What are the management options for Huntington's chorea?

Management of Huntington's Chorea

For symptomatic chorea in Huntington's disease, initiate deutetrabenazine (Austedo) or valbenazine (Ingrezza) as first-line therapy, with antipsychotics (haloperidol, quetiapine, or sulpiride) reserved for patients with concurrent psychiatric symptoms or when VMAT2 inhibitors are contraindicated. 1, 2

Current FDA-Approved Pharmacological Treatments

VMAT2 Inhibitors (First-Line for Isolated Chorea)

• Deutetrabenazine (Austedo) is FDA-approved and demonstrated a statistically significant reduction in Total Maximal Chorea Score of 4.4 units versus 1.9 units with placebo (treatment effect -2.5 units, p<0.0001) in a 12-week randomized controlled trial of 90 patients. 2

• Start deutetrabenazine at 6 mg daily and titrate upward weekly in 6 mg increments until chorea control is achieved, side effects emerge, or maximum dose of 48 mg daily is reached (mean effective dose 40 mg daily). 2

• Valbenazine (Ingrezza) is also FDA-approved for chorea management in HD, though the evidence provided focuses primarily on deutetrabenazine's clinical trial data. 1

• Tetrabenazine requires CYP2D6 genotyping for doses above 50 mg daily; start at 12.5 mg once daily, increase to 25 mg daily (12.5 mg twice daily) after one week, then titrate by 12.5 mg weekly up to maximum 100 mg daily for extensive metabolizers. 3

Antipsychotics (First-Line When Psychiatric Comorbidity Present)

• Haloperidol, sulpiride, and quetiapine effectively manage both chorea and psychiatric symptoms (psychosis, aggression, agitation) when these occur concurrently. 4, 1

• Use antipsychotics as first-line when active depression prevents VMAT2 inhibitor use (due to black box warning for depression/suicidality with tetrabenazine) or when psychotic/aggressive behaviors coexist with chorea. 3, 5

• Apply "start low, go slow" dosing strategy to minimize extrapyramidal side effects and monitor closely for akathisia, parkinsonism, and sedation. 6, 3

Indications for Pharmacological Treatment

Initiate chorea medication when any of the following occur: 5

• Patient stigma or social isolation due to visible movements
• Physical injury or risk of falls from gait instability
• Interference with work or activities of daily living
• Disturbed sleep affecting quality of life

Common pitfall: Do not treat chorea solely based on objective severity scores; treatment decisions must prioritize functional impairment and patient-reported quality of life impact. 5

Treatment Algorithm for Inadequate Response

• Monotherapy failure: When a single VMAT2 inhibitor at maximum tolerated dose provides insufficient chorea control, add an antipsychotic rather than switching agents. 5

• Combination therapy: Use VMAT2 inhibitor plus antipsychotic when severe chorea remains uncontrolled by either drug alone, or when concurrent psychiatric symptoms require dual management. 5

• Adjunctive benzodiazepines: Consider adding benzodiazepines when anxiety exacerbates chorea, though they are ineffective as monotherapy. 5

• Avoid amantadine: Expert consensus indicates amantadine provides only small, transient benefit for chorea and should not be routinely used. 5

Critical Safety Considerations

Depression and Suicidality Monitoring

• Tetrabenazine carries a black box warning for increased risk of depression and suicidal ideation; it is contraindicated in actively suicidal patients or those with untreated/inadequately treated depression. 3

• Close observation for emergence or worsening of depression, suicidality, or unusual behavioral changes must accompany all VMAT2 inhibitor therapy. 3

• Exercise particular caution in patients with prior suicide attempts or ideation, which occur at increased frequency in HD populations. 3

Drug Interactions

• Strong CYP2D6 inhibitors (paroxetine, fluoxetine, quinidine) increase deutetrabenazine metabolite exposure 3-fold; dose reduction is required when co-administered. 2

• For tetrabenazine doses exceeding 50 mg daily, mandatory CYP2D6 genotyping distinguishes extensive metabolizers (maximum 100 mg daily) from poor metabolizers (maximum 50 mg daily). 3

Non-Pharmacological Management

Environmental and Behavioral Strategies

• Establish predictable daily routines with consistent meal times, activities, and sleep schedules to reduce confusion and anxiety. 1, 6

• Create a safe environment by removing fall hazards, installing safety locks, and reducing excessive environmental stimuli that trigger agitation. 1, 6

• Break complex tasks into simple sequential steps with clear instructions and use visual cues (calendars, labels) to assist with orientation. 6

• Apply the "three R's" approach (repeat, reassure, redirect) when managing behavioral disturbances. 6

Critical caveat: Overlooking non-pharmacological interventions before initiating medication leads to suboptimal outcomes; implement environmental modifications concurrently with pharmacotherapy. 1, 6

Emerging Therapies

• Antisense oligonucleotide (ASO) therapy with tominersen showed significant mHTT reduction in cerebrospinal fluid during Phase II trials, but the Phase III GENERATION HD1 trial was halted in 2021 due to faster neurologic decline in high-dose groups compared to placebo. 4, 1

• Gene editing and RNA interference strategies targeting mutant huntingtin at DNA or RNA levels remain in development, with no currently approved disease-modifying therapies available. 4, 1

Diagnostic Confirmation

• Genetic testing demonstrating ≥40 CAG repeats in the huntingtin gene confirms diagnosis with 100% specificity. 7

• Non-contrast brain MRI is the preferred initial imaging modality, though it may appear normal in early disease stages; look for progressive caudate and putamen atrophy in later stages. 4, 7

• CT imaging has limited utility due to poor soft-tissue characterization but can exclude cerebrovascular or acute inflammatory causes of chorea. 4

Real-World Treatment Patterns

• Only 36.1% of patients with manifest chorea receive pharmacological treatment, and approximately 50% of treated patients receive off-label alternatives rather than FDA-approved VMAT2 inhibitors. 8

• Among treated patients, 49.9% receive VMAT2 inhibitors as first-line monotherapy and 27.7% receive antipsychotics, with 92% and 84% respectively remaining on these drug classes (alone or in combination) throughout follow-up. 8