Efficacy and safety of riluzole for treating motor function in rare dyskinesia syndromes: a systematic review with meta-analysis.

OBJECTIVES: We conducted a systematic review and meta-analysis to evaluate the clinical effectiveness and safety of riluzole to treat neurodegenerative dyskinesia in patients, using the Cochrane collaboration guidelines. METHODS: We searched databases including Medline, Embase, and Cochrane without any language filters. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was used as a guideline, and the study protocol was registered in PROSPERO (CRD42022354627). RESULTS: Eleven studies involving 1376 patients were included. There was a significant overall effect of riluzole on changes in motor function scores. However, the level of heterogeneity was I2 = 74%. In the subgroup analyses, there were no significant effects of riluzole on motor scores in hereditary ataxia, Parkinson's disease, or Huntington's disease. In the sensitivity analysis, there were no significant effects of riluzole on motor function scores. Furthermore, there were no significant differences in adverse events between the riluzole and placebo groups. CONCLUSIONS: Although riluzole may not have significant efficacy for improving motor function in neurodegenerative dyskinesia syndromes compared with placebo, it seems to have an acceptable safety profile. Moreover, it may be effective for hereditary ataxia syndromes, although there was a relatively small effect size and limited quality of evidence.

Diabetic striatopathy: Hyperglycemic chorea/ballism successfully treated with L-dopa.

Diabetic striatopathy, a rare hyperglycemia complication, is characterized by chorea/ballism and striatal anomalies on neuroimaging, usually managed with glycemic control and haloperidol. However, practical strategies for haloperidol-resistant cases are scarce. We describe a 76-year-old Japanese woman with diabetic striatopathy who initially presented with polydipsia, polyuria, and lower-extremity weakness. Despite pronounced hyperglycemia (725 mg/dL), her blood glucose levels were reduced through saline infusion and intravenous insulin. Subsequently, she developed whole-body ballism concomitant with striatal hyperintensity on T1-weighted magnetic resonance imaging, which initially responded to haloperidol. Upon discontinuation of haloperidol, her symptoms relapsed and did not improve with the reintroduction of haloperidol. Dopamine transporter single photon emission computed tomography revealed diminished bilateral striatal uptake, suggesting presynaptic dopaminergic dysfunction. This finding prompted the initiation of L-dopa, which significantly improved her symptoms. This case underlines the need to consider presynaptic dopaminergic dysfunction in diabetic striatopathy patients unresponsive to standard treatments, highlighting the effectiveness of L-dopa in such scenarios.

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.

Safety and efficacy of continuous subcutaneous levodopa-carbidopa infusion (ND0612) for Parkinson's disease with motor fluctuations (BouNDless): a phase 3, randomised, double-blind, double-dummy, multicentre trial.

BACKGROUND: Conventional oral levodopa therapy for the treatment of Parkinson's disease can be associated with variations in plasma concentrations. Levodopa infusion strategies might provide more consistent drug delivery and fewer motor fluctuations. We aimed to assess the safety and efficacy of a continuous 24 h/day subcutaneous infusion of ND0612 (a levodopa-carbidopa solution) compared with oral immediate-release levodopa-carbidopa for the treatment of motor fluctuations in people with Parkinson's disease. METHODS: We conducted a phase 3, randomised, double-blind, double-dummy, active-controlled, multicentre trial at 117 academic and community neurology sites in 16 countries, including in Europe, Israel, and the USA. Eligible participants were men and women aged 30 years or older with a diagnosis of Parkinson's disease (Hoehn and Yahr stage ≤3 in the on state) who experienced at least 2·5 h/day of off time. Participants underwent an open-label run-in phase (<12 weeks), during which time optimal regimens were established for both oral immediate-release levodopa-carbidopa and for 24 h/day subcutaneous ND0612 infusion (levodopa-carbidopa 60·0/7·5 mg/mL), with supplemental oral levodopa-carbidopa if needed. Participants were then randomly assigned (1:1) to 12 weeks of double-blind treatment with their optimised regimen of either subcutaneous ND0612 or oral levodopa-carbidopa, with matching oral or subcutaneous placebo given as required to maintain blinding. Randomisation was done via an interactive web response system, stratified by region, using a permuted block schedule. Participants, study partners, treating investigators, study site personnel, and the sponsor were masked to treatment group allocation. The primary efficacy endpoint was the change from baseline (ie, time of randomisation, when all patients were receiving an optimised open-label ND0612 regimen) to end of the double-blind phase in total daily on time without troublesome dyskinesia, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, NCT04006210, and is complete. FINDINGS: Between Sept 30, 2019, and April 8, 2022, 381 participants were enrolled, of whom 259 (68%) were randomly assigned, 128 (49%) to subcutaneous ND0612 and 131 (51%) to oral levodopa-carbidopa. 243 (94%) participants completed the study. Treatment with subcutaneous ND0612 provided an additional 1·72 h (95% CI 1·08 to 2·36) of on time without troublesome dyskinesia compared with oral levodopa-carbidopa (change from baseline of -0·48 h [-0·94 to -0·02] with subcutaneous ND0612 vs -2·20 h [-2·65 to -1·74] with oral levodopa-carbidopa; p<0·0001). Significant treatment differences favouring subcutaneous ND0612 were also found in the first four of nine prespecified hierarchical outcomes of daily off time (-1·40 h [95% CI -1·99 to -0·80]), Movement Disorders Society-Unified Parkinson's Disease Rating Scale part II scores (-3·05 [-4·28 to -1·81]), Patients Global Impression of Change (odds ratio [OR] 5·31 [2·67 to 10·58]), and Clinical Global Impression of Improvement (OR 7·23 [3·57 to 14·64]). Hierarchical testing ended after the fourth secondary endpoint. Adverse events were reported by 287 (89%) of 322 participants during open-label ND0612 optimisation, and by 103 (80%) of 128 in the ND0612 group and 97 (74%) of 131 in the oral levodopa-carbidopa group during the double-blind phase. The most common adverse events were infusion-site reactions (266 [83%] participants during open-label ND0612, and 73 [57%] in the ND0612 group vs 56 [43%] in the oral levodopa-carbidopa group during the double-blind phase), most of which were mild. Serious adverse events in four participants in the ND0612 group were related to study treatment (infusion-site cellulitis [n=2], infusion-site abscess and infusion-site ulcer [n=1]; and paraesthesia and peripheral sensorimotor neuropathy [n=1]). One participant in the ND0612 group died during the double-blind phase, but the death was not related to study treatment (fall leading to traumatic brain injury). INTERPRETATION: Results of this phase 3 study showed that subcutaneous ND0612 used in combination with oral immediate-release levodopa-carbidopa increased on time without troublesome dyskinesia and reduced off time, with a favourable benefit-risk profile. ND0612 might offer a safe and efficacious subcutaneous levodopa infusion approach to managing motor fluctuations in people with Parkinson's disease. The ongoing open-label extension phase will provide further information on the long-term efficacy and safety of treatment. FUNDING: NeuroDerm.

Hyperglycemia-induced hemichorea-hemiballismus syndrome - a systematic review.

Nonketotic hyperglycemia may occur as a cause of chorea in patients with chronic decompensated diabetes. Because it is rare and consequently poorly studied, diagnosis and treatment can be delayed. Therefore, our objective was to summarize clinical and radiological features, as well as treatments performed, from previously reported cases to facilitate adequate management in clinical practice. We searched MEDLINE/PubMed, EMBASE, Cochrane, CINAHL, Web of Science, Scopus, and LILACS databases for studies published before April 23, 2021. We included case reports and case series of adults (aged ≥ 18 years) that described hyperglycemic chorea with measurement ofglycated hemoglobin (HbA1c) and cranial magnetic resonance imaging (MRI). Studies were excluded if participants were pregnant women, aged < 18 years, and had no description of chorea and/or physical examination. We found 121 studies that met the inclusion criteria, for a total of 214 cases. The majority of the included studies were published in Asia (67.3%). Most patients were women(65.3%) aged > 65 years (67.3%). Almost all patients had decompensated diabetes upon arrival at the emergency department (97.2%). The most common MRI finding was abnormalities of the basal ganglia (89.2%). There was no difference in patient recovery between treatment with insulin alone and in combination with other medications. Although rare, hyperglycemic chorea is a reversible cause of this syndrome; therefore, hyperglycemia should always be considered in these cases.

Botulinum neurotoxin as early treatment in acute-onset lesional hemiballism.

BACKGROUND: Hemiballism (HB) and hemichorea (HC) are the most frequent secondary movement disorders, usually caused by cerebrovascular diseases. In only a minority of cases, these involuntary movements are not self-limited, and they may severely compromise patients' quality of life, so that symptomatic treatments are required. Typical and atypical neuroleptics as well as tetrabenazine are considered therapies of choice. However, anecdotal reports of antiseizures medications and botulinum neurotoxin injection effectiveness have been described. METHODS: We described a case of severely disabling acute-onset lesional HB/HC, where high dosage of first- and second-line therapies was contraindicated due to patient's comorbidities. RESULTS: After botulin neurotoxin (BoNT) injections in his left upper limb muscles (biceps brachii, triceps brachii, teres major, and deltoid), the patient experienced gradual reduction of hyperkinetic movements. The gradual discontinuation of topiramate (TPM) did not worsen the clinical picture. DISCUSSION: The reduction of hyperkinetic movements led to rhabdomyolysis resolution as well as cutaneous injuries healing with renal function improvement, so that the patient was able to be eligible for rehabilitation, which was prevented by HB/HC itself. The clinical improvement was consistent with BoNT pharmacokinetic. The administration of BoNT early after the onset of lesional HB/HC remarkably modified the clinical management and drove toward comorbidities resolution and rehabilitation. CONCLUSION: The present case highlights the effectiveness of unconventional therapeutic options in disabling acute onset lesional HB/HC when first-line therapies are contraindicated. Particularly, this report may encourage BoNT application in the early stage of movement disorder emergencies.

Second-generation antipsychotics for Parkinson's disease psychosis: A systematic review and network meta-analysis.

OBJECTIVE: This network meta-analysis assessed the efficacy, tolerability, and acceptability of second-generation antipsychotics (SGAs) for Parkinson's disease psychosis (PDP). METHODS: We searched PubMed, Embase, Cochrane Library, and ClinicalTrials.gov for randomized controlled trials investigating SGAs for PDP up to October 26, 2023. RESULTS: We included 16 trials (N = 1252) investigating clozapine, melperone, olanzapine, pimavanserin, quetiapine, ulotaront, and placebo. In comparisons between SGAs and placebo, the findings were: i) Standardized mean differences, 95% confidence intervals (SMDs, 95%CIs), for psychotic-symptom reduction revealed the first rank of clozapine (-1.31, -1.73 to -0.89), the second rank of pimavanserin, with significant inferiority of quetiapine (SMD = 0.47, 0.02 to 0.92); ii) Mean differences (MDs, 95%CIs) for abnormal movement, as assessed by the Unified Parkinson's Disease Rating Scale - Part III, indicated that clozapine had the least motor side effects (-0.92, -2.75 to 0.91); iii) Risk ratios (RRs, 95% CIs) for adverse-effect dropout rates were lowest for melperone (1.02, 0.20 to 5.24); and iv) RRs (95% CIs) for all-cause dropout rates were lowest for clozapine (0.73, 0.42 to 1.25). CONCLUSIONS: For patients with PDP, clozapine may substantially reduce psychotic symptoms with minimal abnormal movement, high acceptability, and moderate overall tolerability. Pimavanserin, not quetiapine, could be an alternative.

Cath-KP, a novel peptide derived from frog skin, prevents oxidative stress damage in a Parkinson's disease model.

Parkinson's disease (PD) is a neurodegenerative condition that results in dyskinesia, with oxidative stress playing a pivotal role in its progression. Antioxidant peptides may thus present therapeutic potential for PD. In this study, a novel cathelicidin peptide (Cath-KP; GCSGRFCNLFNNRRPGRLTLIHRPGGDKRTSTGLIYV) was identified from the skin of the Asiatic painted frog ( Kaloula pulchra). Structural analysis using circular dichroism and homology modeling revealed a unique αßß conformation for Cath-KP. In vitro experiments, including free radical scavenging and ferric-reducing antioxidant analyses, confirmed its antioxidant properties. Using the 1-methyl-4-phenylpyridinium ion (MPP +)-induced dopamine cell line and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice, Cath-KP was found to penetrate cells and reach deep brain tissues, resulting in improved MPP +-induced cell viability and reduced oxidative stress-induced damage by promoting antioxidant enzyme expression and alleviating mitochondrial and intracellular reactive oxygen species accumulation through Sirtuin-1 (Sirt1)/Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway activation. Both focal adhesion kinase (FAK) and p38 were also identified as regulatory elements. In the MPTP-induced PD mice, Cath-KP administration increased the number of tyrosine hydroxylase (TH)-positive neurons, restored TH content, and ameliorated dyskinesia. To the best of our knowledge, this study is the first to report on a cathelicidin peptide demonstrating potent antioxidant and neuroprotective properties in a PD model by targeting oxidative stress. These findings expand the known functions of cathelicidins, and hold promise for the development of therapeutic agents for PD.

Metoclopramide-induced acute dystonic reaction: A pediatric case report.

INTRODUCTION: This case report presents a unique acute dystonic reaction (ADR) induced by metoclopramide in a 6-year-old male patient with pertussis-associated vomiting. The rarity of such a reaction in pediatric patients underscores the significance of this case in contributing to the scientific literature. This report highlights the need for heightened awareness of the potential adverse effects of medications commonly used in pediatrics and emphasizes the importance of tailored interventions for this population. MAIN SYMPTOMS AND IMPORTANT CLINICAL FINDINGS: Following the administration of metoclopramide for vomiting associated with pertussis cough, the patient exhibited distressing symptoms, including torticollis, facial grimacing, and tongue protrusion. These involuntary movements were promptly recognized, leading to the suspicion of an ADR. The clinical findings underscore the importance of vigilant monitoring for extrapyramidal symptoms following medication administration, especially in children. THE MAIN DIAGNOSES, THERAPEUTIC INTERVENTIONS, AND OUTCOMES: The primary diagnosis of ADR induced by metoclopramide was confirmed, prompting the cessation of the medication and the initiation of anticholinergic therapy with benztropine. This intervention rapidly resolved the patient's symptoms, highlighting the importance of tailored and swift therapeutic strategies. The outcome demonstrated the efficacy of timely intervention in managing ADR in pediatric patients. CONCLUSION: The main takeaway lesson from this case lies in the critical need for healthcare practitioners to remain vigilant for potential adverse reactions in pediatric patients, even when prescribing commonly used medications. The successful management of this case underscores the importance of prompt recognition, appropriate interventions, and continuous monitoring. Ultimately, this case contributes to the scientific literature by highlighting the unique manifestation of ADR in a pediatric patient, reinforcing the significance of individualized patient care and medication safety.