Recent advances in the management of choreas

2011

Huntington disease (HD) is a rare neurodegenerative disorder of the central nervous system characterized by unwanted choreatic movements, behavioral and psychiatric disturbances and dementia. Prevalence in the Caucasian population is estimated at 1/10,000-1/20,000. Mean age at onset of symptoms is 30-50 years. In some cases symptoms start before the age of 20 years with behavior disturbances and learning difficulties at school (Juvenile Huntington's disease; JHD). The classic sign is chorea that gradually spreads to all muscles. All psychomotor processes become severely retarded. Patients experience psychiatric symptoms and cognitive decline. HD is an autosomal dominant inherited disease caused by an elongated CAG repeat (36 repeats or more) on the short arm of chromosome 4p16.3 in the Huntingtine gene. The longer the CAG repeat, the earlier the onset of disease. In cases of JHD the repeat often exceeds 55. Diagnosis is based on clinical symptoms and signs in an individual with a parent with proven HD, and is confirmed by DNA determination. Pre-manifest diagnosis should only be performed by multidisciplinary teams in healthy at-risk adult individuals who want to know whether they carry the mutation or not. Differential diagnoses include other causes of chorea including general internal disorders or iatrogenic disorders. Phenocopies (clinically diagnosed cases of HD without the genetic mutation) are observed. Prenatal diagnosis is possible by chorionic villus sampling or amniocentesis. Preimplantation diagnosis with in vitro fertilization is offered in several countries. There is no cure. Management should be multidisciplinary and is based on treating symptoms with a view to improving quality of life. Chorea is treated with dopamine receptor blocking or depleting agents. Medication and non-medical care for depression and aggressive behavior may be required. The progression of the disease leads to a complete dependency in daily life, which results in patients requiring fulltime care, and finally death. The most common cause of death is pneumonia, followed by suicide.

Frontiers in Neurology, 2019

Given that any symptoms of Huntington's disease (HD) may be worsened by stress, fatigue and intercurrent disorders (e.g. anxiety, digestive disorders, infectious or painful conditions, etc.), these aspects must be assessed and should be treated with appropriate measures in parallel with treating the Huntington's symptoms (Professional agreement). Motor disorders The wide spectrum of motor manifestations are the best known and the most visible symptom in Huntington's disease. Among them, involuntary movements (i.e. chorea) are the most obvious. However, while the diagnosis of manifest HD is based on the presence of motor symptoms, these are frequently preceded by cognitive and behavioral symptoms (1). While motor symptoms are easily detected, and might be the source of anxiety and ostracism, they are often well tolerated by the patients and their proxies in contrast to cognitive and behavioral symptoms that often lead to family and social/professional's issues. Chorea Chorea is characterized by abnormal, involuntary, spontaneous, uncontrollable, irregular, intermittent, non-rhythmic and aimless movements affecting the trunk, the face and the limbs. They are worsened by fatigue and challenges such as emotional stress, and usually disappear during sleep. Affecting about 90% of the patients, chorea is a key element of establishing the clinical diagnosis, but is not always a marker of the severity of the disease (2). Chorea may be absent at the beginning of HD or appear transiently during the course of the disease, and is rarely present with juvenile onset. After motor onset, chorea usually progresses towards a peak phase and then commonly decreases in severity in the later stages of HD, at which time it may disappear alongside an increase in rigidity and/or dystonia (3). Recommendations 1. Drug treatment should be considered if chorea causes the patient distress or discomfort (Professional agreement). 2. Tetrabenazine was shown to have a beneficial effect on chorea (Grade A) (4-20) and is one of the first-line treatments for this symptom. 3. Tetrabenazine has to be used with caution due to the potential of adverse events, which should be explained to patients and relatives/caregivers (Professional agreement). 4. Tetrabenazine is contraindicated when the patient suffers from not well-managed depression or suicidal thoughts, as specified in the product monographs. 5. Tiapride (21-27), sulpiride (28-33) (Grade B), olanzapine (34-43), risperidone (28,44-49), pimozide (9,24,50,51) and aripiprazole (52-57) (Grade C) showed efficacy on chorea and are first-line treatments for this symptom in particular when the patients have associated personality and/or behavioural or psychotic disorders. 6. Haloperidol has a national marketing authorization for chorea in some countries (Grade C) (58-63). It should be considered as second-line treatment but should be used with caution due to the risk of major apathy (Professional agreement). 7. Because of contradictory results in various trials, amantadine cannot be recommended to treat chorea (Grade B) (63-67). However, despite the poor tolerability (confusion and legs oedema) of amantadine several experts of the multidisciplinary group, consulted to evaluate the recommendations, reported a beneficial effect of amantadine to treat chorea. 8. On a regular basis, ongoing treatments should be re-evaluated for their efficacy and tolerability. If effective and well-tolerated, changing ongoing treatment is not recommended (Professional agreement). 9. It may be necessary to reduce the dose or change a neuroleptic or tetrabenazine if the patient experiences adverse events such as worsening of apathy or extrapyramidal side effects (Professional agreement). 10. Monotherapy to treat chorea is preferred because combination therapy (e.g. tetrabenazine and neuroleptic) increases the risk of adverse effects and may complicate the management of non-motor symptoms. Adjunct therapy should therefore be considered on a case-by-case basis for patients who do not respond significantly to monotherapy (Professional agreement). 11. Riluzole (Grade A) (39,68-71) and memantine (Grade C) (44,72-74) are not indicated for the management of chorea. 12. Globus pallidus Deep Brain Stimulation (DBS) (either internal or external) is not yet recommended in severe pharmacoresistant chorea (Grade C) (75-86). The technic is currently assessed in therapeutic trials. 13. In the presence of disturbing chorea, appropriate protective measures (for meal time, washing, bedding, transfers...) should be put in place in order to avoid traumatic injury or chokes. Rehabilitation specialists such as occupational therapists, psychomotor therapists, speech therapists, physiotherapists can help identify appropriate assistive technology devices and positioning techniques (Professional agreement). 14. Where there are recurrent oral-lingual injuries due to biting, mouth guards (splints) may be prescribed, in collaboration with a dentist/oral health specialist where possible. The choking risk due to mouth guards should also be considered (Professional agreement). 15. As an adjuvant measure, therapies that might act by relaxing the patient (e.g. aquatherapy or bathing) might be of benefit to improve transitorily chorea symptoms (Professional agreement). Dystonia Dystonia is highly prevalent in HD patients (90%) and is characterized by abnormal postures that may affect all body segments and is frequently associated with rigidity (54-59)(87). When dystonia manifests in HD, the intensity varies from a slight intermittent abnormal posture, without any impact on independence, to severe twitch of muscles with major impact on movements and functions of daily living. It can lead to impaired chewing and swallowing (for dystonia of the face and the neck), joint deformities, and compromise a comfortable sitting position and prevent secure ambulation (especially when severe axial dystonia is present). Recommendations 1. Both active rehabilitation, with patient participation, and passive rehabilitation, without voluntary participation of patients, in physiotherapy are recommended as a preventive measure in order to maintain the range of joint motion, limit postural and musculoskeletal deformities and, prevent the development of contractures (Professional agreement). 2. The injection of botulinum toxin in the case of focal dystonia (e.g. cervical dystonia, blepharospasm, oromandibular dystonia) or to prevent secondary deformities (e.g. flexum, equinus) should be performed by a trained professional (Professional agreement). 3. The concomitant use of anticholinergic agents to prevent the side effects of neuroleptics has not demonstrated efficacy and should not be used (Professional agreement). 4. The use of adapted equipment, in particular customised chairs, can provide an optimised and comfortable environment in view of the dystonia-related deformities (Professional agreement). Rigidity Rigidity is an increase in muscle tone leading to a resistance to passive movement that can induce joint stiffness and limited range of motion. In HD, it might be related to spasticity and/or parkinsonism (with bradykinesia). Bradykinesia is the slowness of initiation of voluntary movement with a reduction of speed and amplitude, particularly of repetitive actions. Akinesia is a severe degree of bradykinesia leading to inability to initiate voluntary movement. In HD, bradykinesia frequently coexists with involuntary choreatic movements. At late stages, when choreatic activity declines, most HD patients develop an akinetic-rigid syndrome often with a generalized increased tone. Juvenile or late-onset patients often exhibit a predominantly bradykinetic phenotype with or without rigidity but little to no chorea (88). This phenotype might be misdiagnosed as atypical parkinsonism or a psychiatric condition. Recommendations Only low levels of scientific evidence have been provided for the treatments of rigidity and because of the risk of adverse events, they should be used with caution. Nevertheless, rigidity symptoms might be distressing for patients and the following treatments might be attempted on a case by case basis (Professional agreement). 1. Rigidity may be increased or induced by the use of neuroleptics or tetrabenazine. If this impacts the functional capacity of the patient, a reduction in dosage or the withdrawal of neuroleptics and/or tetrabenazine should be considered taking into account overall benefit on chorea and/or behavioural symptoms vs. severity of rigidity (Professional agreement).

The Consultant Pharmacist, 2009

HD is an inheritable, fatal, neurodegenerative condition that is associated with disorders of movement, cognition, and behavior. Initially regarded as a "true" autosomaldominant disorder (i.e., no appreciable difference in disease expression between homozygotes and heterozygotes), recent studies reveal that homozygotes present with a more severe clinical course. The responsible gene located at chromosome 4p16.3 encodes the Objective: Review Huntington's disease (HD) and the role of tetrabenazine (TBZ) in treating chorea associated with this disease. Discuss the pharmacology, side-effect profile, drug interactions, precautions, and contraindications of TBZ. Data Sources: Literature identified within MEDLINE and PubMED. Study Selection: Two manuscripts specifically regarding the management of chorea in patients with HD were identified. Additionally, studies involving the clinical use of TBZ were reviewed. Data Synthesis: The literature identified provided information regarding the efficacy, safety, and pharmacological actions of TBZ. Conclusion: HD is often accompanied by chorea, and the treatment with TBZ in this patient population often results in decreased chorea. Pharmacists managing patients on TBZ need to be well versed in TBZ's potential side effects, drug interactions, and unique dosing considerations.

Neurologic Clinics, 2009

Journal of Huntington's disease, 2020

Background: Anosognosia, or unawareness of illness of deficits, has been observed in Huntington's disease (HD) in relation to motor and cognitive signs and symptoms. Most studies of awareness in HD have used self-report questionnaire methodology rather than asking patients to report on their symptoms in real-time. The two studies in which patients were asked about their chorea in real-time had small sample sizes and only examined patients early in disease progression. Objective: To examine awareness of chorea in real-time in HD patients across a broad range of disease progression. Methods: Fifty HD patients across motor and cognitive impairment severity were asked if they noticed any involuntary movements after completing a simple working memory task used to elicit chorea. A movement disorders specialist rated the presence or absence of chorea while the patients completed the task. Disagreement between the patient and movement disorders specialist's ratings was considered to be an indicator of unawareness. Results: Approximately 46% of patients who exhibited chorea did not report chorea. Eighty-eight percent of participants who acknowledged chorea did not report chorea in all parts of the body that chorea was observed. Conclusions: HD patients demonstrate unawareness of chorea across cognitive and motor sign severity.

Huntington's disease is a genetic neurodegenerative condition transmitted by means of autosomal dominant inheritance. It causes irreversible neuronal damage and leads to disintegration of motor and cognitive functions within two decades after onset. There is no known cure for the disease; however, research is being carried out on prevention of its reproduction in the next generations. The disease has detrimental effects on the health and wellbeing, both mental and physical, of the patient, and causes great emotional and psychological pressure on their friends and family.

International Clinical Psychopharmacology, 2004

Huntington's disease (HD) is a devastating neuropsychiatric disorder for which therapeutic interventions have been rather fruitless to date, except in a slight symptomatic relief. Even the discovery of the gene related to HD in 1993 has not effectively advanced treatments. This article is essentially a review of available double-blind, placebocontrolled trials of therapy for this condition which also includes relevant open label trials. Unfortunately, HD research has tended to concentrate on the motor aspects of the disorder, whereas the major problems are behavioural (e.g. dementia, depression, psychosis), and the chorea is often least relevant in terms of management. We conclude that there is definitely poor evidence in management of HD. The analysis of the 24 best studies fails to result in a treatment recommendation of clinical relevance. Based on data of open-label studies, or even case reports, we recommend riluzole, olanzapine and amantadine for the treatment of the movement disorders associated with HD, selective serotonin reuptake inhibitors and mirtazapine for the treatment of depression, and atypical antipsychotic drugs for HD psychosis and behavioural problems. Moreover , adjuvant psychotherapy, physiotherapy and speech therapy should be applied to supply the optimal management. Finally, some cellular mechanisms are discussed in this paper because they are essential for future neuroprotective modalities, such as minocycline, unsaturated fatty acids or riluzole.

Drugs, 2010

Journal of Neurology, Neurosurgery & Psychiatry, 1977

SUM MARY Fifteen patients affected by Huntington's chorea were divided into two groups, 'slow' and 'fast', according to IQ scores on the Wechsler-Bellevue scale, and scores on some motor performance tests. A possible correlation was looked for between some biochemical data (cerebrospinal fluid (CSF), homovanillic acid (HVA), and 5-hydroxyindolacetic acid (5HIAA) levels, plasma dopamine-beta-hydroxylase (DBH), dopamine (DA) uptake by platelets), and clinical data (duration of illness, severity of symptoms, age of patients, IQ scores, 'slow' and 'fast' groups). The CSF, HVA, and 5HIAA levels were found to be significantly lowered in comparison with normal controls. DBH activity and DA uptake by platelets did not differ significantly from normal subjects. Treatment with haloperidol in all patients and with dipropylacetic acid in three patients did not appear to modify the CSF, HVA, and 5HIAA concentrations, the plasma DBH activity, or the DA uptake. There were no significant differences in the CSF, HVA, and 5HIAA contents between the two groups of patients, and there was no correlation between biochemical data and clinical features.