Comprehensive treatment of Huntington disease and other choreic disorders
ABSTRACTThe management of choreic disorders presents significant challenges, including identifying the etiology of the disorder, treating and preventing motor symptoms, and managing a range of other neurologic and behavioral complications. Chorea may occur in several neurodegenerative, genetic, or drug-related conditions, and a thorough diagnostic evaluation is needed to identify the specific underlying causes. Some choreic disorders have specific treatable underlying etiologies, such as vitamin B12 deficiency or drug-induced dyskinesia. Autoimmune disorders such as Sydenham chorea may be treated with penicillin, corticosteroids, intravenous immunoglobulin, or plasma exchange. Heredodegenerative choreas such as Huntington disease often respond to treatment with tetrabenazine or amantadine. Many other agents may be used nonspecifically for symptom control, including benzodiazepines, neuroleptics, and antiepileptic medications. In addition to motor symptoms, patients with Huntington disease or other choreic disorders often experience increasing depression, bradykinesia, cognitive impairment, aggressive behaviors, and other complications as the disease progresses. Caring for the caregiver is also a significant concern in the long-term treatment of choreic disorders.
Chorea is characterized by continuous, random, brief, involuntary muscle contractions that result from a variety of causes.1 These involuntary movements are nonstereotyped and irregular. Although choreic disorders are among the most common involuntary movement disorders, their diagnosis and treatment present several important challenges, including identifying and removing the cause if possible, controlling and preventing motor symptoms, and managing neuropsychologic complications.1 This article provides an overview of the diagnosis and treatment of choreic disorders, using Sydenham chorea to illustrate the management of autoimmune choreas and Huntington disease as the model for the management of heritable choreas.
Management of choreic disorders begins with a first-pass diagnosis and the use of symptomatic therapies. Even if this first pass yields no firm diagnosis, it at least rules out causes that have the most practical significance. A subsequent second-pass evaluation can be undertaken to look for rarer causes. Symptomatic therapies are continued throughout the diagnostic period. More specific therapies can be administered if an etiologic or pathogenic mechanism is determined (eg, postinfectious, autoimmune, metabolic).
CHOREIC DISORDERS: A PRACTICAL DIAGNOSTIC APPROACH
In general, choreic disorders may be subdivided into six categories:
1. Heredodegenerative disorders, such as Huntington disease and other genetically heterogeneous choreas, include Huntington disease–like 2 (HDL2) and benign hereditary chorea.1 Sporadic cases include those of unknown paternity; X-linked disorders (eg, McLeod syndrome); and autosomal-recessive disorders such as chorea-acanthocytosis, which is characterized by chorea, dystonia with prominent orofacial involvement, self-mutilation, myopathy, and neuropathy.2
2. Drug-induced choreas include neurolepticinduced tardive dyskinesia and nontardive hyperkinetic drug-related choreas, the most common of which is levodopa-induced dyskinesias.3 Tardive drug-induced choreas may occur while using the culprit drug, while tapering the drug, or after it has been discontinued. The culprit drugs are represented by dopamine-receptor blockers and include the first-generation neuroleptics (eg, phenothiazines, haloperidol), antidepressants (lox-apine), and gastrointestinal agents (metoclopramide, prochlorperazine). Drug-induced choreas are possible with a wide range of pharmacologic agents, including antiparkinsonian drugs (eg, levodopa, dopamine agonists, anticholinergics), sympathomimetics (eg, amphetamines, cocaine), anticonvulsants, calcium channel blockers, and oral contraceptives.1
3. Autoimmune choreas include Sydenham chorea, systemic lupus erythematosus, and antiphospholipid antibody syndromes. The latter encompass lupus anticoagulant and anticardiolipin antibodies.
4. Metabolic choreas are most often associated with hyperthyroidism, although case reports have described choreas in patients with vitamin B12 deficiency. A variety of hereditary metabolic diseases are also included in this category.
5. Vascular choreas include polycythemia vera and cerebrovascular accidents, the latter frequently presenting as hemiballismus. Polycythemia vera is associated with a high incidence of neurologic symptoms, including a reported incidence of chorea of 0.5% to 5%,4 and should be considered as a potential cause of chorea.
6. Other choreic disorders include a variety of entities such as rare paraneoplastic disorder/syndrome, and posttraumatic and postanoxic presentations.
The first-pass diagnostic approach includes a family history, drug history, and brain magnetic resonance imaging to identify potential structural causes of chorea. Genetic testing for Huntington disease or other choreic disorders may also be performed, although it is essential to consider the potential implications of a positive test result. Intensive pretest and posttest counseling is important both for the patient and for currently asymptomatic family members who may also be affected.1
Other testing includes:
- Complete blood count
- Creatine phosphokinase
- Peripheral smear for acanthocytes
- Comprehensive metabolic panel
- Ceruloplasmin level
- Measurement of thyroxine (T4) and triiodothyronine (T3)
- B12 tests
- Antinuclear antibody sedimentation rate
- Lupus anticoagulant-anticardiolipin antibodies
- Antistreptolysin O (ASO) titer
- Anti-DNase-B titer.
GENERAL CONSIDERATIONS FOR THE TREATMENT OF CHOREIC DISORDERS
In some cases, choreic disorders have a treatable underlying etiology, such as thyroid disease or vitamin B12 deficiency. Tardive syndromes may require treatment beyond drug discontinuation, including use of dopamine depleters for the classic tardive dyskinetic syndromes and anticholinergics for the tardive dystonic syndromes. Levodopa dyskinesia may be treated using amantadine, clozapine, or deep brain stimulation.5,6 The treatment of patients with autoimmune choreas is not well defined. It may include anticoagulation in patients with positive anticardiolipin antibodies to prevent venous or arterial thromboembolism,7 but the risk of arterial thromboembolism is uncertain, and it is unclear whether chorea is truly a harbinger of vascular events.
A negative ASO titer does not exclude Sydenham chorea, a result of childhood infection with group-A beta-hemolytic streptococcus, and antibiotics should be considered in the appropriate context. Some researchers have argued that immune responses associated with acute infections may result in autoimmune neuropsychiatric symptoms. In pediatric patients, this has been referred to as pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS).8
A related phenomenon has been proposed as a potential mechanism of some types of chorea, although the relationship between acute infection and chorea is controversial. Patients with elevated ASO titer or anti-DNase-B titers may be candidates for antibiotics. By 6 weeks after the onset of infection, these titers will fall and a diagnosis of Sydenham chorea can be postulated or based exclusively on clinical judgment.
