-
Journal of Neurology, Neurosurgery, and... Sep 2023Reliably applied criteria to differentiate functional from primary tics are lacking. In the absence of biological markers, the development of new diagnostic criteria to...
BACKGROUND
Reliably applied criteria to differentiate functional from primary tics are lacking. In the absence of biological markers, the development of new diagnostic criteria to assist clinicians is predicated on expert judgement and consensus. This study examines the level of diagnostic agreement of experts in tic disorders using video footage and clinical descriptions.
METHODS
Using a two-part survey, eight experts in the diagnosis and management of tics were first asked to study 24 case videos of adults with primary tics, functional tics or both and to select a corresponding diagnosis. In the second part of the survey, additional clinical information was provided, and the diagnosis was then reconsidered. Inter-rater agreement was measured using Fleiss' kappa. In both study parts, the factors which influenced diagnostic decision-making and overall diagnostic confidence were reviewed.
RESULTS
Based on phenomenology alone, the diagnostic agreement among the expert raters was only fair for the pooled diagnoses (κ=0.21) as well as specifically for functional (κ=0.26) and primary tics (κ=0.24). Additional clinical information increased overall diagnostic agreement to moderate (κ=0.51) for both functional (κ=0.6) and primary tics (κ=0.57). The main factors informing diagnosis were tic semiology, age at tic onset, presence of premonitory urges, tic suppressibility, the temporal latency between tic onset and peak severity, precipitants and tic triggers and changes in the overall phenotypic presentation.
CONCLUSIONS
This study confirmed that in the absence of clinical information, the diagnostic distinction between primary and functional tics is often difficult, even for expert clinicians.
Topics: Adult; Humans; Tics; Tourette Syndrome; Tic Disorders
PubMed: 37169545
DOI: 10.1136/jnnp-2022-330822 -
CNS Drugs Apr 2024Drug-induced movement disorders (DIMDs) are associated with use of dopamine receptor blocking agents (DRBAs), including antipsychotics. The most common forms are... (Review)
Review
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.
Topics: Humans; Aged; Dystonia; Cholinergic Antagonists; Psychomotor Agitation; Movement Disorders; Tardive Dyskinesia; Antipsychotic Agents; Neuroleptic Malignant Syndrome; Dystonic Disorders
PubMed: 38502289
DOI: 10.1007/s40263-024-01078-z -
Frontiers in Immunology 2023The frequency of antibodies in autoimmune encephalitis (AIE) may vary in different populations, however, data from developing countries are lacking. To describe the...
BACKGROUND
The frequency of antibodies in autoimmune encephalitis (AIE) may vary in different populations, however, data from developing countries are lacking. To describe the clinical profile of AIE in Brazil, and to evaluate seasonality and predictors of AIE in adult and pediatric patients.
METHODS
We evaluated patients with possible AIE from 17 centers of the Brazilian Autoimmune Encephalitis Network (BrAIN) between 2018 and 2022. CSF and serum were tested with TBAs and CBAs. Data on clinical presentation, complementary investigation, and treatment were compiled. Seasonality and predictors of AIE in adult and pediatric populations were analyzed.
RESULTS
Of the 564 patients, 145 (25.7%) were confirmed as seropositive, 69 (12.23%) were seronegative according to Graus, and 58% received immunotherapy. The median delay to diagnosis confirmation was 5.97 ± 10.3 months. No seasonality variation was observed after 55 months of enrolment. The following antibodies were found: anti-NMDAR (n=79, 54%), anti-MOG (n=14, 9%), anti-LGI1(n=12, 8%), anti-GAD (n=11, 7%), anti-GlyR (n=7, 4%), anti-Caspr2 (n=6, 4%), anti-AMPAR (n=4, 2%), anti-GABA-BR (n=4, 2%), anti-GABA-AR (n=2, 1%), anti-IgLON5 (n=1, 1%), and others (n=5, 3%). Predictors of seropositive AIE in the pediatric population (n=42) were decreased level of consciousness (p=0.04), and chorea (p=0.002). Among adults (n=103), predictors of seropositive AIE were movement disorders (p=0.0001), seizures (p=0.0001), autonomic instability (p=0.026), and memory impairment (p=0.001).
CONCLUSION
Most common antibodies in Brazilian patients are anti-NMDAR, followed by anti-MOG and anti-LGI1. Only 26% of the possible AIE patients harbor antibodies, and 12% were seronegative AIE. Patients had a 6-month delay in diagnosis and no seasonality was found. Findings highlight the barriers to treating AIE in developing countries and indicate an opportunity for cost-effect analysis. In this scenario, some clinical manifestations help predict seropositive AIE such as decreased level of consciousness, chorea, and dystonia among children, and movement disorders and memory impairment among adults.
Topics: Adult; Humans; Child; Brazil; Chorea; Brain; Antibodies; Receptors, N-Methyl-D-Aspartate; Autoimmune Diseases of the Nervous System
PubMed: 37954587
DOI: 10.3389/fimmu.2023.1256480 -
Scientific Reports Nov 2023Ataxia telangiectasia is a monogenetic disorder caused by mutations in the ATM gene. Its encoded protein kinase ATM plays a fundamental role in DNA repair of double...
Ataxia telangiectasia is a monogenetic disorder caused by mutations in the ATM gene. Its encoded protein kinase ATM plays a fundamental role in DNA repair of double strand breaks (DSBs). Impaired function of this kinase leads to a multisystemic disorder including immunodeficiency, progressive cerebellar degeneration, radiation sensitivity, dilated blood vessels, premature aging and a predisposition to cancer. Since allogenic hematopoietic stem cell (HSC) transplantation improved disease outcome, gene therapy based on autologous HSCs is an alternative promising concept. However, due to the large cDNA of ATM (9.2 kb), efficient packaging of retroviral particles and sufficient transduction of HSCs remains challenging.We generated lentiviral, gammaretroviral and foamy viral vectors with a GFP.F2A.Atm fusion or a GFP transgene and systematically compared transduction efficiencies. Vector titers dropped with increasing transgene size, but despite their described limited packaging capacity, we were able to produce lentiviral and gammaretroviral particles. The reduction in titers could not be explained by impaired packaging of the viral genomes, but the main differences occurred after transduction. Finally, after transduction of Atm-deficient (ATM-KO) murine fibroblasts with the lentiviral vector expressing Atm, we could show the expression of ATM protein which phosphorylated its downstream substrates (pKap1 and p-p53).
Topics: Animals; Mice; Ataxia Telangiectasia; Genome, Viral; Transgenes; Genotype; Genetic Therapy
PubMed: 37938627
DOI: 10.1038/s41598-023-46332-4 -
Neurological Sciences : Official... Apr 2024Zonisamide (ZNS) has shown some efficacy in motor symptoms of PD; however, more evidence is lacking, and its effects on nonmotor symptoms (NMSs) and quality of life... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Zonisamide (ZNS) has shown some efficacy in motor symptoms of PD; however, more evidence is lacking, and its effects on nonmotor symptoms (NMSs) and quality of life (QoL) remain to be investigated. This randomized double-blinded placebo-controlled crossover study investigated the effect of ZNS on motor and NMS symptoms and QoL in advanced PD.
METHODS
PD patients with Hoehn and Yahr stage ≥ 2 ("On" state) and at least 2 h off time daily were randomized to groups: ZNS 25 mg, ZNS 50 mg and placebo. Groups were assessed at baseline and at the 1- and 3-month follow-ups. The primary endpoint was the change in the total MDS-UPDRS III "On", while the secondary endpoint was the change in the total and parts I and IV MDS-UPDRS, Nonmotor Symptoms Scale and Parkinson's disease questionnaire-39 at the final assessment.
RESULTS
Sixty-nine patients were assessed for efficacy at the 1-month follow-up, and 58 patients were assessed at the 3-month follow-up. The primary endpoint showed significant improvement in the ZNS 25 mg group compared to the placebo group (p = 0.009). At the final assessment, the ZNS 25 mg group showed significant improvement of total and part VI MDS-UPDRS, bradykinesia, tremor and functional impact of fluctuations compared to placebo. There was no change in dyskinesia, NMSs, QoL or side effects except for sedation.
CONCLUSION
ZNS has a favourable effect on motor symptoms in patients with wearing off as adjunctive therapy with other dopaminergic drugs, with no exacerbation of dyskinesia and a limited impact on NMSs and QoL.
TRIAL REGISTRATION
Clinicaltrials.gov, NCT04182399, in 24/11/2019.
Topics: Humans; Zonisamide; Parkinson Disease; Quality of Life; Cross-Over Studies; Tremor
PubMed: 38376645
DOI: 10.1007/s10072-024-07396-w -
Advances in Therapy Sep 2023Spasticity and cervical dystonia (CD) are movement disorders with considerable direct and indirect healthcare cost implications. Although several studies have discussed...
INTRODUCTION
Spasticity and cervical dystonia (CD) are movement disorders with considerable direct and indirect healthcare cost implications. Although several studies have discussed their clinical impact, few have calculated the economic burden of these disorders. This study aimed to understand treatment/injection patterns of botulinum toxins type A (BoNT-As) and the characteristics, healthcare resource utilization (HCRU), and costs among patients with spasticity or CD.
METHODS
Retrospective analyses were conducted using administrative healthcare claims from the IQVIA PharMetrics Plus database, from October 1, 2015 to December 31, 2019. Eligible patients were selected based on Healthcare Common Procedure Coding System codes for BoNT-A (index date) and ICD-10 diagnosis codes for spasticity or CD with 6 months of continuous enrollment pre-index and 12 months post-index. Patients were stratified into adult spasticity, pediatric spasticity, and CD cohorts, and were evaluated for injection patterns, HCRU, and costs in the post-index period.
RESULTS
Overall, 2452 adults with spasticity, 1364 pediatric patients with spasticity, and 1529 adults with CD were included. Total mean all-cause healthcare costs were US$42,562 (adult spasticity), $54,167 (pediatric spasticity), and $25,318 (CD). Differences were observed in the cost of BoNT-A injection visits between toxins, with abobotulinumtoxinA (aboBoNT-A) having the lowest injection cost across all indications.
CONCLUSIONS
AboBoNT-A had the lowest injection visit costs across indications. These results are suggestive of real-world resource utilization patterns and costs, and, while helpful in informing insurers' BoNT-A management strategies, further research into cost differences is warranted.
Topics: Adult; Humans; Child; Torticollis; Neuromuscular Agents; Retrospective Studies; Botulinum Toxins, Type A; Muscle Spasticity; Health Care Costs; Treatment Outcome
PubMed: 37414904
DOI: 10.1007/s12325-023-02563-5 -
Revue Neurologique May 2024Genetic cerebellar ataxias are still a diagnostic challenge, and yet not all of them have been identified. Very recently, in early 2023, a new cause of late-onset... (Review)
Review
Genetic cerebellar ataxias are still a diagnostic challenge, and yet not all of them have been identified. Very recently, in early 2023, a new cause of late-onset cerebellar ataxia (LOCA) was identified, spinocerebellar ataxia 27B (SCA27B). This is an autosomal dominant ataxia due to a GAA expansion in intron 1 of the FGF14 gene. Thanks to the many studies carried out since its discovery, it is now possible to define the clinical phenotype, its particularities, and the progression of SCA27B. It has also been established that it is one of the most frequent causes of LOCA. The core phenotype of the disease consists of slowly progressive late-onset ataxia with cerebellar syndrome, oculomotor disorders including downbeat nystagmus, and episodic symptoms such as diplopia. Therapeutic approaches have been proposed, including acetazolamide, and 4-aminopyridine, the latter with a better benefit/tolerance profile.
Topics: Humans; Spinocerebellar Ataxias; Age of Onset; Cerebellar Ataxia; Fibroblast Growth Factors; Spinocerebellar Degenerations
PubMed: 38609751
DOI: 10.1016/j.neurol.2024.03.007 -
Parkinsonism & Related Disorders Oct 2023Previous studies have suggested an association between Impulsive Compulsive Behaviour (ICB) and dyskinesia in Parkinson's disease (PD). However, none of these studies...
INTRODUCTION
Previous studies have suggested an association between Impulsive Compulsive Behaviour (ICB) and dyskinesia in Parkinson's disease (PD). However, none of these studies have employed an objective home-based measure of dyskinesia.
OBJECTIVES
To evaluate in advanced PD the relationship between ICB and dyskinesia, objectively measured with a wearable device.
METHODS
In this cross-sectional study, ICB and other neuropsychiatric symptoms were assessed by means of structured clinical interview and specific screening instruments. Presence and severity of motor fluctuations and dyskinesia were rated with patient's and clinician's based rating instruments. Motor fluctuations and dyskinesia were also measured at home for 5-days using a validated wearable devise, the Parkinson's KinetiGraph™(PKG).
RESULTS
We included 89 subjects with PD (29 females, 62 ± 7 years, disease duration 10.3 ± 4.5), of whom 36 (40%) had ICB. Patients with and without ICB did not differ by presence and severity of dyskinesia measured by clinical scales and PKG. There was no association between the presence of ICB and dyskinesia in the whole sample.
CONCLUSION
Our data suggest that ICB and dyskinesia are common but unrelated disorders in advanced PD.
Topics: Female; Humans; Parkinson Disease; Cross-Sectional Studies; Impulsive Behavior; Dyskinesias; Compulsive Behavior
PubMed: 37669582
DOI: 10.1016/j.parkreldis.2023.105813 -
Tremor and Other Hyperkinetic Movements... 2024Tardive Dyskinesia (TD) is a neurological disorder characterized by involuntary movements, often caused by dopamine receptor antagonists. Vesicular Monoamine Transporter... (Comparative Study)
Comparative Study Review
BACKGROUND
Tardive Dyskinesia (TD) is a neurological disorder characterized by involuntary movements, often caused by dopamine receptor antagonists. Vesicular Monoamine Transporter 2 (VMAT2) inhibitors, such as valbenazine and deutetrabenazine, have emerged as promising therapies for TD and several clinical trials have shown their efficacy. This study aims to compare the efficacy and safety profile of VMAT2 inhibitors, focusing on a recent trial conducted in the Asian population.
METHODS
We reviewed the PubMed, Cochrane Library, Embase database, and clinicaltrials.gov between January 2017 and October 2023, using the keywords "tardive dyskinesia" AND ("valbenazine" [all fields] OR " deutetrabenazine " [all fields]) AND "clinical trial". The reviewed articles were studied for efficacy and side effects.
RESULTS
An initial search yielded 230 articles, of which 104 were duplicates. Following the title and abstract screening, 25 additional articles were excluded. A full-text review resulted in the exclusion of 96 more articles. Ultimately, four double-blind clinical trials met the inclusion criteria. The deutetrabenazine studies demonstrated significant improvements in Abnormal Involuntary Movement Scale (AIMS) scores compared to placebo, with no difference in adverse events. The valbenazine studies showed favorable results in reducing TD symptoms and were well-tolerated.
DISCUSSION
The studies reviewed in this analysis underscore the potential of deutetrabenazine and valbenazine as valuable treatment options for TD in diverse populations. Both medications demonstrated significant improvements in AIMS scores, suggesting their effectiveness in managing TD symptoms. Additionally, they exhibited favorable safety profiles, with low rates of serious adverse events and no significant increase in QT prolongation, parkinsonism, suicidal ideation, or mortality.
CONCLUSION
The studies reviewed highlight the promising efficacy and tolerability of deutetrabenazine and valbenazine as treatments for Tardive Dyskinesia, providing new hope for individuals affected by this challenging condition.
Topics: Humans; Randomized Controlled Trials as Topic; Tardive Dyskinesia; Tetrabenazine; Valine; Vesicular Monoamine Transport Proteins
PubMed: 38497033
DOI: 10.5334/tohm.842 -
EBioMedicine Jan 2024SCA27B caused by FGF14 intronic heterozygous GAA expansions with at least 250 repeats accounts for 10-60% of cases with unresolved cerebellar ataxia. We aimed to assess...
BACKGROUND
SCA27B caused by FGF14 intronic heterozygous GAA expansions with at least 250 repeats accounts for 10-60% of cases with unresolved cerebellar ataxia. We aimed to assess the size and frequency of FGF14 expanded alleles in individuals with cerebellar ataxia as compared with controls and to characterize genetic and clinical variability.
METHODS
We sized this repeat in 1876 individuals from France sampled for research purposes in this cross-sectional study: 845 index cases with cerebellar ataxia and 324 affected relatives, 475 controls, as well as 119 cases with spastic paraplegia, and 113 with familial essential tremor.
FINDINGS
A higher frequency of expanded allele carriers in index cases with ataxia was significant only above 300 GAA repeats (10.1%, n = 85) compared with controls (1.1%, n = 5) (p < 0.0001) whereas GAA alleles were detected in 1.7% of both groups. Eight of 14 index cases with GAA repeats had other causal pathogenic variants (4/14) and/or discordance of co-segregation (5/14), arguing against GAA causality. We compared the clinical signs in 127 GAA carriers to cases with non-expanded GAA ataxia resulting in defining a key phenotype triad: onset after 45 years, downbeat nystagmus, episodic ataxic features including diplopia; and a frequent absence of dysarthria. All maternally transmitted alleles above 100 GAA were unstable with a median expansion of +18 repeats per generation (r = 0.44; p < 0.0001). In comparison, paternally transmitted alleles above 100 GAA mostly decreased in size (-15 GAA (r = 0.63; p < 0.0001)), resulting in the transmission bias observed in SCA27B pedigrees.
INTERPRETATION
SCA27B diagnosis must consider both the phenotype and GAA expansion size. In carriers of GAA repeats, the absence of documented familial transmission and a presentation deviating from the key SCA27B phenotype, should prompt the search for an alternative cause. Affected fathers have a reduced risk of having affected children, which has potential implications for genetic counseling.
FUNDING
This work was supported by the Fondation pour la Recherche Médicale, grant number 13338 to JLM, the Association Connaître les Syndrome Cérébelleux - France (to GS) and by the European Union's Horizon 2020 research and innovation program under grant agreement No 779257 ("SOLVE-RD" to GS). DP holds a Fellowship award from the Canadian Institutes of Health Research (CIHR). SK received a grant (01GM1905C) from the Federal Ministry of Education and Research, Germany, through the TreatHSP network. This work was supported by the Australian Government National Health and Medical Research Council grants (GNT2001513 and MRFF2007677) to MB and PJL.
Topics: Child; Humans; Ataxia; Australia; Canada; Cerebellar Ataxia; Cross-Sectional Studies; Friedreich Ataxia
PubMed: 38150853
DOI: 10.1016/j.ebiom.2023.104931