Real-world experience with Deutetrabenazine management in patients with Huntington's disease using video-based telemedicine.

BACKGROUND: Huntington's disease (HD) is a rare progressive neurological disorder, and telemedicine has the potential to improve the quality of care for patients with HD. Deutetrabenazine (DTBZ) can reduce chorea symptoms in HD; however, there is limited experience with this medication in Asian countries. METHODS: Retrospective and prospective studies were employed to explore the feasibility and reliability of a video-based telemedicine system for HD patient care. Reliability was demonstrated through consistency between selected-item scores (SIS) and total motor scores (TMS) and the agreement of scores obtained from hospital and home videos. Finally, a single-centre real-world DTBZ management study was conducted based on the telemedicine system to explore the efficacy of DTBZ in patients with HD. RESULTS: There were 77 patients included in the retrospective study, and a strong correlation was found between SIS and TMS (r = 0.911, P < 0.0001), indicating good representativeness. There were 32 patients enrolled in the prospective study. The reliability was further confirmed, indicated by correlations between SIS and TMS (r = 0.964, P < 0.0001) and consistency of SIS derived from the in-person and virtual visits (r = 0.969, P < 0.0001). There were 17 patients included in the DTBZ study with a mean 1.41 (95% confidence interval, 0.37-2.46) improvement in chorea score and reported treatment success. CONCLUSIONS: A video-based telemedicine system is a feasible and reliable option for HD patient care. It may also be used for drug management as a supplementary tool for clinical visits.

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.

Systematic review of drug therapy for chorea in NXK2-1-related disorders: Efficacy and safety evidence from case studies and series.

BACKGROUND: The NKX2-1-related disorders (NKX2-1-RD) is a rare disorder characterized by choreiform movements along with respiratory and endocrine abnormalities. The European Reference Network of Rare Neurological Disorders funded by the European Commission conducted a systematic review to assess drug treatment of chorea in NKX2-1-RD, aiming to provide clinical recommendations for its management. METHODS: A systematic pairwise review using various databases, including MEDLINE, Embase, Cochrane, CINAHL, and PsycInfo, was conducted. The review included patients diagnosed with chorea and NKX2-1-RD genetic diagnosis, drug therapy as intervention, no comparator, and outcomes of chorea improvement and adverse events. The methodological quality of the studies was assessed, and the study protocol was registered in PROSPERO. RESULTS: Of the 1417 studies examined, 28 studies met the selection criteria, consisting of 68 patients. The studies reported 22 different treatments for chorea, including carbidopa/levodopa, tetrabenazine, clonazepam, methylphenidate, carbamazepine, topiramate, trihexyphenidyl, haloperidol, propranolol, risperidone, and valproate. No clinical improvements were observed with carbidopa/levodopa, tetrabenazine, or clonazepam, and various adverse effects were reported. However, most patients treated with methylphenidate experienced improvements in chorea and reported only a few negative effects. The quality of evidence was determined to be low. CONCLUSIONS: The management of chorea in individuals with NKX2-1-RD presents significant heterogeneity and lack of clarity. While the available evidence suggests that methylphenidate may be effective in improving chorea symptoms, the findings should be interpreted with caution due to the limitations of the studies reviewed. Nonetheless, more rigorous and comprehensive studies are necessary to provide sufficient evidence for clinical recommendations.

A proof-of-concept study with SOM3355 (bevantolol hydrochloride) for reducing chorea in Huntington's disease.

AIMS: The study's aim is to investigate the efficacy and safety of SOM3355 (bevantolol hydrochloride), a ß1 -adrenoreceptor antagonist with recently identified vesicular monoamine transporter type 2 inhibitory properties, as a repositioned treatment to reduce chorea in Huntington's disease (HD). METHODS: A randomized, placebo-controlled proof-of-concept study was performed in 32 HD patients allocated to 2 arms of 4 sequential 6-week periods each. Patients received placebo and SOM3355 at 100 and 200 mg twice daily in a crossover design. The primary endpoint was improvement by at least 2 points in the total maximal chorea score in any active drug period compared with the placebo period. RESULTS: The primary endpoint was met in 57.1% of the patients. Improvements ≥3, ≥4, ≥5 and ≥6 points vs. placebo treatment were observed in 28.6, 25.0, 17.9 and 10.7% of the patients, respectively. A mixed-model analysis found a significant improvement in the total maximal chorea score of -1.14 (95% confidence interval, -2.11 to -0.16; P = .0224) with 200 mg twice daily SOM3355 treatment compared with placebo treatment. These results were paralleled by Clinical and Patient Global Impression of Change ratings (secondary endpoints). An elevation in plasma prolactin levels by 1.7-1.9-fold was recorded (P < .005), probably reflecting the effect on the dopamine pathway, consistent with vesicular monoamine transporter type 2 inhibition. The most frequent adverse events during SOM3355 administration were mild to moderate. CONCLUSION: Within the limits of this study, the results suggest that SOM3355 reduces chorea in patients with HD and is well-tolerated. Larger studies are necessary to confirm its therapeutic utility as an antichoreic drug. EudraCT number: 2018-000203-16 and ClinicalTrials.gov Identifier: NCT03575676.

Diabetic striatopathy: a case report.

Diabetic striatopathy, a rare condition also known as hyperglycemic nonketotic hemichorea, is characterized by chorea or hemiballismus and distinctive basal ganglia abnormalities visible on neuroimaging. We present the case of an 86-year-old woman with diabetic striatopathy exhibiting hemichorea. She had a history of poorly controlled type 2 diabetes and presented with involuntary movements of her left limb along with facial expressions suggestive of chorea. Laboratory tests confirmed hyperglycemia, with an elevated hemoglobin A1c level. Neuroimaging revealed T1-hyperintensity in the right basal ganglia. The patient was diagnosed with diabetic striatopathy and responded well to intensive insulin therapy with a rapid resolution of symptoms.

Sydenham chorea in the top end of Australia's Northern Territory: A 20-year retrospective case series.

AIM: Sydenham chorea is an immune-mediated neuropsychiatric condition, and a major criterion for diagnosis of acute rheumatic fever (ARF). Children in remote Northern Australia experience disproportionately high rates of ARF, yet studies looking at the epidemiology, clinical presentation and management of Sydenham chorea are limited in this population. METHODS: We conducted a retrospective case series from January 2002 to April 2022 of all paediatric patients aged ≤18 years admitted to Royal Darwin Hospital with Sydenham chorea. Cases were identified using the hospital's clinical coding system (ICD10). Medical records were reviewed and data on demographics, clinical presentation, investigation results, treatment and outcome were extracted, deidentified and analysed. RESULTS: One hundred ten presentations of Sydenham chorea occurred between 2002 and 2022, 109 (99%) of these were in First Nations children, with 85% residing in very remote locations. Most commonly, chorea presented as a generalised movement disorder affecting all four limbs (49%). Neuropsychiatric symptoms were reported in 33 (30%), and there was evidence of rheumatic heart disease on echocardiogram in 86 (78%) at presentation. All patients received benzathine penicillin, but there was significant variation in management of chorea, ranging from supportive management, to symptomatic management with anticonvulsants, to immunomodulatory medications including corticosteroids. CONCLUSION: This case series highlights the significant burden of Sydenham chorea among First Nations children living in Northern Australia and demonstrates wide variation in treatment approaches. High-quality clinical trials are required to determine the best treatment for this disabling condition.

Is diabetic striatopathy the culprit of seizures in a patient with ketotic hyperglycemia-induced hemichorea-hemiballismus?

BACKGROUND: Diabetic striatopathy is a rare neurological manifestation of nonketotic hyperglycemia that presents with contralateral hemichorea-hemiballismus. Presentation with concurrent seizures is rarely reported. CLINICAL PRESENTATION: We report a case of diabetic striatopathy presenting with focal and generalized tonic-clonic seizures (GTCS) with right hemichorea-hemiballismus induced by a ketotic hyperglycemic state. Head MRI showed high T1-weighted signal intensity in the left lentiform nucleus with no significant diffusion restriction or postcontrast enhancement. The patient's condition gradually improved, with seizure control on AEDs. Hemichorea-hemiballismus significantly improved with adequate blood sugar control and resolved with low-dose haloperidol. CONCLUSIONS: Diabetic striatopathy presenting with hemichorea-hemiballismus and concurrent GTCS has been reported previously in two cases; however, it has never been reported in ketotic hyperglycemia. To the best of our knowledge, we herein report the first case report of focal and generalized seizures in a ketotic hyperglycemic state and mesial temporal sclerosis.

Treatment-resistant diabetic chorea manifesting with psychiatric symptoms: a case report.

We report a case of a 69-year-old man with treatment-resistant diabetic chorea presenting psychiatric symptoms. The right chorea lasted for 3 months and was refractory to control of diabetes mellitus or administration of haloperidol and benzodiazepines. Only administration of tiapride was efficacious. Magnetic resonance spectrometry and dopamine transporter-single photon emission computed tomography suggested that sustained ischemia at the striatum may lead to impaired expression of dopamine transporters, thereby resulting in deterioration in the indirect pathway. Tiapride inhibited dopamine D2 receptors, thereby restoring the function of the indirect pathway and resulting in improvement of diabetic chorea.

Successful Rituximab Therapy for Pediatric Antiphospholipid-Related Chorea: A Case Report and Review of the Literature.

Chorea is considered a nonthrombotic manifestation of the antiphospholipid syndrome, often preceding thrombotic events in children. It can be present in up to 5% of pediatric patients with antiphospholipid syndrome. Immunomodulatory treatment regimens seem to be successful in these patients, emphasizing the underlying immunological etiology. Corticosteroids are considered first-line treatment, but chorea tends to be therapy-resistant and guidelines about second-line therapy in children are solely based on small case studies. We present a case of a therapy-resistant chorea, successfully treated with rituximab. Furthermore, we give an overview of the existing literature concerning rituximab for the treatment of chorea in children. Our findings indicate that rituximab can be considered a safe option to treat antiphospholipid syndrome-related chorea in children.

Recent developments in the management of Huntington's disease.

Huntington's disease (HD) is a rare, incurable, inheritedneurodegenerative disorder manifested by chorea, hyperkinetic, and hypokinetic movements. The FDA has approved only two drugs, viz. tetrabenazine, and deutetrabenazine, to manage the chorea associated with HD. However, several other drugs are used as an off-label to manage chorea and other symptoms such as depression, anxiety, muscle tremors, and cognitive dysfunction associated with HD. So far, there is no disease-modifying treatment available. Drug repurposing has been a primary drive to search for new anti-HD drugs. Numerous molecular targets along with a wide range of small molecules and gene therapies are currently under clinical investigation. More than 200 clinical studies are underway for HD, 75% are interventional, and 25% are observational studies. The present review discusses the small molecule clinical pipeline and molecular targets for HD. Furthermore, the biomarkers, diagnostic tests, gene therapies, behavioral and observational studies for HD were also deliberated.

Pimozide and pancreatic cancer in diabetic chorea: a case report.

PURPOSE/AIM: Diabetic chorea is a rare movement disorder associated with diabetes mellitus. We report the case of a patient that benefited from pimozide and died of pancreatic cancer. CASE REPORT: A 70-year-old woman presented with pollakiuria and involuntary movements of left limbs since three months. Laboratory tests revealed high serum levels of glycemia and glycated haemoglobin. She was admitted to internal medicine department and discharged one week later: insulin was administered with normalization of blood glucose levels and the involuntary movements gradually disappeared. Three weeks later she was admitted to neurological department due to the recurrence of the involuntary movements. Glycemia and other routine laboratory tests were normal. Neurological examination showed choreic movements involving left limbs. MRI showed a hyperintensity on T1- and T2-weighted sequences of right putamen and caudate nucleus head. Haloperidol was administered without improvement, it was successively substituted with tetrabenazine and the patient was discharged with an unvaried clinical picture. Two months later tetrabenazine was discontinued because of inefficacy and pimozide was started. The choreic movements considerably diminished after few days. Four months later, a pancreatic cancer was diagnosed and the patient died in the same month. CONCLUSION: Clinical and radiological features were suggestive of diabetic chorea. Our patient benefited exclusively from pimozide, it could be reasonable to use pimozide in resistant form and also propose it as first choice treatment. Another important element is the diagnosis of pancreatic cancer some months after chorea onset: a causal link could exist.

Acute Rheumatic Fever: Case Report and Literature Review.

A previously healthy 8-year-old Native American female presented with right-sided weakness and joint pain for two weeks. Following an initially unremarkable workup including negative brain and spine MRI she was noticed to have chorea and subsequently diagnosed with acute rheumatic fever (ARF). ARF is a group A streptococcus-related disease that most commonly is a sequelae of pharyngitis. The diagnosis of ARF utilizes the Jones criteria which includes heart disease, arthritis, chorea, the characteristic rash of erythema marginatum, and subcutaneous nodules. The most serious consequences of ARF include rheumatic heart disease and chorea. ARF can be treated with a combination of antibiotics and anti-inflammatories like aspirin.

A novel therapeutic approach using the Zipper method to treat chorea in a pediatric-onset systemic lupus erythematosus patient.

Pediatric-onset systemic lupus erythematosus is among the prototypic systemic autoimmune diseases seen in children. Although the neuropsychiatric involvement rate varies during the course of the disease, it is an important cause of morbidity and mortality. The clinical picture of neuropsychiatric SLE (NPSLE) is highly variable, and neurological features can precede systemic findings, leading to some diagnostic difficulties. NPSLE requires early and aggressive immunosuppressive therapy. Some patients can be resistant to immunosuppressive therapy. Chorea is a rare manifestation that occurs in 1.2%-2% of SLE patients and can result from an immunologically mediated mechanism, antiphospholipid autoantibodies or ischemia. Herein we present the first case of pediatric-onset SLE diagnosed with central nervous system involvement and treated with Zipper method. The Zipper method is a new immunomodulation treatment. The clinical findings of the patient, which were resistant to corticosteroids and cyclophosphamide, resolved by this novel treatment.

Antidopaminergic treatment is associated with reduced chorea and irritability but impaired cognition in Huntington's disease (Enroll-HD).

OBJECTIVES: Alterations in dopamine neurotransmission underlie some of the clinical features of Huntington's disease (HD) and as such are a target for therapeutic intervention, especially for the treatment of chorea and some behavioural problems. However, justification for such an intervention is mainly based on case reports and small open label studies and the effects these drugs have on cognition in HD remain unclear. METHODS: In this study, we used the Enroll-HD observational database to assess the effects of antidopaminergic medication on motor, psychiatric and cognitive decline, over a 3-year period. We first looked at the annual rate of decline of a group of HD patients taking antidopaminergic medication (n=466) compared with an untreated matched group (n=466). The groups were matched on specified clinical variables using propensity score matching. Next, we studied a separate group of HD patients who were prescribed such medications part way through the study (n=90) and compared their rate of change before and after the drugs were introduced and compared this to a matched control group. RESULTS: We found that HD patients taking antidopaminergic medication had a slower progression in chorea and irritability compared with those not taking such medications. However, this same group of patients also displayed significantly greater rate of decline in a range of cognitive tasks. CONCLUSION: In conclusion we found that antidopaminergic treatment is associated with improvements in the choreic movements and irritability of HD but worsens cognition. However, further research is required to prospectively investigate this and whether these are causally linked, ideally in a double-blind placebo-controlled trial.

Preliminary data on prednisone effectiveness in children with Sydenham chorea.

The objective of the study is to evaluate the efficacy of corticosteroids in Sydenham chorea. This is a retrospective observational study. Clinical information of children with Sydenham chorea were collected. Outcome of Sydenham chorea was evaluated in consideration of presence or absence of corticosteroid therapy. Thirty patients were enrolled. A total of 15 were treated with prednisone, 15 received symptomatic drugs or no treatment. Patients who were treated with prednisone showed faster improvement (4 vs 16 days; p = 0.002) and shorter median time of remission (30 vs 135 days; p < 0.001).Conclusion: Our study showed that corticosteroid therapy is an effective treatment of Sydenham chorea.What is Known:• Steroid treatment in Sydenham chorea is widely used but it is not standardized.• Few manuscript report a beneficial use of steroids in Sydenham chorea if compared with no treatment.What is New:• Steroid treatment seems to be effective in both clinical remission and clinical improvement of symptoms among patients with Sydenham chorea.• Steroid treatment seems to be superior to conventional treatment.

Efficacy of levetiracetam in the treatment of Sydenham chorea.

BACKGROUND: To study the effect of levetiracetam in treating Sydenham chorea. METHODS: We retrospectively collected the data of 140 patients diagnosed with Sydenham chorea in the pediatric neurology and pediatric cardiology outpatient clinics of Van Training and Research Hospital between January 2010 and December 2018. RESULTS: There were 140 patients, 102 (70%) of whom were girls, with mean age of onset 11.8 ± 2.7 years. Symptomatic treatment was initiated in all patients at the time of diagnosis; this medication was changed during follow up in 15 patients. The most frequently prescribed drugs were haloperidol and sodium (Na) valproate, and the most frequently discontinued one was haloperidol, due to side effects. The second-choice drug was most often levetiracetam. Clinical response often began within the first 2 weeks, with Na valproate (P = 0.002), within 4 weeks with carbamazepine (P = 0.037) but 1-6 months with haloperidol (P = 0.018) and levetiracetam (P = 0.008). Time to full remission was similar with Na valproate, carbamazepine, haloperidol, and levetiracetam (P = 0.276). Our study indicated that levetiracetam was as effective as the other commonly used drugs in the symptomatic treatment of Sydenham chorea. CONCLUSION: Levetiracetam might be an option in the treatment of Sydenham chorea because of its acceptable effect and safety profile. This observation needs further support with evidence obtained through controlled and blinded trials.

Treatment of Movement Disorder Emergencies in Autoimmune Encephalitis in the Neurosciences ICU.

Immune response against neuronal and glial cell surface and cytosolic antigens is an important cause of encephalitis. It may be triggered by activation of the immune system in response to an infection (para-infectious), cancer (paraneoplastic), or due to a patient's tendency toward autoimmunity. Antibodies directed toward neuronal cell surface antigens are directly pathogenic, whereas antibodies with intracellular targets may become pathogenic if the antigen is transiently exposed to the cell surface or via activation of cytotoxic T cells. Immune-mediated encephalitis is well recognized and may require intensive care due to status epilepticus, need for invasive ventilation, or dysautonomia. Patients with immune-mediated encephalitis may become critically ill and display clinically complex and challenging to treat movement disorders in over 80% of the cases (Zhang et al. in Neurocrit Care 29(2):264-272, 2018). Treatment options include immunotherapy and symptomatic agents affecting dopamine or acetylcholine neurotransmission. There has been no prior published guidance for management of these movement disorders for the intensivist. Herein, we discuss the immune-mediated encephalitis most likely to cause critical illness, clinical features and mechanisms of movement disorders and propose a management algorithm.

Levodopa-responsive retrocollis on the background of choreic dyskinesia.

Purpose/aim: Retrocollis can substantially disturb the daily living of individuals with Parkinson's disease (PD). Clinician often encounter the difficulty in managing the retrocollis. Materials and Methods: We describe a patient with PD who presented with choreic dyskinesia and levodopa-responsive retrocollis. Results: The patient had dyskinesia and the off periods, and received levodopa (700 mg, 14 times/day). The patient received levodopa-carbidopa intestinal gel (LCIG) treatment. After several months, the patient complained of difficulty in swallowing and speech due to severe retrocollis. Thirty minutes following a fast levodopa infusion of LCIG, the retrocollis improved. As a result, a frontal view was obtained, and her talking abilities showed improvement. Conclusions: Severe retrocollis can be superimposed on choreic dyskinesia, and it was likely to increase during the off periods. Duodenal levodopa infusion may reduce the severity of retrocollis.

Impact of Deuterium Substitution on the Pharmacokinetics of Pharmaceuticals.

OBJECTIVE: Stable heavy isotopes of hydrogen, carbon, and other elements have been incorporated into drug molecules, largely as tracers for quantitation during the drug development process. Studies involving the human use of drugs labeled with deuterium suggest that these compounds may offer some advantages when compared with their nondeuterated counterparts. Deuteration has gained attention because of its potential to affect the pharmacokinetic and metabolic profiles of drugs. Deutetrabenazine (Austedo, Teva Pharmaceutical Industries, Ltd) is the first deuterated drug to receive Food and Drug Administration approval. This deuterated form of the drug tetrabenazine is indicated for the treatment of chorea associated with Huntington's disease as well as tardive dyskinesia. Ongoing clinical trials suggest that a number of other deuterated compounds are being evaluated for the treatment of human diseases and not merely as research tools. DATA SOURCES: A search of the MEDLINE (1946 to present) database was undertaken using the Ovid interface. The search was conducted using the heading deuterium and then limited to Administration & Dosage, Adverse Effects, Pharmacokinetics, Pharmacology, Poisoning, Therapeutic Use, and Toxicity. STUDY SELECTION AND DATA EXTRACTION: All articles were reviewed and those with human information were included. Review articles were likewise interrogated for additional published human data. CONCLUSIONS: Deuterated compounds may, in some cases, offer advantages over nondeuterated forms, often through alterations in clearance. Deuteration may also redirect metabolic pathways in directions that reduce toxicities. The approval of additional deuterated compounds may soon follow. Clinicians will need to be familiar with the dosing, efficacy, potential side effects, and unique metabolic profiles of these new entities.

Hydromorphone-induced chorea as an atypical presentation of opioid neurotoxicity: A case report and review of the literature.

BACKGROUND: While opioid-induced myoclonus is well described, there are limited reports of opioid-induced chorea. Here we present the first case of chorea as a manifestation of opioid neurotoxicity due to hydromorphone. CASE PRESENTATION: A 20-year-old woman presenting with fevers and cutaneous lesions was diagnosed with hemophagocytic lymphohistiocytosis secondary to primary cutaneous lymphoma. Surgical resection of a cutaneous lesion was complicated by severe postoperative pain requiring rapid opioid dose escalation. Seven days after hydromorphone was initiated, she developed positive myoclonus, hallucinations, delirium, and involuntary, flowing movements consistent with chorea. She had no personal or family history of nervous system disorders and was not taking any medications associated with drug-induced chorea. Case management: The remainder of her neurologic examination was unremarkable. Her renal function was normal and no etiology was found on neuroimaging or laboratory workup. Hydromorphone was discontinued and pain control was achieved with fentanyl. Case outcome: The patient's neurotoxic symptoms including chorea resolved within 72 h of hydromorphone discontinuation. CONCLUSION: Further studies are needed to determine which patients have a unique sensitivity to opioids predisposing them to chorea. Clinicians should be aware that chorea may be a sign of such toxicity so that rapid corrective action can be taken.