Pallidal and Thalamic Deep Brain Stimulation in the Treatment of Unilateral Dystonia: A Prospective Assessment.

BACKGROUND: The complexities of unilateral dystonia have led to exploring simultaneous (dual) globus pallidus internus (GPi) and motor ventral thalamus (Vim/Vop) deep brain stimulation (DBS), yet detailed assessments are lacking. OBJECTIVES: To assess the efficacy of GPi, Vim/Vop, and dual DBS in unilateral dystonia. METHODS: Three patients with unilateral dystonia (two idiopathic, one acquired), implanted with two DBS electrodes targeting ipsilateral Vim/Vop and GPi, were included. Three stimulation modalities were assessed. First, one electrode was activated, then the other, and finally, both electrodes were activated simultaneously. RESULTS: DBS yielded substantial symptomatic reductions in all three evaluated stimulation modalities. Patients exhibited varying responses regarding quality-of-life and depressive symptoms. Treatment satisfaction didn't align with clinical improvements, potentially affected by unrealistic expectations. CONCLUSIONS: This study contributes critical insights into GPi, Vim/Vop and simultaneous stimulation for unilateral dystonia. The safety of the procedure underscores the promise of this approach.

ZNF91 is an endogenous repressor of the molecular phenotype associated with X-linked dystonia-parkinsonism (XDP).

X-linked dystonia-parkinsonism (XDP) is a severe neurodegenerative disorder resulting from an inherited intronic SINE-Alu-VNTR (SVA) retrotransposon in the TAF1 gene that causes dysregulation of TAF1 transcription. The specific mechanism underlying this dysregulation remains unclear, but it is hypothesized to involve the formation of G-quadruplexes (G4) structures within the XDP-SVA that impede transcription. In this study, we show that ZNF91, a critical repressor of SVA retrotransposons, specifically binds to G4-forming DNA sequences. Further, we found that genetic deletion of ZNF91 exacerbates the molecular phenotype associated with the XDP-SVA insertion in patient cells, while no difference was observed when ZNF91 was deleted from isogenic control cells. Additionally, we observed a significant age-related reduction in ZNF91 expression in whole blood and brain, indicating a progressive loss of repression of the XDP-SVA in XDP. These findings indicate that ZNF91 plays a crucial role in controlling the molecular phenotype associated with XDP. Since ZNF91 binds to G4-forming DNA sequences in SVAs, this suggests that interactions between ZNF91 and G4-forming sequences in the XDP-SVA minimize the severity of the molecular phenotype. Our results showing that ZNF91 expression levels significantly decrease with age provide a potential explanation for the age-related progressive neurodegenerative character of XDP. Collectively, our study provides important insights into the protective role of ZNF91 in XDP pathogenesis and suggests that restoring ZNF91 expression, destabilization of G4s, or targeted repression of the XDP-SVA could be future therapeutic strategies to prevent or treat XDP.

Connecting the dots - A systematic review on coherence analysis in dystonia.

BACKGROUND: Increased 4-12 Hz oscillatory activity in the cortico-basal ganglia-thalamo-cortical (CBGTC) loop is reported in dystonia. Coherence analysis is a measure of linear coupling between two signals, revealing oscillatory activity drives that are common across motor units. By performing coherence analysis, activity of the CBGTC-loop can be measured with modalities like local field potentials (LFPs), electromyography (EMG), and electro-encephalography (EEG). The aim of this study is to perform a systematic review on the use of coherence analysis for clinical assessment and treatment of dystonia. METHODS: A systematic review was performed on a search in Embase and PubMed on June 28th, 2023. All studies incorporating coherence analysis and an adult dystonia cohort were included. Three authors evaluated the eligibility of the articles. Quality was assessed using the QUADAS-2 checklist. RESULTS: A total of 41 articles were included, with data of 395 adult dystonia patients. In the selected records, six different types of coherence were investigated: corticocortical, corticopallidal, corticomuscular, pallidopallidal, pallidomuscular, and intermuscular coherence. Various types of 4-12 coherence were found to be increased in all dystonia subtypes. CONCLUSION: There is increased 4-12 Hz coherence found between the cortex, basal ganglia, and affected muscles in all dystonia subtypes. However, the relationship between 4-12 Hz coherence and the dystonic clinical state has not been established. DBS treatment leads to a reduction of 4-12 Hz coherence. In combination with the results of this review, the 4-12 Hz frequency band can be used as a promising phenomenon for the development of a biomarker.

Management of neurological symptoms in Lesch-Nyhan disease: A systematic review.

Lesch-Nyhan Disease (LND) is an X-linked recessive genetic disorder arising from hypoxanthine phosphoribosyltransferase 1 gene mutations, leading to a complete deficiency. LND presents a complex neurological profile characterized by generalized dystonia, motor dysfunctions and self-injurious behavior, which management is challenging. We conducted a systematic review of studies assessing the efficacy of pharmacological and non-pharmacological interventions in management of neurological symptoms in LND (PROSPERO registration number:CRD42023446513). Among 34 reviewed full-text papers; 22 studies were rated as having a high risk of bias. Considerable heterogeneity was found in studies regarding the timing of treatment implementation, adjunctive treatments and outcome assessment. Single-patient studies and clinical trials often showed contradictory results, while therapeutic failures were underreported. S-Adenosylmethionine and Deep Brain Stimulation were the most studied treatment methods and require further research to address inconsistencies. The evidence from levodopa studies underlines that optimal timing of treatment implementation should be thoroughly investigated. Standardized study design and reducing publication bias are crucial to overcome current limitations of assessing intervention efficacy in LND.

Thalamic ventral-Oralis complex/rostral zona incerta deep brain stimulation for midline tremor.

BACKGROUND: Midline Tremor is defined as an isolated or combined tremor that affects the neck, trunk, jaw, tongue, and/or voice and could be part of Essential Tremor (ET), or dystonic tremor. The clinical efficacy of deep brain stimulation for Midline Tremor has been rarely reported. The Ventral Intermediate Nucleus and Globus Pallidus Internus are the preferred targets, but with variable outcomes. Thalamic Ventral-Oralis (VO) complex and Zona Incerta (ZI) are emerging targets for tremor control in various etiologies. OBJECTIVE: To report on neuroradiological, neurophysiological targeting and long-term efficacy of thalamic Ventral-Oralis complex and Zona Incerta deep brain stimulation in Midline Tremor. METHODS: Three patients (two males and one female) with Midline Tremor in dystonic syndromes were recruited for this open-label study. Clinical, surgical, neurophysiological intraoperative testing and long-term follow-up data are reported. RESULTS: Intraoperative testing and reconstruction of volume of tissue activated confirmed the position of the electrodes in the area stimulated between the thalamic Ventral-Oralis complex and Zona Incerta in all patients. All three patients showed optimal control of both tremor and dystonic features at short-term (6 months) and long-term follow-up (up to 6 years). No adverse events occurred. CONCLUSION: In the syndromes of Midline Tremor of various origins, the best target for DBS might be difficult to identify. Our results showed that thalamic Ventral-Oralis complex/Zona Incerta may be a viable and safe option even in specific forms of tremor with axial distribution.

Central Mechanisms and Pathophysiology of Laryngeal Dystonia: An Up-to-Date Review.

OBJECTIVE: Laryngeal dystonia (LD), previously termed spasmodic dysphonia, is an isolated focal dystonia that involves involuntary, uncontrolled contractions of the laryngeal muscles during speech. It is a severely disabling condition affecting patients' work and social lives through prevention of normal speech production. Our understanding of the pathophysiology of LD and available therapeutic options are currently limited. The aim of this short review is to provide an up-to-date summary of what is known about the central mechanisms and the pathophysiology of LD. METHODS: A systematic review of the literature was performed searching Embase, CINHAL, Medline, and Cochrane with the cover period January 1990-October 2023 with a search strategy (("Laryngeal dystonia" OR "Spasmodic dysphonia") AND ("Central Mechanism" OR "Pathophysiology")). Original studies involving LD patients that discussed central mechanisms and/or pathophysiology of LD were chosen. RESULTS: Two hundred twenty-six articles were identified of which 27 articles were included to formulate this systematic review following the screening inclusion and exclusion criteria. LD is a central neurological disorder involving a multiregional altered neural network. Affected neural circuits not only involve the motor control circuit, but also the feedforward, and the feedback circuits of the normal speech production neural network, involving higher-order planning, somatosensory perception and integration regions of the brain. CONCLUSION: Speech production is a complex process, and LD is a central neurological disorder involving multiregional neural network connectivity alteration reflecting this. Neuromodulation targeting the central nervous system could therefore be considered and explored as a new potential therapeutic option for LD in the future, and should assist in elucidating the underlying central mechanisms responsible for causing the condition.

In vitro study of ATP1A3 p.Ala275Pro mutant causing alternating hemiplegia of childhood and rapid-onset dystonia-parkinsonism.

Introduction: We previously reported that ATP1A3 c.823G>C (p.Ala275Pro) mutant causes varying phenotypes of alternative hemiplegia of childhood and rapid-onset dystonia-parkinsonism in the same family. This study aims to investigate the function of ATP1A3 c.823G>C (p.Ala275Pro) mutant at the cellular and zebrafish models. Methods: ATP1A3 wild-type and mutant Hela cell lines were constructed, and ATP1A3 mRNA expression, ATP1A3 protein expression and localization, and Na+-K+-ATPase activity in each group of cells were detected. Additionally, we also constructed zebrafish models with ATP1A3 wild-type overexpression (WT) and p.Ala275Pro mutant overexpression (MUT). Subsequently, we detected the mRNA expression of dopamine signaling pathway-associated genes, Parkinson's disease-associated genes, and apoptosisassociated genes in each group of zebrafish, and observed the growth, development, and movement behavior of zebrafish. Results: Cells carrying the p.Ala275Pro mutation exhibited lower levels of ATP1A3 mRNA, reduced ATP1A3 protein expression, and decreased Na+-K+-ATPase activity compared to wild-type cells. Immunofluorescence analysis revealed that ATP1A3 was primarily localized in the cytoplasm, but there was no significant difference in ATP1A3 protein localization before and after the mutation. In the zebrafish model, both WT and MUT groups showed lower brain and body length, dopamine neuron fluorescence intensity, escape ability, swimming distance, and average swimming speed compared to the control group. Moreover, overexpression of both wild-type and mutant ATP1A3 led to abnormal mRNA expression of genes associated with the dopamine signaling pathway and Parkinson's disease in zebrafish, and significantly upregulated transcription levels of bad and caspase-3 in the apoptosis signaling pathway, while reducing the transcriptional level of bcl-2 and the bcl-2/bax ratio. Conclusion: This study reveals that the p.Ala275Pro mutant decreases ATP1A3 protein expression and Na+/K+-ATPase activity. Abnormal expression of either wild-type or mutant ATP1A3 genes impairs growth, development, and movement behavior in zebrafish.

Canine paroxysmal dyskinesia-a review.

Paroxysmal dyskinesias (PDs) are a group of involuntary, hyperkinetic movement disorders that recur episodically and may last seconds to hours. An important feature of PD is that there is no loss of consciousness during the episode. Using a clinical classification, three main types of PDs have been distinguished in canine PD: (1) paroxysmal kinesigenic dyskinesia (PKD) that commences after (sudden) movements, (2) paroxysmal non-kinesigenic dyskinesia (PNKD) not associated with exercise and can occur at rest, and (3) paroxysmal exertion-induced dyskinesia (PED) associated with fatigue. Canine PDs are diagnosed based on the clinical presentation, history, and phenomenology. For the latter, a video recording of the paroxysmal event is extremely useful. An etiological classification of canine PDs includes genetic (proven and suspected), reactive (drug-induced, toxic, metabolic, and dietary), structural (neoplasia, inflammatory, and other structural causes), and unknown causes. In this review, an overview of all reported canine PDs is provided with emphasis on phenotype, genotype, and, where possible, pathophysiology and treatment for each reported canine PD.

Phenomenological patterns and aetiological spectrum in patients visiting a tertiary care Movement disorders service in India: An observational study.

OBJECTIVE: Although previous studies have described phenomenological diagnoses, they lacked description of aetiological spectrum in patients visiting movement disorders (MD) service. Herein, we classify the MD phenomenology and describe aetiology wise distribution of each phenomenology in patients visiting a tertiary care movement disorders service. METHODS: Collected information included demographic profile (age of onset, age at presentation, gender, duration of illness before presentation), predominant MD phenomenology [such as parkinsonism, dystonia, ataxia, tremor, chorea, ballism, myoclonus, tics, stereotypy, restless legs syndrome (RLS) and others], diagnostic evaluations and detected aetiology. RESULTS: This observational study included 1140 MD patients over a span of 5 years. The median (IQR) age of onset was 49 (35-60) years and age at presentation was 54 (40-65) years, with median duration of illness being 36 (18-72) months. Nearly two-third of patients were males (M:F=731:409). Parkinsonism (n=494, 43.3 %) was the most common MD phenomenology observed, followed by dystonia (n=219, 19.2 %), ataxia (n=125, 11 %), tremor (n=118, 10.4 %), myoclonus (n=73, 6.4 %), chorea (n=40, 3.5 %), spasticity (n=22, 1.9 %), tics (n=8, 0.7 %), and RLS (n=8, 0.7 %). Thirty-three (2.9 %) patients were grouped under miscellaneous MDs. Overall, neurodegenerative disorders (57.4 %) were the most common cause of MDs. Parkinson's disease, genetic dystonia, essential tremor, genetic ataxias, hemifacial spasm, and Huntington's disease were the most common aetiologies for parkinsonism, dystonia, tremor, ataxia, myoclonus, and chorea, respectively. CONCLUSION: Parkinsonism was the most common phenomenology observed in MD patients, and was followed by dystonia, ataxia and tremor. Neurodegenerative disorders were the most common aetiology detected.

Incobotulinum Toxin-A in Professional Musicians with Focal Task-Specific Dystonia: A Double Blind, Placebo Controlled, Cross-Over Study.

Background: Musician's focal task-specific dystonia is a complex disorder of fine motor control, with incomplete understanding of its etiology. There have been relatively few trials of botulinum toxin in upper limb task-specific dystonia, and prior studies have yielded variable results, leading to skepticism regarding the utility of this approach in elite performers. Methods: We conducted a double-blind, placebo-controlled, randomized, cross-over study of incobotulinum toxin-A in 21 professional musicians with focal upper extremity task-specific dystonia affecting performance on their instrument, using a novel paradigm of initial injections followed by booster injections at two- and four-week intervals. The primary outcome measure was the change in blinded dystonia rating of the active arm by two expert raters using a Clinical Global Impression numeric scale at week 8 compared to enrollment. Findings: 19 men and 2 women with musicians' dystonia were enrolled over a six-year period. Nineteen patients completed the study. Analysis of the primary outcome measure in comparison to baseline revealed a change in dystonia severity of P = 0.04 and an improvement in overall musical performance of P = 0.027. No clinically significant weakness was observed, and neutralizing antibodies to toxin were not found. Interpretation: Despite its small sample size, our study demonstrated a statistically significant benefit of incobotulinum toxin-A injections as a treatment for musicians' task-specific dystonia. Tailoring the use of toxin with booster injections allowed refinement of dosing strategy and outcomes, with benefits that were meaningful to patients clearly visible on videotaped evaluations. In addition to its application to musicians' dystonia, this approach may have relevance to optimize application of botulinum toxin in other forms of focal dystonia such as blepharospasm, cervical dystonia, writer's cramp, and spasmodic dysphonia.

Efficacy and safety of zolpidem for musician's dystonia.

Background: The efficacy and safety of zolpidem in treating musician's dystonia are not well understood. Objective: We aimed to retrospectively investigate the efficacy and safety of zolpidem for musician's dystonia. Methods: We retrospectively reviewed medical records between January 2021 and December 2023 to identify patients with musician's dystonia who had been prescribed zolpidem. The Tubiana's musician's dystonia rating scale (range, 1-5; lower scores indicating greater severity) was used to evaluate musician's dystonia. Results: Fifteen patients were included in this study. The mean effective dose of zolpidem was 5.3±2.0 mg. The mean effective duration of zolpidem was 4.3±1.2 h. With zolpidem administration, the Tubiana's musician's dystonia rating scale score significantly improved from 2.2±1.0 to 4.3±0.8 (48.9% improvement, p<0.001). Two patients (13.3%) discontinued the drug owing to unsatisfactory results or sleepiness. Conclusion: This study suggests that zolpidem may be an alternative treatment option for musician's dystonia.

Spinal movement disorders in NMOSD, MOGAD, and idiopathic transverse myelitis: a prospective observational study.

BACKGROUND: Retrospective studies suggest that spinal movement disorders, especially tonic spasms, are prevalent in NMOSD. However, there have been no prospective studies evaluating spinal movement disorders in NMOSD, MOGAD, and idiopathic transverse myelitis (ITM). METHODS: Patients referred to a tertiary neuroimmunology clinic for spinal cord demyelination (excluding MS) were evaluated. All patients answered a movement disorders survey and underwent a movement disorder-focused exam. Movement disorders were compared among patients with NMOSD with and without AQP4-IgG, MOGAD, and ITM. Patients with and without involuntary movements were also compared to identify predictors of spinal movement disorders. RESULTS: Sixty-three patients were evaluated from 2017 to 2021 (71% females, median age 49 years, range 18-72 years, median disease duration 12 months, range 1-408). Of the total, 49% had ITM, 21% had NMOSD without AQP4-IgG, 19% had NMOSD with AQP4-IgG, and 11% had MOGAD. Movement disorders were present in 73% of the total patients and were most frequent in NMOSD with AQP4-IgG (92%) and least frequent in MOGAD (57%). The most frequent spinal movement disorders were tonic spasms (57%), focal dystonia (25%), spinal tremor (16%), spontaneous clonus (9.5%), secondary restless limb syndrome (9.5%), and spinal myoclonus (8%). Multivariate analysis showed that longitudinally extensive myelitis and AQP4-IgG are independent risk factors for the development of spinal movement disorders, while MOG-IgG and African American race were associated with a lower risk of developing these movement disorders. CONCLUSIONS: Spinal movement disorders are highly prevalent in non-MS demyelinating disorders of the spinal cord. Prevalence rates exceed those reported in MS and retrospective NMOSD studies.

Anismus-A Very Unusual Extrapyramidal Side Effect of Paliperidone Palmitate in an Adolescent with Schizo-Affective Disorder.

Here, authors report on an interesting case of an adolescent with a diagnosis of schizo-affective disorder, maintained on LAI paliperidone palmitate that developed an unusual dystonic reaction in form of anismus that masquerade as constipation and faecal impaction. To our knowledge, this is one of the earliest reports of antipsychotic-induced anismus notably in adolescent population. Clinicians should be mindful of unusual forms of dyskinesias that might be associated with high-potency antipsychotic use.