A Choreographed Approach to the Treatment of Chorea

Chorea is a hyperkinetic movement disorder characterized by involuntary, irregular, purposeless movements that vary in amplitude and velocity, occur randomly, and move from one body part to another. Chorea can affect people at all ages. Because of the heterogenous nature of chorea, there are no large studies that estimate the overall prevalence of this condition; however, the most common cause of inherited chorea—Huntington disease (HD)—affects 4.8 in 100,000 people globally.¹

Chorea can be inherited or acquired, and the underlying cause dictates whether it presents in childhood or adulthood. Numerous genetic conditions can present with an HD-like phenotype, including C9orf72 repeat expansions and spinocerebellar ataxia type 17 (SCA17).^2,3 Neuroacanthocytosis, Wilson disease, Fahr disease, dentatorubropallidoluysian atrophy, and other progressive neurologic syndromes can include chorea. Benign hereditary chorea typically presents in childhood and has a milder, less progressive course.

Medication-induced chorea is likely the most common cause of secondary chorea and includes tardive phenomena associated with the use of neuroleptics (antipsychotics) and levodopa-induced dyskinesia. Poststreptococcal chorea (Sydenham chorea) is a common example of postinfectious chorea, which may also be seen with viral infections. Chorea may be a presenting feature of an autoimmune disorder (with systemic lupus erythematosus being the most common) or a paraneoplastic disorder (most commonly associated with anti-Hu or anti–CRMP-5 antibodies in the context of small cell lung cancer). In addition, structural or metabolic lesions to the basal ganglia can cause acute onset of chorea, typically presenting asymmetrically or with hemichorea.

When Does Chorea Require Treatment?

Not all chorea cases require treatment. Among the phenomenological classifications of movement disorders, chorea is associated with a high degree of anosognosia.⁴ It may be socially embarrassing (including for caregivers), but this feature can make chorea less bothersome to the individual, therefore precluding the need for treatment. However, even if chorea is not bothersome, examination and a detailed history from patients and caregivers may reveal indications to treat, as patients may not be aware of how the movements are affecting their daily lives.

Chorea that interferes with activities of daily living (eg, the ability to dress, eat, chew, or attend to personal hygiene effectively) likely requires treatment. Chorea can cause safety concerns or physical harm. For example, oral-buccal chorea may cause injury to the tongue, oral mucosa, or teeth. Falls or injury can be sustained when safe ambulation or balance are affected, or in individuals who cannot maintain a seated position because of trunk or limb movements.⁵ Because chorea can persist during sleep, falls from bed can cause injury and require accommodations. Large-amplitude movements can put caregivers or others in proximity (particularly children or elderly people) at risk of injury. Furthermore, chorea may cause fatigue or pain. Because of a constant caloric deficit, individuals may precipitously and unintentionally lose weight in the setting of chorea. All these factors can lead to a loss of independence and psychosocial impairment.

Social factors influencing the decision to treat chorea include embarrassment or perceived stigma, difficulty maintaining relationships or employment, and social isolation because of the inability to participate in activities or conversations at the same level as peers.⁶ Common perceptions that chorea is uncomfortable or painful or that it is caused by intoxication contribute to stigma and lead to further social embarrassment. Careful attention must be paid to individual function and social factors to determine the need for treatment and to avoid overtreating chorea.

Treatment Approach

Once the decision to treat chorea has been made, consideration of etiology can have a large influence on management strategies (see Figure; see also article by Furr Stimming, Zadegan, and Patino elsewhere in this issue for an overview of the etiologies of chorea and the essential clinical steps for evaluation and differential diagnosis). Treating the underlying cause of chorea is preferred over symptomatic management. Autoimmune or paraneoplastic chorea should be addressed by the appropriate immunosuppressive therapy. Some inherited conditions associated with chorea can be treated with disease-specific therapies (eg, chelation therapy for Wilson disease), although disease-modifying treatments for these conditions are limited. In the case of medication- or substance-induced chorea, decreasing or stopping causative agents should be attempted.

Symptomatic pharmacotherapy can be offered when the root cause of chorea cannot be treated directly (see Table); however, the etiology may continue to influence medication selection. For example, neuroleptic exposure should be avoided in individuals with tardive chorea. In individuals requiring neuroleptic therapy, changing to an antipsychotic regimen with lower affinity to dopamine receptors, such as quetiapine or clozapine, might reduce harm. Conversely, in individuals with HD, neuroleptics with higher D2 affinity may be preferred to address a combination of symptoms (including psychiatric and behavioral symptoms, weight loss, and sleep disturbance) with one medication. Similarly, in individuals with levodopa-induced dyskinesia, amantadine can reduce dyskinesia, parkinsonism, and tremor.⁷

Once a medication has been selected, close monitoring for adverse effects must ensue. Vesicular monoamine transporter 2 (VMAT2) inhibitors carry risks of depression, suicidality, and parkinsonism, and individuals treated with VMAT2 inhibitors must be assessed carefully for these symptoms at each visit.⁸ Individuals being treated with dopamine receptor blockers are at risk of developing parkinsonism or other extrapyramidal side effects.^9,10 Moreover, many of the available medications can cause metabolic syndrome; therefore, weight, lipid levels, and blood glucose levels must be monitored, and caution is advised when prescribing dopamine receptor blockers to individuals with comorbidities such as diabetes and obesity.¹¹

Individuals with progressive chorea can benefit from multidisciplinary evaluation and treatment that can be modified over time.¹² Incorporation of physical and occupational therapy can help individuals with compensatory strategies, balance and strength training, fall safety education, and use of assistive devices. Speech therapy is particularly beneficial for those with facial or head and neck chorea that leads to problems with speech, eating, or swallowing. Evaluation by a nutritionist can assist with unintended weight loss and avoidance of medication side effects. Multidisciplinary team members can include social workers and psychiatric specialists to help with psychosocial comorbidities.

For medically refractory chorea or for people with medication contraindications, participation in research and clinical trials can be considered. Likewise, research participation is also highly encouraged to further ellucidate disease-specific mechanisms and therapies. Current research into chorea is largely focused on HD, with many exciting investigations of disease-modifying therapies that could address chorea as well as other symptoms. A common goal of many interventions is to lower the amount of mutant huntingtin (HTT) production. Intrathecal delivery of tominersen, an antisense oligonucleotide against the HTT gene transcript, is currently being investigated again (A Study to Evaluate the Safety, Biomarkers, and Efficacy of Tominersen Compared With Placebo in Participants With Prodromal and Early Manifest Huntington’s Disease [GENERATION HD2], NCT05686551) after the first phase III trial was stopped early due to concerns about worse outcomes in the treatment group.^13,14 An orally administered small molecule splicing-modulator of HTT mRNA is also under investigation (A Study to Evaluate the Safety and Efficacy of PTC518 in Participants With Huntington’s Disease [HD], NCT05358717).¹⁵ Two ongoing trials are investigating intracranial administration of AMT130, a modified viral vector expressing a microRNA targeting exon 1 HTT mRNA (Safety and Efficacy of AMT-130 in European Adults With Early Manifest Huntington’s Disease, NCT05243017; Safety and Proof-of-Concept [POC] Study With AMT-130 in Adults With Early Manifest Huntington’s Disease, NCT04120493).^16,17 A phase 2 study of pridopidine, a sigma-1 receptor agonist with neuroprotective effects against mutant huntingtin (mHTT)-induced cell death, showed modest improvement in functional outcomes for patients with HD (PRidopidine’s Outcome On Function in Huntington Disease [PROOF-HD], NCT04556656) and outcomes of a phase 3 trial are pending.^18,19 Some trials (eg, Efficacy and Safety on SOM3355 in Huntington’s Disease Chorea, NCT05475483) focus primarily on symptomatic treatments, such as SOM3355, a beta-1 adrenoreceptor antagonist with VMAT2 inhibitory properties, which is currently being studied in phase II studies evaluating reduction in chorea in HD.²⁰

There are no FDA-approved surgical treatments for chorea, however FDA expanded pathway programs allow for investigational medical products to be used for treatment outside of clinical trials in severe, refractory cases. Evidence of chorea treatment with pallidotomy is limited to case reports, and this approach is not commonly used.^21-23 Published case series on the use of deep brain stimulation suggest that stimulation of the globus pallidus interna can improve chorea, but improvement in functional outcomes have not been demonstrated clearly.^24,25 Limitations of these studies include lack of blinding, randomization, and long-term follow-up.

Pharmacologic Therapy

VMAT2 inhibitors are the only class of medications approved by the Food and Drug Administration to treat chorea. Medications in this class vary in indication, molecular structure, receptor selectivity, dosing, and side effect profile. Their specific indications include HD and tardive syndromes, but they are frequently used off-label to treat people with other types of chorea. Cost can be a limiting factor when using this class of medications, especially in off-label use, and many individuals may need support from patient assistance programs.

Tetrabenazine, the first in its class to be approved, was shown in randomized controlled trials (RCTs) to be effective for treating chorea in individuals with HD.^26,27 Use of tetrabenazine can be limited by sedation, depressed mood, and need for frequent dosing.²⁶ Deutetrabenazine (Austedo; Teva Neuroscience, Kansas City, MO) replaces 2 hydrogen atoms in tetrabenazine with deuterium, reducing its metabolism, stabilizing blood concentrations, and providing less frequent dosing options. Deutetrabenazine is effective for treating both HD-associated chorea and tardive dyskinesia, and side effects of deutetrabenazine treatment were not significantly different when compared with placebo groups.^28,29 Valbenazine (Ingrezza; Neurocrine Biosciences, San Diego, CA), which selectively targets the VMAT2 protein, was recently approved for the treatment of chorea in people with HD and tardive dyskinesia after a RCT showed its ability to lower the total chorea score on the Unified Huntington’s Disease Rating Scale. Sedation was the most common side effect associated with valbenazine treatment.^30,31

Dopamine receptor blockers are commonly used off-label to treat chorea. Atypical antipsychotics (eg, olanzapine, risperidone) are favored over older typical antipsychotics (eg, haloperidol) because of their reduced side effect profile. In small open-label studies, olanzapine improved chorea in individuals with HD and was well-tolerated overall with beneficial effect on behavioral symptoms as well.^32,33 Small studies have also demonstrated that clozapine improved chorea in individuals with HD despite its minimal D2 receptor blockade, but clozapine treatment also requires frequent laboratory monitoring because of the risk of agranulocytosis.³⁴

Other classes of medications are used clinically despite less robust evidence supporting their use, including antiglutaminergic medications, antiseizure medications, cannabinoids, and botulinum toxins. Antiglutamatergic medications are often used to treat chorea and have been studied in several populations. Amantadine is best known for effectiveness against levodopa-induced dyskinesia. However, data are mixed in randomized studies of individuals with HD and tardive dyskinesia.^35-37 Placebo-controlled trials of riluzole showed a significant reduction in Unified Huntington’s Disease Rating Scale total chorea scores at high doses.³⁸

Antiseizure medications can be a particularly attractive option for individuals with comorbid epilepsy and chorea. Sodium channel blockers appear to be most beneficial for chorea of specific etiologies in children, including Sydenham chorea and paroxysmal kinesigenic dyskinesia, and are also used to treat HD.^39-41 Some evidence supports the use of longer-acting benzodiazepines to treat tardive dyskinesia, although its effect may be more on dystonic rather than choreic dyskinesia, and relief of symptoms is usually limited by side effects.⁴²

Despite much discussion of the use of cannabinoids in treating chorea, there is limited evidence of associated benefit with use. Nabilone (Cesamet; Bausch Health US, Bridgewater, NJ), a synthetic cannabinoid, was linked with improvements in chorea symptoms in a double-blind placebo-controlled study; however, a study of Sativex, a combination of delta-9-tetrahydrocannabinol and cannabidiol, which likely more accurately reflects the composition of commercially available cannabis products, did not show any significant improvement in chorea.^43,44

There is not sufficient evidence to support the use of botulinum toxin to treat generalized chorea as the movements are typically too widespread for this therapy to be effective. In cases of focal and localized chorea, however, treatment with botulinum toxin may be attempted.

Conclusion

Chorea treatment requires a careful assessment of the suspected etiology as well as the underlying indication for treatment. Clinicians should be strategic when considering medication options and keep in mind the underlying cause as well as any comorbid symptoms to select the optimal medication for each individual. Additionally, there are many benefits to multidisciplinary, nonpharmacologic approaches to the treatment of chorea.