What is the clinical classification and treatment approach for a patient with hyperkinetic movement disorders, specifically chorea associated with Huntington's disease?

Clinical Classification of Hyperkinetic Movement Disorders

Primary Classification Framework

Hyperkinetic movement disorders are classified into two main categories: primary (genetic/idiopathic) and secondary (acquired), with specific subtypes based on phenomenology including chorea, ballism, dystonia, myoclonus, and tics. 1

Phenomenological Classification

The hyperkinetic disorders are categorized by their characteristic movement patterns:

• Chorea: Purposeless, involuntary, non-stereotypical movements of trunk or limbs, frequently associated with muscle weakness and emotional lability 2
• Ballism: Large amplitude, violent flinging movements (rarest form) 3
• Dystonia: Sustained muscle contractions causing twisting movements 3
• Myoclonus: Brief, shock-like jerks 1
• Tics: Sudden, brief, intermittent, involuntary or semi-voluntary movements or sounds that can be suppressed 3

Etiological Classification

Primary (Genetic) Causes

For adult-onset chorea, Huntington's disease is the most common cause, caused by CAG repeat expansions in the huntingtin gene on chromosome 4p16.3. 2, 4

• Huntington's Disease: Autosomal dominant inheritance with complete penetrance for alleles ≥40 CAG repeats; average onset 35-45 years with 15-20 year survival 4
• Benign Hereditary Chorea: Caused by NKX2-1/TITF1 gene mutations on chromosome 14q13.3 2
• Paroxysmal Kinesigenic Dyskinesia (PKD): Autosomal dominant with 60-90% penetrance, primarily caused by PRRT2 gene mutations 3

PKD is further classified into:

• Pure form: Only kinesigenic involuntary movements 3
• Complicated type: Additional neurological symptoms including benign familial infantile epilepsy, febrile convulsions, migraine, episodic ataxia, or developmental delay 3

Secondary (Acquired) Causes

Secondary causes must be systematically excluded through targeted testing before diagnosing primary disorders. 2

Metabolic Disorders

• Hyperthyroidism, hypoparathyroidism, hypoglycemia, kernicterus 2
• Wilson's disease (requires serum ceruloplasmin measurement) 2

Autoimmune/Inflammatory

• Sydenham's chorea: Most common cause of acute onset chorea in childhood (96% of pediatric cases), associated with Group A Streptococcal infection 2
• Systemic lupus erythematosus 2

Vascular

• Acute cerebral infarction involving contralateral hemisphere, basal ganglia, thalamus, or corpus callosum 5

Drug-Induced

• Neuroleptics causing tardive dyskinesia 2
• Various medications affecting dopaminergic pathways 1

Diagnostic Approach for Huntington's Disease-Associated Chorea

Definitive Diagnosis

Genetic testing for CAG repeat expansion in the huntingtin gene provides 100% specificity, with ≥40 repeats confirming diagnosis; genetic counseling is mandatory before testing. 4

Neuroimaging

Brain MRI without contrast is the optimal initial imaging modality, showing progressive marked atrophy of the neostriatum (particularly caudate nucleus head) with enlargement of frontal horns of lateral ventricles and abnormal T2 signal in caudate and putamen. 4, 3

Essential Laboratory Testing

The following blood tests must be conducted to exclude secondary causes:

• Thyroid function tests 2
• Serum calcium, phosphorus, parathyroid hormone 2
• Blood glucose 2
• Serum ceruloplasmin 2
• Alpha-fetoprotein (if ataxia-telangiectasia suspected) 2

Treatment Algorithm for Huntington's Disease Chorea

First-Line Pharmacological Management

Tetrabenazine is FDA-approved for HD-associated chorea and demonstrated a statistically significant 3.5-unit reduction in Total Chorea Score compared to placebo (5.0 units vs 1.5 units). 6

Dosing Protocol for Tetrabenazine

Initial dosing up to 50 mg/day:

• Start 12.5 mg once daily in morning 6
• After one week, increase to 25 mg/day (12.5 mg twice daily) 6
• Titrate upward weekly by 12.5 mg increments 6
• Doses 37.5-50 mg/day require three-times-daily regimen; maximum single dose 25 mg 6

Dosing above 50 mg/day:

• Mandatory CYP2D6 genotyping required before exceeding 50 mg/day 6
• Extensive/intermediate metabolizers: Maximum 100 mg/day in three divided doses; maximum single dose 37.5 mg 6
• Poor metabolizers: Different dosing required 6

Critical Safety Considerations

Tetrabenazine carries a BLACK BOX WARNING for depression and suicidality; it is contraindicated in actively suicidal patients and those with untreated or inadequately treated depression. 6

• Close monitoring for emergence or worsening of depression, suicidality, or unusual behavioral changes is mandatory 6
• Particular caution in patients with history of depression or prior suicide attempts 6
• If adverse reactions (akathisia, parkinsonism, depression, insomnia, anxiety, sedation) occur, stop titration and reduce dose 6

Alternative VMAT2 Inhibitors

• Deutetrabenazine: Longer half-life, reduced plasma fluctuations, twice-daily dosing; real-world data shows mean treatment difference in chorea scores of 4.4 with 32.8% adverse event rate 7
• Valbenazine: VMAT2-selective, potentially fewer off-target effects (parkinsonism, behavioral changes, akathisia) but cost may be prohibitive 8

Non-Pharmacological Management

Speech therapy and occupational therapy are essential components with moderate strength of evidence for functional improvement. 4

• Speech therapy addresses orofacial chorea affecting speech and swallowing 4
• Occupational therapy assists with activities of daily living impacted by choreiform movements 4

Psychiatric and Cognitive Management

Aggressive treatment of psychiatric manifestations is recommended as they are major drivers of emergency department visits, hospital admissions, and institutionalization—often more than motor symptoms. 4

• SSRIs or low-dose amitriptyline for mood symptoms 4
• Cognitive Behavioral Therapy for maladaptive beliefs and avoidance behaviors 4
• Psychiatric consultation warranted given high morbidity burden 4
• Comprehensive neuropsychological testing at baseline, then at 1-year, 2-year, and 4-5 year intervals 4

Interdisciplinary Team Approach

A comprehensive team including dementia subspecialist, movement disorder specialist, neuropsychologist, psychiatrist, speech and occupational therapists is essential for managing the devastating triad of motor dysfunction, cognitive decline, and psychiatric disturbances. 4

Important Clinical Pitfalls

Discontinuation Rates

Real-world data shows 41.8% of HD patients experience ≥60-day gap in tetrabenazine therapy with median time to discontinuation of 293.5 days, highlighting tolerability challenges 9

Functional Decline

One functional measure (UHDRS Part 4) showed statistically significant decrement in activities of daily living capacity for tetrabenazine-treated patients compared to placebo, requiring monitoring 6

Juvenile HD Considerations

Juvenile HD (onset <20 years, ~5% of cases) presents with rigidity, spasticity, and intellectual decline rather than chorea, often with CAG repeats >55 4