidade da distonia (p < 0.0001), principalmente do blefarospasmo. CONCLUSãO: Nossos resultados corroboram que a TBA é uma terapêutica eficaz e segura no tratamento da SM. O efeito da TBA é superior no manejo do blefarospasmo em relação à distonia oromandibular.

Genetic Update and Treatment for Dystonia.

A neurological condition called dystonia results in abnormal, uncontrollable postures or movements because of sporadic or continuous muscular spasms. Several varieties of dystonia can impact people of all ages, leading to severe impairment and a decreased standard of living. The discovery of genes causing variations of single or mixed dystonia has improved our understanding of the disease's etiology. Genetic dystonias are linked to several genes, including pathogenic variations of VPS16, TOR1A, THAP1, GNAL, and ANO3. Diagnosis of dystonia is primarily based on clinical symptoms, which can be challenging due to overlapping symptoms with other neurological conditions, such as Parkinson's disease. This review aims to summarize recent advances in the genetic origins and management of focal dystonia.

Myoclonus and Dystonia as Recurrent Presenting Features in Patients with the SCA21-Associated TMEM240 p.Pro170Leu Variant.

Background: Spinocerebellar ataxia 21 (SCA21) is a rare neurological disorder caused by heterozygous variants in TMEM240. A growing, yet still limited number of reports suggested that hyperkinetic movements should be considered a defining component of the disease. Case Series: We describe two newly identified families harboring the recurrent pathogenic TMEM240 p.Pro170Leu variant. Both index patients and the mother of the first proband developed movement disorders, manifesting as myoclonic dystonia and action-induced dystonia without co-occurring ataxia in one case, and pancerebellar syndrome complicated by action-induced dystonia in the other. We reviewed the literature on TMEM240 variants linked to hyperkinetic disorders, comparing our cases to described phenotypes. Discussion: Adding to prior preliminary observations, our series highlights the relevance of hyperkinetic movements as clinically meaningful features of SCA21. TMEM240 mutation should be included in the differential diagnosis of myoclonic dystonia and ataxia-dystonia syndromes.

Posterior Interosseous Neuropathy with Peripheral Dystonia: A Case Report.

Background: Posterior interosseous neuropathy is an uncommon cause of peripheral dystonia. Case Report: A 62-year-old man awakened and noticed right finger drop. A neurological examination revealed posterior interosseous neuropathy with dystonia-like finger movements. Abnormal movements were predominantly observed in the right thumb, ring finger, and little finger. Within 2 weeks, the muscle weakness in the right fingers had completely improved. However, a brief abnormal posture of the right thumb was persistent. Discussion: The residual abnormal posture of the right thumb may reflect pre-existing motor control abnormalities, which may have contributed to the onset of posterior interosseous neuropathy-associated peripheral dystonia.

Successful treatment of cranial dystonia using a Zolpidem+Melatonin combination: A video case-series.

INTRODUCTION: Cranial dystonias (CrD) are challenging to treat. Oral pharmacotherapy is often sub-optimal, while delicate anatomy and limited availability of skilled botulinum toxin injectors makes this approach risky, and often difficult to access; neurosurgical options e.g. deep brain stimulation, are high-risk in the elderly populations most affected. We observed significant improvement in CrD in 2 patients prescribed Zolpidem+Melatonin combination treatment for insomnia, and therefore trialled this treatment in a further 4 patients with CrD. METHODS: Six patients were treated with Zolpidem+Melatonin. Pre- and post-treatment videotaped clinical examinations were blindly rated by an independent assessor (EM) and scored using the 'Facial and Oral Movements' section of the abnormal involuntary movements scale (AIMS), as well as the Jankovic rating scale for blepharospasm. RESULTS: Dystonic features, as measured by the abnormal involuntary movements scale (AIMS) improved by an average of 75% after treatment (6.5±3.1 before treatment to 1.7 +/- 0.8 after treatment). Improvements were also observed in blepharospasm severity scores, and in cervical dystonic features. CONCLUSION: Zolpidem+Melatonin combination treatment represents a safe and effective treatment for CrD. Low cost and wide availability makes it an attractive option, particularly in resource-constrained healthcare settings, or in patients who have failed, or lack access to alternatives.

Dystonic Tremor: Time to Change.

BACKGROUND: The term dystonic tremor is being increasingly used in neurological publications despite uncertainties about its meaning. We provide here a historical reconstruction from its original introduction in 1984 to help distinguish dystonia from essential tremor. METHODS: A comprehensive Pubmed search of MeSH terms "dystonia", "tremor", and "essential tremor" provided the information base for reconstructing historical usage of the term "dystonic tremor". RESULTS: Over the years, this expression was enriched of additional meanings and sided by companion descriptors, such as tremor associated with dystonia. Dystonic tremor has been considered characteristically coarse, jerky, irregular, directional and asymmetrical. These characteristics, however, are not included in the most recent definitions of tremor. The relationship between tremor and dystonia is not easy to untangle, as the two phenomena are often recognized in association. Tremor and dystonia experts have developed different visions of dystonic tremor that have been variably implemented. There are currently two independent consensus definitions, which are not coincident and imply different pathophysiological interpretations. CONCLUSIONS: This historical reappraisal highlights that usage of the expression dystonic tremor has evolved over time to lose its original meaning. Notwithstanding inconsistencies of current definitions, its usage has steadily increased and it is time now to agree on an updated terminology.

Compound heterozygous mutations in three Chinese patients of Segawa syndrome and their treatment outcomes.

Segawa syndrome is a rare autosomal recessive form of dopa-responsive dystonia resulting from TH gene dysfunction. Patients typically exhibit symptoms such as generalized dystonia, rigidity, tremors, infantile Parkinsonism, and pseudo-spastic paraplegia. Levodopa is often an effective treatment. Due to its rarity, high heterogeneity, and poorly understood pathological mutation and phenotype spectrums, as well as genotype-phenotype and genotype-treatment outcome correlations, Segawa syndrome poses diagnostic and therapeutic challenges. In our study, through clinical and molecular analyses of three Chinese Segawa patients, we re-evaluated the pathogenicity of a TH mutation (c.880G>C;p.G294R) previously categorized as "Conflicting classifications of pathogenicity" in ClinVar. Also, we summarized the clinical phenotypes of all reported Segawa syndrome cases until 2023 and compared them with our patients. We identified a novel phenotype, "cafe-au-lait macules," not previously observed in Segawa patients. Additionally, we discussed the correlation between specific genotypes and phenotypes, as well as genotypes and treatment outcomes of our three cases. Our findings aim to enhance the understanding of Segawa syndrome, contributing to improved diagnosis and treatment approaches in the future.

Can calcitonin gene-related peptide monoclonal antibodies ameliorate writer's cramp and migraine?

Recently, calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) have become available as a prophylactic treatment for migraine and have shown high efficacy and safety in clinical practice. CGRP mAbs have been reported to be effective not only for migraine but also for other comorbidities, such as psychiatric complications in patients with migraine. However, there are no reports examining the effect of CGRP mAbs on dystonia. We treated a patient with comorbid migraine and focal task-specific dystonia (writer's cramp) with a CGRP mAb (erenumab) because of an increase in monthly migraine days despite the addition of migraine prophylaxis. In this patient, erenumab treatment for 3 months led to improvements in symptoms of both focal dystonia and migraine, suggesting a role for CGRP in the pathophysiology of both conditions.

Pallidal deep brain stimulation for patients with myoclonus-dystonia without SGCE mutations.

BACKGROUND: Pallidal deep brain stimulation (GPi-DBS) is effective for treating myoclonus and dystonia caused by SGCE mutations (DYT-SGCE, DYT11). However, it is unknown whether GPi-DBS is effective for the treatment of myoclonus-dystonia which is not associated with the SGCE gene mutations. In this study, we investigated the efficacy of GPi-DBS in treating myoclonus-dystonia in SGCE mutation-negative cases. METHODS: Three patients with myoclonus-dystonia without SGCE mutations who underwent GPi-DBS were evaluated preoperatively and 6 months postoperatively using the Unified Myoclonus Rating Scale (UMRS) and Fahn-Marsden Dystonia Rating Scale (FMDRS) for myoclonus and dystonia, respectively. In two of the three patients, myoclonus was more evident during action. Myoclonus was predominant at rest in the other patient, and he was unaware of his dystonia symptoms. The results were compared with those of the four DYT-SGCE cases. RESULTS: The mean UMRS score in patients with myoclonus-dystonia without SGCE mutations improved from 61.7 to 33.7 pre- and postoperatively, respectively, and the mean FMDRS score improved from 7.2 to 4.5. However, the degree of improvement in myoclonus-dystonia in patients without SGCE mutations was inferior to that in patients with DYT-SGCE (the UMRS score improved by 45% and 69%, respectively). CONCLUSIONS: GPi-DBS is effective for treating myoclonus-dystonia in patients with and without SGCE mutations. GPi-DBS should be considered as a treatment option for myoclonus-dystonia without SGCE mutations.

An Evidence-Based Update on Anticholinergic Use for Drug-Induced Movement Disorders.

Drug-induced movement disorders (DIMDs) are associated with use of dopamine receptor blocking agents (DRBAs), including antipsychotics. The most common forms are drug-induced parkinsonism (DIP), dystonia, akathisia, and tardive dyskinesia (TD). Although rare, neuroleptic malignant syndrome (NMS) is a potentially life-threatening consequence of DRBA exposure. Recommendations for anticholinergic use in patients with DIMDs were developed on the basis of a roundtable discussion with healthcare professionals with extensive expertise in DIMD management, along with a comprehensive literature review. The roundtable agreed that "extrapyramidal symptoms" is a non-specific term that encompasses a range of abnormal movements. As such, it contributes to a misconception that all DIMDs can be treated in the same way, potentially leading to the misuse and overprescribing of anticholinergics. DIMDs are neurobiologically and clinically distinct, with different treatment paradigms and varying levels of evidence for anticholinergic use. Whereas evidence indicates anticholinergics can be effective for DIP and dystonia, they are not recommended for TD, akathisia, or NMS; nor are they supported for preventing DIMDs except in individuals at high risk for acute dystonia. Anticholinergics may induce serious peripheral adverse effects (e.g., urinary retention) and central effects (e.g., impaired cognition), all of which can be highly concerning especially in older adults. Appropriate use of anticholinergics therefore requires careful consideration of the evidence for efficacy (e.g., supportive for DIP but not TD) and the risks for serious adverse events. If used, anticholinergic medications should be prescribed at the lowest effective dose and for limited periods of time. When discontinued, they should be tapered gradually.

RANBP17 Overexpression Restores Nucleocytoplasmic Transport and Ameliorates Neurodevelopment in Induced DYT1 Dystonia Motor Neurons.

DYT1 dystonia is a debilitating neurological movement disorder, and it represents the most frequent and severe form of hereditary primary dystonia. There is currently no cure for this disease due to its unclear pathogenesis. In our previous study utilizing patient-specific motor neurons (MNs), we identified distinct cellular deficits associated with the disease, including a deformed nucleus, disrupted neurodevelopment, and compromised nucleocytoplasmic transport (NCT) functions. However, the precise molecular mechanisms underlying these cellular impairments have remained elusive. In this study, we revealed the genome-wide changes in gene expression in DYT1 MNs through transcriptomic analysis. We found that those dysregulated genes are intricately involved in neurodevelopment and various biological processes. Interestingly, we identified that the expression level of RANBP17, a RAN-binding protein crucial for NCT regulation, exhibited a significant reduction in DYT1 MNs. By manipulating RANBP17 expression, we further demonstrated that RANBP17 plays an important role in facilitating the nuclear transport of both protein and transcript cargos in induced human neurons. Excitingly, the overexpression of RANBP17 emerged as a substantial mitigating factor, effectively restoring impaired NCT activity and rescuing neurodevelopmental deficits observed in DYT1 MNs. These findings shed light on the intricate molecular underpinnings of impaired NCT in DYT1 neurons and provide novel insights into the pathophysiology of DYT1 dystonia, potentially leading to the development of innovative treatment strategies.