Chorea & Huntington's Disease

Diagnosis is challenging since chorea has the same phenomenology regardless of its etiology.  Chorea is usually classified as being primary (idiopathic, hereditary) or secondary (acquired). Hereditary choreiform disorders tend to develop insidiously and are generally symmetrical, whereas acquired chorea are more likely to be acute or subacute and can be asymmetrical or unilateral. There is a wide range of seemingly unrelated causes, from pregnancy (chorea gravidarum) to inherited forms such as Huntington’s disease and benign hereditary chorea, infection/immune-related such as Sydenham’s chorea and systemic lupus erythematosus, focal vascular lesions in the basal ganglia, drugs such as levodopa, neuroleptics and oral contraception, or various metabolic and endocrinological disorders such as hyperthyroidism, hypo/hyperparathyroidism and hypo/hyperglycemia. Its pathophysiology involves a functional dysregulation of the basal ganglia motor circuit, where the final thalamic-cortical output is increased, resulting in increased movement and chorea. The disruption of basal ganglia circuitry may be due to structural damage, selective neuronal degeneration, neurotransmitter receptor blockade, metabolic derangements, or autoimmune conditions.

Treatment of chorea entails addressing its root etiology. Unfortunately, no agent has been proven to slow or halt progression of hereditary chorea, with the exception of copper-reducing therapies in Wilson disease. The most common symptomatic treatments of chorea  include the use of dopamine receptor blocking agents and dopamine depleters such as tetrabenazine, valbenazine, and deutetrabenazine.  Autoimmune chorea syndromes such as systemic lupus erythematosus (SLE) and antiphospholipid antibody syndrome may also be responsive to treatment with glucocorticoids, plasma exchange, or intravenous immunoglobulin (IVIG).

Contributed by Shu-Leong Ho, MD, FRCP
Henry G. Leong Professor & Chief of Division University of Hong Kong,
Queen Mary Hospital
Division of Neurology, Dept. of Medicine
Hong Kong

2019 Updates Contributed by:

Esther Cubo, MD, PhD
Neurologist
Hospital Universitario Burgos
Burgos, Spain

Mark Guttman, MD, FRCPC
Director
Center for Movement Disorders
Toronto, ON, Canada

Brandon Barton, MD
Assistant Professor
Rush University Medical Center
Chicago, IL USA

Huntington’s disease is clinically characterized by a triad of motor, cognitive and psychiatric symptoms. Motor features include: impairment of involuntary (chorea) and voluntary movements; reduced manual dexterity, slurred speech, swallowing difficulties, balance problems and falls. It may also present with parkinsonism and dystonia (more common in young onset, termed the Westphal variant). Cognitive features are characterized initially by loss of speed and flexibility in thinking, but later develop into global dementia. Psychiatric features may include: depression (most common), mania, obsessive-compulsive disorder, irritability, anxiety, agitation, impulsivity, apathy, and social withdrawal.

Definitive diagnosis is through genetic testing and confirmed by targeted mutation analysis finding of a CAG trinucleotide expansion of ≥36 repeats in the HTT gene. Predictive genetic testing is an option for individuals who are at risk for developing HD, a category which includes asymptomatic individuals with a positive family history of HD, or patients with a positive family history who have prodromal symptoms (e.g., irritability, anxiety, depression, or cognitive impairment) that suggest the impending onset of symptomatic HD. Pretest genetic counseling is recommended before pursuing predictive genetic testing. For HD families, preimplantation genetic testing is possible and therefore to select embryos for transfer without the HD genetic mutation. Prenatal testing is only done in situations where the mother would consider termination of the pregnancy should the fetus test positive. Otherwise, prenatal testing is the same as testing an asymptomatic child, which is not ethically recommended.

For a patient with chorea who is atypical for HD or is negative for HD genetic mutation,  the differential diagnosis is broad and consists of hereditary and acquired causes of chorea.  In these cases, brain MRI can be useful in identifying an alternative diagnosis, such as ischemic infarction, pantothenate kinase-associated neurodegeneration, multiple sclerosis, neoplasm, or Creutzfeldt-Jakob disease. Otherwise, additional testing should be indicated based on medical and family history, physical and neurological exam.

The best care for patients with HD is provided by a multidisciplinary team of health professionals and supportive caregivers that addresses the broad physical and psychologic needs of patients and families, and manages new issues as they arise through long-term follow-up. Dopamine receptor blocking agents or dopamine depleting agents may be used if the chorea is disrupting quality of life. Psychiatric symptoms such as depression, psychosis and agitation are similarly managed as any other psychiatric condition. Non-pharmacologic approaches to some functional difficulties and behavioral dysfunction in Huntington’s disease are important Non-pharmacological interventions include speech therapy and dietary serviced to manage dysphagia and weight loss, physical therapist to address gait impairment and falls, Unfortunately, there is no known effective therapy for dementia associated with HD. Stereotactic surgery (DBS) for severe and disabling cases of chorea has been reported.  Investigational therapies such gene silencing through antisense oligonucleotide techniques are currently underway.

Contributed by Hubert Fernandez, MD
Head, Movement Disorders
Department of Neurology
Cleveland Clinic
Cleveland, Ohio USA
 

2019 Update by Esther Cubo, MD, PhD and Mark Guttman, MD, FRCPC