Tetrabenazine in the treatment of severe pediatric chorea.

Tetrabenazine (TBZ) is widely used to treat adults with hyperkinetic movement disorders; however, published experience with the drug in pediatric patients is limited. We report on 5 children with severe chorea who were treated with TBZ. TBZ effectively controlled chorea in 4 patients, and despite the need for relatively high doses, it was well tolerated.     

Tetrabenazine treatment in movement disorders

Tetrabenazine (TBZ) is a catecholamine depletor used for the treatment of a variety of movement disorders. The purpose of this study was to assess the efficacy of TBZ in a retrospective chart review in 3 tertiary care movement disorders centers over long-term treatment. Of 150 patients to whom TBZ was prescribed, 118 were followed up and assessed using the Clinical Global Impression of Change (CGIC), (-3 to +3), a composite grade from a patient and caregiver scale over variable periods. The patients had a variety of hyperkinetic movement disorders including dystonia (generalized and focal: axial, Meige syndrome, torticollis, blepharospasm, bruxism), Huntington disease (HD) or other choreas, tardive dyskinesia (TD) or akathisia, and Tourette syndrome. Mean patient age was 48.8 +/- 18.7 years; 48 were men (40.7%) with a mean disease duration of 93 months. The mean follow-up time was 22 months and the mean TBZ dose was 76.2 +/- 22.5 mg/d (median 75 mg, range 25-175 mg/d). The mean CGIC score was +1 (mild improvement). The group of patients who scored +3 on the CGIC (very good improvement) represented 18.6% (n = 22) of all patients. They had HD or other types of chorea 7.6% (n = 9), facial dystonia/dyskinesia (n = 7, 5.9%), 1 with TD, 2 with trunk dystonia, 2 with Tourette syndrome, and 1 with tardive akathisia. This group had the longest treatment duration and received a mean TBZ dose of 70.5 mg/d (median 75 mg/d) for a mean of 25.4 +/- 21.3 months. The report concludes that TBZ is a moderately effective treatment of a large variety of hyperkinetic movement disorders, with excellent effects in a subgroup with chorea and facial dystonia/dyskinesias.     

Long-term tolerability of tetrabenazine in the treatment of hyperkinetic movement disorders.

We sought to review the long-term tolerability of tetrabenazine (TBZ) and seek determinants of tolerability in the treatment of hyperkinetic movement disorders. A retrospective chart review was performed on patients treated with TBZ between 1997 and 2004. Efficacy of TBZ was assessed by a 1- to 5-point response scale (1 = marked reduction in abnormal movements, 5 = worsening). All adverse events (AEs) were captured according to their relationship with study drug. A total of 448 patients (42% male) were treated for a variety of hyperkinesias, including tardive dyskinesia (n = 149), dystonia (n = 132), chorea (n = 98), tics (n = 92), and myoclonus (n = 19). The mean age at onset of the movement disorder was 43.0 +/- 24.2 years, with TBZ starting at a mean age of 50.0 +/- 22.3 years. Patients remained on treatment for a mean of 2.3 +/- 3.4 years. An efficacy response rating of 1 or 2 was sustained in the majority of patients between the first and last visit. Common AEs included drowsiness (25.0%), Parkinsonism (15.4%), depression (7.6%), and akathisia (7.6%). Comparison of log-likelihood ratios revealed that age was a reliable predictor of Parkinsonism (P < 0.0001). TBZ is a safe and effective drug for the long-term treatment of hyperkinetic movement disorders.     

Tetrabenazine for the treatment of chorea and other hyperkinetic movement disorders

Tetrabenazine (TBZ; Xenazine) is a potent, selective, reversible depletor of monoamines from nerve terminals. TBZ inhibits the vesicular monoamine transporter type 2 which, in humans, is expressed nearly exclusively in the brain. TBZ is rapidly metabolized in the liver by carbonyl reductase to stereoisomers of hydrotetrabenazine, some of which are potent inhibitors of vesicular monoamine transporter type 2. Initially developed in the 1950s for schizophrenia, since the 1970s several publications have reported on the efficacy of TBZ in the treatment of various hyperkinetic movement disorders. Although quite effective in controlling the involuntary movements, there were considerable inter-individual differences in the optimal dose, defined as the dose judged by the investigator to provide the greatest efficacy with minimal or tolerable adverse events. This variability is in part owing to differences in severity and mechanism of the target symptoms and to variable activity of the enzyme carbonyl reductase that metabolizes TBZ to its active metabolites. Dose-limiting adverse events, consisting mainly of sedation, parkinsonism, akathisia and depression, are usually rapidly reversible upon dosage reduction. In addition to its established antichorea efficacy in Huntington's disease, the drug has been reported to also be effective in a variety of other hyperkinetic movement disorders, including tardive dyskinesia and tics associated with Tourette's syndrome.     

Tetrabenazine treatment for Huntington's disease-associated chorea

Tetrabenazine (TBZ), a monoamine depleter and dopamine receptor blocker, is used to treat a variety of hyperkinetic movement disorders. The objective was to study the efficacy and tolerability of TBZ for chorea associated with Huntington's disease (HD). Nineteen patients (12 female), mean age 56.3 +/- 12.4 years (range 37-76 years) diagnosed with HD were prospectively evaluated at initial and follow-up visits using a modified Abnormal Involuntary Movement Scale (AIMS). Patients were videotaped, and the randomized videotapes were rated with the motor subset of the AIMS by two investigators who were blinded to treatment assignment. Eighteen patients completed and were rated after 5.9 +/- 3.3 months (range 2-11) at a final mean TBZ dose of 62.5 +/- 37.4 mg/day (range 25-150). The blinded videotaped motor scores showed that 15 were better on TBZ, 2 were better before TBZ, and 1 was unchanged (p < 0.001, Wilcoxon signed rank test). The mean score improved from 16.2 +/- 4.8 to 12.8 +/- 4.4. Adverse events included akathisia, insomnia, constipation, depression, drooling, and subjective weakness. All 18 of these patients have continued to take TBZ since completion of the study. TBZ was well tolerated and resulted in a significant improvement in modified AIMS scores in HD patients. These results support the use of TBZ for chorea in patients with HD.     

Psychogenic movement disorders in children: A report of 15 cases and a review of the literature

Data on psychogenic movement disorders (PMD) in children are scarce, with most existing literature relating to adults only. We report 15 cases with the aim of highlighting the clinical characteristics, risk factors, comorbidity, treatment, outcome, and prognosis of PMD in children. Only 13% of cases had onset before age 10, with the mean age at onset being 12.3 years. Females were predominantly affected (F:M = 4:1). The most common types of movement disorders seen were dystonia (47%), tremor (40%), and gait disorders (13%). Multiple hyperkinetic phenomenologies were observed in many cases. Abrupt onset and precipitation by minor injuries, and stressful life events were commonly reported. Clinical clues on examination suggesting a psychogenic origin were similar to those identified in adults. A distinct feature of PMD in children was the predominant involvement of the dominant limb. The underlying psychiatric diagnosis was conversion disorder in the majority of cases. Time from symptom onset until diagnosis of a PMD varied broadly (between 2 weeks and 5 years). Treatment with cognitive and behavioral therapy and rehabilitation by a multidisciplinary team led to improvement in most cases. However, treatment was much more effective in children with a short time from symptom onset to diagnosis and treatment. © 2008 Movement Disorder Society     

Tetrabenazine in the treatment of Huntington’s disease

Tetrabenazine (TBZ), a catecholamine-depleting agent initially developed for the treatment of schizophrenia, when tested for other indications, has proven to be more useful for the treatment of a variety of hyperkinetic movement disorders. These disorders include neurological diseases characterized by abnormal involuntary movements such as chorea associated with Huntington’s disease, tics in Tourette’s syndrome, dyskinesias and dystonias in tardive dyskinesia, also primary dystonias and myoclonus. This review will include and discuss studies published during the period of 1960–2006 regarding the clinical efficacy and tolerability of TBZ in Huntington’s disease (HD). It will also review the chemistry, pharmacokinetics and dynamics of the drug and its mechanism of action compared to that of reserpine, the only similar compound. This review emphasizes the advantage of TBZ over dopamine-depleting compounds used in the treatment of chorea and reveals its clinical efficacy and side effects.     

Hyperkinetic movement disorder in a child treated by globus pallidus stimulation

We report herein the case of a 9-year-old girl with life-threatening hyperkinetic involuntary movement of unknown etiology. Medical treatment was ineffective for her stereotypy and choreoathetotic/ballistic movements, but bilateral stimulation of the globus pallidus immediately alleviated these symptoms. Pallidal deep-brain stimulation may be considered the therapy of choice for children with intractable hyperkinetic movement disorders.     

Tardive tremor.

A variety of hyperkinetic movement disorders has been associated with the use of neuroleptics (dopamine receptor blocking drugs), but tardive tremor has not been previously documented. We describe five patients in whom tremor occurred after chronic treatment with neuroleptics, was aggravated by and persisted after neuroleptic withdrawal, and improved after treatment with the dopamine depleting drug tetrabenazine. This involuntary oscillatory movement, with a frequency range of 3-5 Hz, was most prominent during maintenance of a posture, but was also present at rest and during a goal-directed movement. The tremor was accompanied by other tardive movement disorders, including akathisia, chorea, dystonia, myoclonus, and stereotypy. There was no family history or other explanation for tremor in these patients. We suggest that this hitherto unreported movement disorder is best termed "tardive tremor."     

Contemporary encephalitis lethargica presenting with agitated catatonia, stereotypy, and dystonia-parkinsonism.

Encephalitis lethargica (EL) syndrome was classically described by Von Economo and has somnolent-ophthalmoplegic, hyperkinetic, and amyostatic-akinetic forms. We describe 2 recent cases of EL characterized by an acute encephalitis with mixed movement disorders (dystonia-Parkinsonism plus stereotypy) and psychiatric disorders (agitated catatonia, coprolalia, and echo phenomena). Both patients suffered concurrent hyperkinetic and Parkinsonian features resulting in therapeutic challenges. Bradykinetic features responded to dopamine replacement therapy and both patients also had adverse affects to dopamine antagonists (oculogyric crises plus neuroleptic malignant syndrome). Investigation was unremarkable other than the presence of CSF lymphocytosis and oligoclonal bands. Despite prolonged in-patient stays and intensive care management, both patients have made complete recoveries. We believe these cases support the hypothesis that this syndrome is an inflammatory encephalitis that specifically effects dopamine neurotransmission.     

Treatment of hyperkinetic movement disorders

Parkinson's disease, the most common hypokinetic movement disorder, has received much attention from the clinical and scientific community, but there has been a relative paucity of comprehensive reviews of hyperkinetic disorders, even though they are equally or even more disabling. Hyperkinetic movement disorders include tremors, dystonia, chorea, tics, myoclonus, stereotypies, restless legs syndrome, and various other disorders with abnormal involuntary movements. Substantial progress has been made in the understanding of the role of the basal ganglia in the pathophysiology of these hyperkinesia disorders and in motor control, muscle tone, posture, and cognitive processes. Although therapies that target pathogenesis are still lacking, effective management of hyperkinetic movement disorders demands that physicians are knowledgeable about current and novel pharmacological and surgical approaches. In addition to tetrabenazine, a monoamine-depleting drug, new formulations of botulinum toxin are being increasingly used in the treatment of these movement disorders. Finally, success with surgical approaches, particularly deep brain stimulation in patients with Parkinson's disease who have levodopa-induced dyskinesias, has been extended to the treatment of many hyperkinetic movement disorders.     

Tetrabenazine in the treatment of Huntington's chorea and other hyperkinetic movement disorders.

Tetrabenazine (Nitoman, Roche) is a synthetic benzoquinolizine derivative which resembles reserpine pharmacologically and depletes dopamine and other monoamines in the central nervous system. Considerable evidence has now been accumulated regarding the physiologic equilibrium which exists between dopamine and acetylcholine in the human striatum and it appears that dopamine excess or dopaminergic receptor supersensitivity are mechanisms operating in hyperkinetic disorders like Huntington's Chorea. The treatment of hyperkinetic disorders by dopamine depleting agents, like tetrabenazine or reserpine, or by dopamine blocking agents, like Haloperidol and Pimozide, has not been tried for more than a decade. We report here our own observations in 15 patients with various hyperkinetic disorders treated with tetrabenazine in doses up to 200 mgm. daily for periods up to 12 months.     

Clinical value of botulinum toxin in neurological indications

Botulinum toxin type-A (BoNT-A) prevents the release of acetylcholine at cholinergic junctions, thereby causing temporary muscle weakness lasting 3–4 months. It is now widely used to treat a broad range of clinical disorders characterized by muscle hyperactivity. BoNT-A has proved effective in the management of several neurological conditions and, in particular, in the management of movement disorders (e.g. blepharospasm, cervical dystonia, laryngeal dystonia, limb dystonia, hemifacial spasm, focal tics, tremor and other hyperkinetic disorders). As a treatment of spasticity, BoNT-A can improve mobility and dexterity as well as preventing the development of distressing and costly secondary complications. In cerebral palsy, BoNT-A is of value, being able to delay or even avoid surgery until motion patterns have become established.     

Tardive dyskinetic syndrome in rats infected with Borna disease virus

Tardive Dyskinesia (TD) is a hyperkinetic movement disorder caused by chronic treatment of psychiatric patients with dopamine (DA) receptor blocking drugs (Stacy & Jankovic 1991). Although TD is one of the most important and frequently encountered iatrogenic disorders in clinical medicine, its pathophysiology is poorly understood. We have observed a hyperkinetic movement disorder in rats experimentally infected with a neurotropic RNA virus, Borna disease virus, that may provide important insights into the pathophysiology of TD. Like TD patients, infected rats show prominent orofacial dyskinesias. In keeping with the dopamine (Goetz & Klawans 1982) and anatomic (Fibiger & Lloyd 1984) hypotheses of TD, the Borna disease rat model shows enhanced behavioural sensitivity to DA agonists and selective striatal cell damage. There is also evidence of DA deafferentation and heterogeneous reduction of D2 binding in the caudate-putamen, particularly from sites implicated in oral behaviour. These observations on a virus-induced movement disorder offer novel approaches to TD pathogenesis.     

Tardive dyskinesia is caused by maladaptive synaptic plasticity: A hypothesis

It has been 50 years since the first patients with tardive dyskinesia (TD) were described, but the pathophysiology is only partially understood and effective treatments have remained elusive. Newer atypical antipsychotics with less nonspecific activity at dopamine receptors have not heralded the end of tardive dyskinesia and merely highlight the incomplete understanding of the disorder. We present an overview of the existing pathophysiology of the disorder and incorporate recent developments in genetics and the study of human synaptic plasticity in other hyperkinetic movement disorders. We propose a hypothesis that dopamine-receptor sensitization and altered function of the N-methyl-D-aspartate receptor produces maladaptive synaptic plasticity, which allows the encoding of abnormal motor programs, and propose studies that would falsify or support this hypothesis. In conclusion, a maladaptive synaptic plasticity" hypothesis goes some way toward filling in the gaps of existing theories of TD with the pathophysiology of other hyperkinetic movement disorders. ? 2012 Movement Disorder Society.     

Progabide in the treatment of hyperkinetic extrapyramidal movement disorders

The ability of the selective GABA-receptor agonist, progabide, to suppress abnormal involuntary movements was evaluated in a preliminary open pilot study. 17 patients, 10 males and 7 females, aged 10-78 years, with hyperkinetic movement disorders were included in the study. Daily doses of progabide ranged from 900 to 3600 mg (median 2400 mg) corresponding to 14-45 mg/kg (median 45 mg/kg), while the duration of treatment varied from 2 to 52 weeks. Improvement, with a reduction of involuntary movements exceeding 25%, occurred in two of four patients with Gilles de la Tourette's syndrome, and in two of three patients with postanoxic intention myoclonus, while no consistent beneficial effects were registered in ten patients with Huntington's chorea, postanoxic choreoathetosis, torsion dystonia, tardive dyskinesia, action tremor, essential myoclonus, or oro-branchio-respiratory myoclonus.     

Movement disorders in genetically confirmed mitochondrial disease and the putative role of the cerebellum

Background : Mitochondrial disease can present as a movement disorder. Data on this entity's epidemiology, genetics, and underlying pathophysiology, however, is scarce. Objective : The objective of this study was to describe the clinical, genetic, and volumetric imaging data from patients with mitochondrial disease who presented with movement disorders. Methods : In this retrospective analysis of all genetically confirmed mitochondrial disease cases from three centers (n = 50), the prevalence and clinical presentation of video‐documented movement disorders was assessed. Voxel‐based morphometry from high‐resolution MRI was employed to compare cerebral and cerebellar gray matter volume between mitochondrial disease patients with and without movement disorders and healthy controls. Results : Of the 50 (30%) patients with genetically confirmed mitochondrial disease, 15 presented with hypokinesia (parkinsonism 3/15), hyperkinesia (dystonia 5/15, myoclonus 3/15, chorea 2/15), and ataxia (3/15). In 3 patients, mitochondrial disease presented as adult‐onset isolated dystonia. In comparison to healthy controls and mitochondrial disease patients without movement disorders, patients with hypo‐ and hyperkinetic movement disorders had significantly more cerebellar atrophy and an atrophy pattern predominantly involving cerebellar lobules VI and VII. Conclusion : This series provides clinical, genetic, volumetric imaging, and histologic data that indicate major involvement of the cerebellum in mitochondrial disease when it presents with hyper‐ and hypokinetic movement disorders. As a working hypothesis addressing the particular vulnerability of the cerebellum to energy deficiency, this adds substantially to the pathophysiological understanding of movement disorders in mitochondrial disease. Furthermore, it provides evidence that mitochondrial disease can present as adult‐onset isolated dystonia. © 2017 International Parkinson and Movement Disorder Society     

Movement disorders in adult surviving patients with maple syrup urine disease

Maple syrup urine disease is a rare metabolic disorder caused by mutations in the branched‐chain α‐keto acid dehydrogenase complex gene. Patients generally present early in life with a toxic encephalopathy because of the accumulation of the branched‐chain amino acids leucine, isoleucine, and valine and the corresponding ketoacids. Movement disorders in maple syrup urine disease have typically been described during decompensation episodes or at presentation in the context of a toxic encephalopathy, with complete resolution after appropriate dietary treatment. Movement disorders in patients surviving childhood are not well documented. We assessed 17 adult patients with maple syrup urine disease (mean age, 27.5 years) with a special focus on movement disorders. Twelve (70.6%) had a movement disorder on clinical examination, mainly tremor and dystonia or a combination of both. Parkinsonism and simple motor tics were also observed. Pyramidal signs were present in 11 patients (64.7%), and a spastic‐dystonic gait was observed in 6 patients (35.2%). In summary, movement disorders are common in treated adult patients with maple syrup urine disease, and careful neurological examination is advisable to identify those who may benefit from specific therapy. © 2011 Movement Disorder Society     

Gastrointestinal disorders in hyperkinetic movement disorders and ataxia

BackgroundGastrointestinal (GI) disorders have been thoroughly investigated in hypokinetic disorders such as Parkinson's disease, but much less is known about GI disorders in hyperkinetic movement disorders and ataxia. The aim of this review is to draw attention to the GI disorders that are associated with these movement disorders.MethodsReferences for this systematic review were identified by searches of PubMed through May 2020. Only publications in English were reviewed.ResultsData from 249 articles were critically reviewed, compared, and integrated. The most frequently reported GI symptoms overall in hyperkinetic movement disorders and ataxia are dysphagia, sialorrhea, weight changes, esophago-gastritis, gastroparesis, constipation, diarrhea, and malabsorption. We report in detail on the frequency, characteristics, pathophysiology, and management of GI symptoms in essential tremor, restless legs syndrome, chorea, and spinocerebellar ataxias. The limited available data on GI disorders in dystonias, paroxysmal movement disorders, tardive dyskinesias, myoclonus, and non-SCA ataxias are also summarized.ConclusionThe purpose of our systematic review is to draw attention that, although primarily motor disorders, hyperkinetic movement disorders and ataxia can involve the GI system. Raising awareness about the GI symptom burden in hyperkinetic movement disorders and ataxia could contribute to a new research interest in that field, as well as improved patient care.     

Movement disorders in Friedreich's ataxia

Since the discovery of the gene mutation causing Friedreich's ataxia (FA), the rich spectrum of clinical manifestations of this autosomal recessive disorder is being increasingly recognized. Movement disorders besides ataxia, however, have not been fully characterized in patients with FA. We describe here two young male patients who, in addition to progressive ataxia, kinetic tremor and other typical features of FA, also manifest axial and limb dystonia. The primary purpose of this report is to draw attention to the broad spectrum of hyperkinetic movement disorders that can present as or be associated with FA.