Huntington disease: Management

INTRODUCTION — Huntington disease (HD) is an inherited progressive neurodegenerative disorder characterized by choreiform movements, psychiatric problems, and dementia. It is caused by a trinucleotide (cytosine-adenine-guanine [CAG]) expansion in the huntingtin (HTT) gene on chromosome 4p and inherited in an autosomal dominant pattern.

Specific issues that affect patients with HD include motor symptoms (chorea, dystonia, other movement disorders, dysphagia, speech and language problems, gait impairment and falls), psychiatric symptoms (psychosis, agitation, anxiety, depression), and cognitive impairment (poor judgment, lack of insight, and eventually dementia). Nonmotor symptoms are becoming increasingly recognized, such as apathy, fatigue, pain, and weight loss.

Treatment of HD is symptomatic and supportive, as there are no disease-modifying therapies yet available. A variety of approaches are under active investigation.

This topic will review the management of HD. Other aspects of HD are discussed separately. (See "Huntington disease: Genetics and pathogenesis" and "Huntington disease: Clinical features and diagnosis".)

GENERAL PRINCIPLES

Multidisciplinary care — HD is a complex and progressive disease with a broad impact on the lives of patients, families, and caregivers. Care is best provided by a multidisciplinary team of clinicians and caregivers who can address both physical and psychological needs and manage new issues as they arise through long-term follow-up.

Ideally, the team spans numerous areas of expertise, including neurology, psychiatry, genetics, social work, physiotherapy, occupation therapy, speech pathology, and nutrition (table 1).

Physical and occupational therapy — Use of physical therapy, occupational therapy, and home care may allow for prolongation of community living.

Evidence-based physical therapy interventions for patients with HD include aerobic exercise and resistance training to improve fitness and motor function, and supervised gait training to improve walking and balance [1]. Limited studies also support inspiratory and expiratory training to improve breathing function and capacity as well as patient and caregiver training on transfers, seating, and positioning in later stages of disease.

Palliative care and advance care planning — HD is a chronic disease with a relatively slow course, and the principles of palliative care are appropriate throughout the course of illness. Palliative care focuses on preventing and relieving suffering and on supporting the best possible quality of life for patients and their families and caregivers facing serious illness.

Prognostic awareness is important to build and reassess at multiple time points in the disease, realizing that there is a large element of individual variability in the natural history of HD. Clinicians should also advise patients about treatment options and help them make treatment decisions while incorporating patient preferences and values (table 2).

Advance care planning is an ongoing process in which patients and their families and caregivers reflect on the patient's goals, values, and beliefs with health care workers. The best time to initiate advance care planning for patients with HD is uncertain [2]. However, it is generally recommended that the discussion be initiated by the clinician when patients begin to show symptoms and signs of disease progression and revisited periodically until clear directives are in place. Conversations should ideally take place while patients can communicate clearly and while they have robust decision-making capacity. (See "Advance care planning and advance directives", section on 'A practical approach to ACP'.)

Advance care planning allows patients to express views on goals of care, future treatments (eg, intensive care unit interventions, resuscitation status, potential use of gastric tube feeding), the place of care, the place of death (eg, home, hospice, or hospital), their legal will, and funeral plans [3,4]. These wishes can be incorporated into an advance directive to guide health care decision-making when capacity is impaired. Despite the importance of advance planning in HD and other neurodegenerative diseases, data indicate that only a minority of patients endorse having an advance directive (38 percent among over 500 patients with HD in one study) [5]. (See 'Late-stage disease' below.)

As a number of countries, including Canada and Switzerland, offer medical assistance in dying, some patients may inquire about and choose this option. It is important to note that only patients who retain capacity can make this decision. Patients who wish to consider this option should be referred to an appropriate team for assessment. (See "Medical aid in dying: Ethical and legal issues" and "Medical aid in dying: Clinical considerations".)

Patient resources — Reputable HD organizations are important community resources, both at the time of diagnosis and throughout the disease process. These include:

●Huntington's Disease Society of America

●Huntington Society of Canada

●European Huntington Association

●Huntington's New South Wales and Australian Capital Territory

●International Huntington Association

The 2011 publication "A Physician's Guide to the Management of Huntington's disease" is a comprehensive source of management information for practitioners regarding the various motor, cognitive, and psychiatric problems associated with HD, and is available as a free PDF download.

MANAGEMENT OF CHOREA — The impact of chorea in patients with HD should be carefully assessed to determine whether any specific treatment is necessary, since it may not be a debilitating or bothersome symptom [6].

Goals and natural history — Treatment is indicated if chorea is prominent and interferes with function, as it may result in injury, falls, difficulty with speech and swallowing, and poor sleep, and contribute to pain and weight loss [7]. Such patients may benefit from pharmacologic and nonpharmacologic interventions. However, pharmacologic treatment of chorea may worsen other aspects of HD, including parkinsonism, cognition, and depression [8]. Suicidality is an additional risk associated with tetrabenazine, deutetrabenazine, and valbenazine.

In many patients, the chorea reaches a peak at approximately 10 years after disease onset followed by a plateau and decline [7], while bradykinesia and rigidity gradually become more prominent in late stages of disease. Thus, treatment directed at chorea should be periodically reconsidered.

Nonpharmacologic interventions — Chorea may increase with anxiety and stress [7]. Providing a calm, predictable, and structured environment along with management of mood disorders may help to ameliorate these problems. Patients with severe chorea may benefit from the use of assistive equipment such as helmets, padded reclining chairs, low beds, and protective padding of the environment.

VMAT2 inhibitors

Patient selection and rationale — For most patients with chorea that interferes with function, we suggest a vesicular monoamine transporter type 2 (VMAT2) inhibitor as first-line therapy (algorithm 1). A major exception is patients with depression, in whom VMAT2 inhibitors should be avoided due to risk of worsening depression and suicidality. In such patients, as well as those with concurrent agitation or psychosis, we use a second-generation antipsychotic drug as first-line therapy. (See 'Antipsychotics' below.)

VMAT2 inhibitors are dopamine-depleting agents that act by inhibiting presynaptic VMAT2 and thus inhibiting release of dopamine at the synapse. In randomized trials in patients with HD, VMAT2 inhibitors reduce chorea by clinically meaningful amounts compared with placebo [9-12]. They may result in reversible parkinsonism, but there is minimal risk of developing tardive dyskinesia, as compared with the antipsychotic drugs. In the absence of comparative studies in patients with HD, the preference for VMAT2 inhibitors over second-generation antipsychotics is largely based on side effect profile.

Three VMAT2 inhibitors are approved for use in patients with HD in the United States. Tetrabenazine is an older drug; deutetrabenazine was approved by the US Food and Drug Administration (FDA) in 2017 but is not available in all countries, including Canada, and valbenazine was approved by the FDA for use in patients with HD in 2023 [13].

In many areas, availability and cost are the main determinants of which VMAT2 inhibitor is chosen. Where available, deutetrabenazine or valbenazine may be preferred over tetrabenazine due to longer half-life and more convenient dosing. Indirect comparisons also suggest better tolerability, although more studies are needed [14,15]. Supportive evidence for each drug is discussed below.

Pretreatment counseling — Before beginning a VMAT2 inhibitor, patients and caregivers should be warned about the potential side effect of depression and suicidality, which may be severe and rapid in onset. When considering the use of these drugs, the risk of suicide must be weighed against the need for treatment of chorea.

We avoid VMAT2 inhibitors as first-line therapy for chorea in patients with depression. There is a lack of agreement on whether depression represents an absolute contraindication to use of VMAT2 inhibitors, however, and some experts may consider cautious use for refractory chorea in patients with adequately treated depression.

Depression may be triggered or exacerbated by all of the VMAT2 inhibitors; although it appears that deutetrabenazine may have lower risk than tetrabenazine, long-term studies in more varied patient groups are needed to confirm whether there is a meaningful difference. (See 'Tetrabenazine' below and 'Deutetrabenazine' below.)

Tetrabenazine — Tetrabenazine can be useful for controlling chorea in patients with HD [8,9], particularly those with milder forms of chorea. Its mechanism of action involves blocking the transport of dopamine into vesicles in the presynaptic terminal. This depletes dopamine from the vesicles and reduces dopamine transmission at the synapse.

●Dosing – The usual starting dose of tetrabenazine is 12.5 mg daily. The dose can be increased to 12.5 mg twice daily after one week, and then by 12.5 mg increments at weekly intervals until chorea improves or side effects become troublesome. Tetrabenazine is usually given three times a day with meals. Since chorea disappears with sleep, a bedtime dose is not required.

Because tetrabenazine is metabolized by cytochrome P450 2D6 (CYP2D6), the manufacturer recommends genotyping to determine CYP2D6 expression for patients requiring doses >50 mg/day. For poor metabolizers, the maximum recommended dose is 50 mg daily (25 mg per dose). For extensive or intermediate metabolizers, the maximum dose is 100 mg/day. When tetrabenazine is used with medications that are CYP2D6 inhibitors (table 3), such as paroxetine and fluoxetine, the dose of tetrabenazine should be decreased by 50 percent [16].

●Side effects – Adverse effects of tetrabenazine include sedation, akathisia, parkinsonism, orthostatic hypotension, and depressed mood. There is also a risk of suicidality, and labeling in the United States carries a boxed warning on the risk of depression and suicidal thoughts and behaviors in patients with HD. Among 54 patients assigned to tetrabenazine in a 12-week trial, there was one suicide, and poor tolerance led to a dose reduction in 44 percent [17].

Subsequent observational studies have attempted to further understand the relationship between depression, suicidality, and tetrabenazine use [18,19]. A retrospective study of over 4000 patients with HD enrolled in a multicenter longitudinal observational study included 542 patients exposed to tetrabenazine for a median of 2.6 years [18]. In analyses stratified by a baseline history of depression, tetrabenazine use was not associated with an increased risk of depression or suicidality compared with nonuse. Nonetheless, clinicians should remain vigilant in monitoring patients for depressive symptoms, including suicidal thoughts and behaviors, at every visit. (See 'Depression and anxiety' below.)

●Efficacy – In a double-blind controlled trial, ambulatory patients with HD were randomly assigned to tetrabenazine at a maximum dose of 100 mg daily (n = 54) or placebo (n = 30) for 12 weeks [17]. Tetrabenazine treatment resulted in a significant reduction in chorea severity, measured as a change in the chorea score of the Unified Huntington Disease Rating Scale (UHDRS), compared with placebo (5 versus 1.5 units, adjusted mean effect size -3.5, 95% CI -5.2 to -1.9). This change represented a clinically meaningful 24 percent reduction in chorea from baseline severity. Another randomized trial of 30 patients on tetrabenazine treatment for HD found that tetrabenazine withdrawal led to a statistically significant increase in the UHDRS chorea score [20].

Deutetrabenazine — Deutetrabenazine is the deuterated form of tetrabenazine. The potential advantages of deutetrabenazine include attenuated metabolism and a prolonged plasma half-life, permitting less frequent and lower dosing and a more favorable risk-benefit profile compared with tetrabenazine [10]. However, deutetrabenazine does not have regulatory approval in some countries, such as Canada.

●Dosing – The recommended starting dose of deutetrabenazine in patients with HD is 6 mg twice daily. A once-daily extended-release formulation is also available. The dose may be titrated weekly in increments of 6 mg/day based upon response and tolerability. Deutetrabenazine is given in two divided doses if the total daily dose is ≥12 mg. The maximum recommended dose is 36 mg/day in patients taking CYP2D6 inhibitors (table 3) and 48 mg/day in all others.

●Side effects – In the randomized trial, the rate of adverse events with deutetrabenazine was similar to placebo [10]. Like tetrabenazine, deutetrabenazine can cause sedation, akathisia, parkinsonism, orthostatic hypotension, and depression, and the label carries a boxed warning on the risk of depression and suicidality. Additional warnings include the potential for QT prolongation and neuroleptic malignant syndrome.

●Efficacy – In a 12-week, randomized controlled trial of 90 ambulatory patients with HD, the mean total maximal chorea score decreased by 2.5 units compared with placebo (95% CI 1.3-3.7) [10]. The deutetrabenazine group also had improvement on several secondary endpoints. However, it is uncertain whether the observed difference in the total maximal chorea score was clinically meaningful [10,21]. Dosing was started at 3 mg twice a day, with some patients taking up to 48 mg a day. In patients with impaired CYP2D6 metabolism, the highest dose tolerated was 42 mg.

Further studies are needed to determine longer-term safety and efficacy in comparison with other VMAT2 inhibitors.

Valbenazine — Valbenazine is a selective VMAT2 inhibitor with a 15- to 22-hour half-life that allows for once-daily dosing. Valbenazine is approved in the United States for treatment of tardive dyskinesia as well as for treatment of chorea in patients with HD.

●Dosing – The starting dose of valbenazine is 40 mg daily. The dose can be increased by 20 mg every two weeks as needed to a maximum dose of 80 mg daily. The maximum recommended dose is 40 mg per day in patients taking strong CYP2D6 inhibitors (eg, paroxetine, fluoxetine, bupropion) (table 3) or strong CYP3A4 inhibitors (table 4). Specific interactions may be determined using the drug interactions program included within UpToDate.

●Side effects – In the randomized trial, the rate of adverse events with valbenazine was generally well tolerated [12]. The most common reasons for dose reduction were fatigue and somnolence. Like other VMAT2 inhibitors, valbenazine can also cause akathisia, parkinsonism, orthostatic hypotension, and depression, and the label carries a boxed warning on the risk of depression and suicidality. Additional warnings include the potential for QT prolongation and neuroleptic malignant syndrome.

●Efficacy – Supporting evidence includes results of a 12-week randomized controlled trial in 128 patients with HD, in which valbenazine improved the mean total maximal chorea score by 3.2 units compared with placebo (95% CI 2.0-4.4) [12]. The starting dose of valbenazine was 40 mg daily and could be titrated by 20 mg every two weeks up to a target dose of 80 mg daily (reached by 82 percent of patients by the week 12 visit).

Further studies are needed to determine longer-term safety and efficacy in comparison with other VMAT2 inhibitors.

Switching from tetrabenazine to deutetrabenazine — Results from a small observational study suggest that overnight conversion from tetrabenazine to deutetrabenazine therapy is safe and well tolerated, beginning with a deutetrabenazine dose that is approximately one-half the prior tetrabenazine dose [22]. Thereafter, the deutetrabenazine dose can be adjusted each week for optimum control of chorea.

Second-line and adjunctive pharmacotherapies — For patients who have chorea that does not respond to tetrabenazine or deutetrabenazine or in whom VMAT2 inhibitors are not tolerated, we switch to antipsychotic therapy (algorithm 1). In such cases, adding the antipsychotic drug and then gradually tapering tetrabenazine or deutetrabenazine once the chorea improves is recommended. (See 'Antipsychotics' below.)

Benzodiazepines may be added intermittently when there is a transient worsening of chorea in stressful situations. (See 'Benzodiazepines' below.)

Combining a VMAT2 inhibitor with an antipsychotic agent may be beneficial for patients with debilitating chorea who fail treatment with first-line monotherapy. This is usually only considered in patients without depression (see 'Pretreatment counseling' above). Cautious dosing is required due to overlapping toxicities. Use of a first-generation antipsychotic may be helpful or necessary for refractory chorea.

For patients who do not respond to or tolerate the VMAT2 inhibitors or antipsychotic drugs, other treatment options such as cannabinoids, amantadine, levetiracetam, and topiramate have been suggested. The effectiveness of these agents is not established, however. (See 'Other medications' below.)

Antipsychotics — Antipsychotics act by blocking dopamine transmission, and have the potential benefit of treating both chorea and psychiatric symptoms such as agitation and psychosis. (See 'Psychosis and agitation' below.)

Few studies are available comparing different agents in HD. Thus, the choice among antipsychotics is largely empiric and based on clinical experience. In patients with moderate chorea, the use of first-generation antipsychotics has been largely replaced by the use of second-generation agents, such as risperidone, olanzapine, or aripiprazole, which may have fewer side effects [23]. In cases of severe chorea, treatment with the more potent first-generation antipsychotic agents such as haloperidol or chlorpromazine may be helpful.

Caution should be used if parkinsonian features are present prior to starting these agents, as all antipsychotics can worsen these symptoms.

We suggest not using clozapine or quetiapine for chorea since they do not have a significant antichoreic effect until very high doses are used [24,25]. In addition, use of clozapine is associated with a risk of life-threatening agranulocytosis.

●Second-generation antipsychotics – The following second-generation antipsychotic agents have been used to treat chorea in patients with HD:

•Risperidone may be beneficial for treating chorea in patients with HD, although supporting evidence is limited to case series and case reports [23,26-29]. Risperidone should be started at 0.5 to 1 mg once or twice a day, and the total dose may be increased up to 10 mg daily as needed and tolerated [7,26,30]. Side effects include sedation and parkinsonism.

•Olanzapine was considered possibly useful for treating chorea in a systematic review [31]. In one 14-day open-label study, nine patients were treated with olanzapine starting at 5 mg daily, and the dose was increased every third day until an adverse event or a satisfactory response occurred, up to a maximum of 30 mg daily [32]. All patients experienced a response in most of the motor subscores of the UHDRS. However, based upon the author's clinical experience, olanzapine should be started at 2.5 mg daily, and is usually effective in the range of 5 to 10 mg daily. Sedation and weight gain can be seen, in addition to parkinsonism.

•Aripiprazole may have beneficial effects on chorea, as reported in a case series of three patients with HD [33] and a six-month crossover trial of six patients with HD that compared aripiprazole with tetrabenazine [34]. In the trial, the drug was initiated at 2.5 mg daily, with slow escalation up to 15 mg daily. In addition to benefit on chorea, psychiatric symptoms (and perhaps even cognition) were improved.

Aripiprazole has a longer half-life than most other antipsychotics (≥75 hours), and a week or more should generally elapse in between dose increases. Side effects are similar to other second-generation antipsychotics, except that the risk of metabolic syndrome may be less. It may also result in less sedation than tetrabenazine. Larger controlled trials are warranted.

●First-generation antipsychotics – A systematic review of clinical studies evaluating pharmacologic treatments for HD concluded that haloperidol and fluphenazine were possibly useful for treating chorea in patients with HD [31]. Haloperidol can be started at 0.5 to 1 mg daily and increased up to 10 mg daily [7]. Occasionally, higher doses are required. Fluphenazine can be used at the same doses as haloperidol. Side effects of these drugs include sedation, parkinsonism, dystonia, akathisia, and hypotension.

Benzodiazepines — Benzodiazepines such as clonazepam or lorazepam may be used in the short term to decrease severe episodes of chorea, but they are not useful or well tolerated as continuous therapy. As there are no studies to determine dosing, clinician experience and good clinical judgment are important, particularly as their use may be associated with worsening cognition.

Other medications — Other medications (eg, amantadine, cannabinoids, and anticonvulsants) have limited or inconsistent evidence of efficacy for treating chorea.

●Cannabinoids – A few small placebo-controlled trials have evaluated cannabinoids in HD. In a crossover trial of 15 patients with HD, cannabidiol (CBD) was not effective for improving clinical outcomes, including chorea [35]. Another crossover trial of 22 patients with five-week treatment blocks found that the synthetic cannabinoid nabilone (1 or 2 mg daily) decreased UHDRS chorea scores by 1.7 points compared with placebo [36].

Guidelines from the American Academy of Neurology concluded that nabilone possibly modestly improves HD chorea [8]. However, nabilone is not available in the United States and is a psychoactive controlled substance with a potential for drug abuse and dependency. Further trials are needed to determine long-term benefits and potential side effects for cannabinoids.

●Amantadine – The utility of amantadine for chorea in patients with HD is uncertain. Although amantadine may be tried, the author's clinical experience suggests it is not effective.

Evidence from four small, randomized, double-blind, placebo-controlled trials is conflicting [37-40]. However, based upon results from two of these trials [37,39], guidelines from the American Academy of Neurology conclude that amantadine is likely effective in decreasing HD chorea, though the degree of benefit is unknown [8].

Amantadine can worsen cognitive function in patients with HD, particularly at high doses (eg, ≥300 mg daily). Therefore, it should be dosed cautiously. Leg swelling and livedo reticularis are relatively common side effects.

●Anticonvulsants – Levetiracetam reduced chorea in a small open-label study [41]. Other anticonvulsants, such as topiramate, have been reported to improve chorea (but not specifically in HD) in case reports [42].

OTHER MOTOR SYMPTOMS

Dystonia and other movement disorders — Other movement disorders that may complicate HD include dystonia, rigidity, bradykinesia, tics, myoclonus, and impaired voluntary motor control. There are only limited data for pharmacologic treatment of these motor impairments in patients with HD.

●Dystonia is a characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive movements, postures, or both. Dystonic movements are typically patterned and twisting, and may be tremulous. Generally, dystonia is not prominent or disabling in adult patients with HD.

Pharmacologic treatment options in more severe cases include benzodiazepines, baclofen, and dopaminergic agents [7]. Botulinum toxin injections may be considered as an option for focal dystonia. Nonpharmacologic treatments including braces, pads, or splints may be helpful for patients with severe dystonia, under the supervision of physical or occupational therapy.

●Bradykinesia and rigidity can be unmasked or worsened with pharmacologic treatment of chorea. Generally, rigidity and bradykinesia in HD do not respond to addition of dopaminergic therapy. In exceptional cases when patients with HD develop or present with a severe akinetic-rigid syndrome (such as seen in juvenile-onset HD), treatment with levodopa or dopamine agonists (eg, pramipexole and ropinirole) has been tried. However, the evidence of benefit is limited to case series and case reports [31,43,44]. In addition, these medications may worsen the cognitive and behavioral problems associated with HD. Therefore, the use of levodopa and dopamine agonists to treat motor problems for patients with HD should be attempted only by clinicians with expertise in movement disorders and/or HD.

●Tics are sudden, brief, intermittent movements (motor tics), gestures, or vocalizations. Treatment options for severe tics include benzodiazepines, selective serotonin reuptake inhibitors, antipsychotics, and tetrabenazine or deutetrabenazine [7].

●Myoclonus is characterized by brief, shock-like, involuntary movements. It may respond to treatment with clonazepam [7].

●Impaired voluntary motor control is a major problem for patients with HD but lacks any effective pharmacologic treatment [7].

Dysphagia — Speech therapy and dietary services are beneficial in managing dysphagia and weight loss. A high-calorie diet is frequently needed due to the high metabolic requirements in patients with HD.

As the disease progresses and oral and pharyngeal coordination declines, the diet can be switched to pureed foods and thickened beverages to reduce the risk of choking [7]. Routine dental care may help to maintain oral and dental health [45].

Dysphagia and aspiration pneumonia are common causes of death in patients with end-stage HD [3]. The potential use of gastric tube feeding should be discussed with the patient and caregivers, ideally while the patient can communicate clearly and has full capacity, and before motor symptoms and cognitive decline become severe. (See 'Palliative care and advance care planning' above.)

Speech and language problems — Patients with HD frequently develop language impairment due to difficulties with articulation, speech initiation, and cognitive deficits [46]. Speech comprehension is generally preserved even in mid- to late-stage HD. However, the ability to speak is often impaired.

Speech therapy is the main option when speech articulation or intelligibility is affected by motor or cognitive dysfunction in HD [7]. Strategies that may help the patient with HD improve communication include allowing additional time for the person with HD to respond, using yes or no questions, and using short, simple sentences [46].

Gait impairment and falls — Gait and balance issues should be assessed by a physical therapist, and a walker and/or wheelchair used as indicated to prevent falls. Hip protectors may be considered to help decrease the risk of hip fractures, since falls are common in the late stages, although evidence of benefit is lacking.

NEUROPSYCHIATRIC SYMPTOMS

Psychosis and agitation — For patients with HD who have psychosis and/or disruptive behavioral symptoms, we suggest starting treatment with quetiapine 12.5 mg daily given at bedtime, and gradually titrating up by 25 mg every one to two weeks as tolerated until symptoms improve. The maximum suggested dose is 600 mg daily, given in two or three divided doses. Quetiapine does not cause worsening of bradykinesia.

Olanzapine, aripiprazole, and risperidone are alternative choices that may be preferred for patients who also have debilitating chorea. In rare cases, first-generation antipsychotics such as haloperidol can be considered. Ongoing assessment by a psychiatrist is recommended to determine treatment optimization. (See 'Antipsychotics' above.)

There are no rigorous or head-to-head clinical trials confirming the effectiveness of these drugs [47,48]. However, there is evidence from case reports and case series showing benefit with quetiapine [25,49,50], olanzapine [51,52], risperidone [27,30,53], and aripiprazole [33,54,55].

As with chorea, providing a calm, predictable, and structured environment may be helpful for ameliorating psychiatric and behavioral symptoms in patients with HD [56]. Additional nonpharmacologic strategies for managing agitation are reviewed separately. (See "Management of neuropsychiatric symptoms of dementia", section on 'Agitation or aggression'.)

Depression and anxiety — Depression is a common symptom of HD and should be asked about at every visit, along with a screen for suicidal thoughts or behavior. (See "Unipolar depression in adults: Assessment and diagnosis" and "Suicidal ideation and behavior in adults", section on 'Patient evaluation'.)

Depression can be effectively managed with selective serotonin reuptake inhibitors or with tricyclic antidepressants. However, patients with HD may have an increased risk of cognitive side effects with some antidepressants, and some experts avoid older agents such as tricyclic antidepressants or consider them as second line [56]. The treatment of depression is reviewed separately. (See "Unipolar major depression in adults: Choosing initial treatment" and "Unipolar depression in adults: Choosing treatment for resistant depression".)

Anxiety can be a major symptom, and treatment with selective serotonin reuptake inhibitors and benzodiazepines can be helpful. Formal assessment and ongoing care by a psychiatrist for depression and anxiety to optimize treatment is recommended.

Cognitive impairment and dementia — There is no known effective therapy for the dementia associated with HD, which includes lack of insight and poor judgment. Apathy can be prominent in some patients, leading to family confrontations.

Small studies and case reports in patients with HD have failed to show clear improvement for cognitive impairment with the cholinesterase inhibitors donepezil [57], rivastigmine [58,59], and galantamine [60]. Side effects from these medications in patients with HD can be significant. Clinical data for memantine in HD are scant.

Counseling for family and caregivers is frequently needed to explain symptoms and how best to deal with them. The care of patients with advanced dementia is reviewed in more detail separately. (See "Management of neuropsychiatric symptoms of dementia" and "Care of patients with advanced dementia".)

Driving safety — Driving restrictions should be addressed when cognitive impairment begins to impact decision-making. (See "Management of the patient with dementia", section on 'Driving'.)

PAIN MANAGEMENT — Common causes of pain in patients with HD include severe chorea, dystonia, or rigidity; contractures; occult fractures and musculoskeletal injuries; pressure sores; urinary retention; and severe constipation [7]. Pain can also occur as a nonmotor symptom. However, pain in HD may be underreported due to unawareness (agnosia) related to cognitive dysfunction.

The management of pain in HD should include treatment directed at the underlying motor disorders (eg, chorea, dystonia, repetitive falls) and complications (eg, urinary retention) that are contributing causes [7]. Treatment with simple analgesics (eg, acetaminophen, nonsteroidal antiinflammatory drugs) can be helpful. No studies are available that address treatment of pain specifically in the HD population.

LATE-STAGE DISEASE — Patients in the late stage of HD, which can last five years or longer, require round-the-clock supervision and care in all activities of daily living [3]. Most often, this necessitates placement into a long-term care facility. (See "Huntington disease: Clinical features and diagnosis", section on 'Late stage'.)

In this stage of disease, multidisciplinary, palliative care is important to attend to issues involving diet, behavior, communication, safety, hygiene, comorbid medical problems, caregiver support, and spiritual support [3]. Some experts recommend that all patients in late-stage HD should receive regularly scheduled analgesics (eg, acetaminophen or nonsteroidal antiinflammatory drugs every six to eight hours) to treat pain caused by rigidity and immobility; analgesics may be used in combination with low-dose opioids (eg, hydrocodone with acetaminophen) as immobility worsens [7]. Dysphagia increases the risk of aspiration pneumonia, highlighting the importance of advance care planning for decisions about placing a gastrostomy tube. (See 'Palliative care and advance care planning' above.)

The terminal stage of HD may be heralded by loss of ambulation, inability to speak or interact, inability to eat, and/or weight loss [3]. For patients who appear to be at increased risk of death within a few days to a few months, hospice care is often appropriate and can be performed in the home, in a hospital, or in a care facility. The emphasis of care shifts to comfort, pain relief, caregiver involvement, and dignity rather than aggressive treatment of symptoms. Medications necessary for comfort should be continued. Some symptoms can increase in the terminal phase, including dystonia, drooling, and agitation. These may be treated with appropriate agents (eg, muscle relaxants for dystonia, glycopyrrolate or botulinum toxin injections into the salivary glands for drooling, and antianxiety medications for agitation) if they are causing pain or discomfort. (See "Management of nonmotor symptoms in Parkinson disease", section on 'Sialorrhea' and "Palliative care: The last hours and days of life".)

INVESTIGATIONAL THERAPIES — Disease-modifying treatment for HD is not yet available [61], but a number of pharmacologic, surgical, and genetic approaches that might delay disease onset or slow progression are being tested [62-65].

Gene silencing through RNA interference [66] and antisense oligonucleotide (ASO) [67,68] techniques can reduce mutant human huntingtin expression in HD animal models and improve motor and/or neuropathologic disease manifestations. In an early-phase trial in 46 patients with early-onset HD, monthly intrathecal injections of an ASO directed against mutant huntingtin (HTT) were safe and resulted in a dose-dependent decrease in the concentration of mutant huntingtin protein in cerebrospinal fluid compared with placebo injections [69]. Several large ASO trials were halted prior to completion due to lack of efficacy, however [70-72]. Trials with alternative ASO formulations have resumed.

Other therapies under investigation include splicing modifiers and monoclonal antibodies. Challenges that persist include a lack of good biomarkers to inform efficacy and timing of disease-modifying treatments.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Huntington disease".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Huntington disease (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Goals of care – Huntington disease (HD) is a condition of relentless progression of motor, cognitive, and psychiatric symptoms. Treatment is supportive and aims to manage symptoms and optimize quality of life. Care is best provided by a multidisciplinary team (table 1). (See 'General principles' above.)

Prognostic awareness is important to build and reassess at multiple time points, realizing that there is a large element of individual variability in the natural history of HD. (See 'Palliative care and advance care planning' above.)

●Chorea – Symptomatic treatment of chorea should be reserved for patients with symptoms that interfere with functioning, as treatment may worsen other aspects of HD, including parkinsonism, cognition, and mood. (See 'Goals and natural history' above.)

For patients who require therapy, we choose among therapies according to whether there are significant psychiatric symptoms or comorbidity (algorithm 1):

•In most nondepressed patients with HD who have chorea that interferes with function, we suggest initial treatment with a vesicular monoamine transporter type 2 (VMAT2) inhibitor (deutetrabenazine, valbenazine, or tetrabenazine) (Grade 2C). VMAT2 inhibitors carry a risk of depression and suicidality; pretreatment counseling and monitoring are essential. (See 'VMAT2 inhibitors' above.)

Second-generation antipsychotics are an alternative to VMAT2 inhibitors and are appropriate first-line therapy in patients with depression or concurrent agitation or psychosis. (See 'Antipsychotics' above.)

•Among second-generation antipsychotic drugs in patients with chorea, we suggest use of risperidone, olanzapine, or aripiprazole (Grade 2C). These drugs tend to have a more favorable balance of efficacy to adverse effects compared with other second-generation antipsychotics and compared with first-generation antipsychotics. (See 'Antipsychotics' above.)

•For patients who fail or do not tolerate first-line therapy, treatment depends on prior therapies, side effects, and comorbidities (algorithm 1). We generally try monotherapy with the alternative class before resorting to combination therapy. (See 'Second-line and adjunctive pharmacotherapies' above.)

•When chorea becomes severe, padded reclining chairs and bed padding are recommended to reduce the risk of injury. (See 'Nonpharmacologic interventions' above.)

●Other movement disorders – Other movement disorders that may complicate HD include dystonia, rigidity, bradykinesia, tics, myoclonus, and impaired voluntary motor control. Symptomatic therapies exist for some of these symptoms. (See 'Dystonia and other movement disorders' above.)

●Psychotic symptoms – For patients with HD who have psychosis and/or disruptive behavioral symptoms but lack debilitating chorea, we suggest initial treatment with quetiapine (Grade 2C). Olanzapine, aripiprazole, or risperidone are alternative choices, which may be preferred for patients who also have severe chorea. (See 'Psychosis and agitation' above.)

●Mood disorders – Depression and anxiety are common symptoms of HD. These are usually managed with selective serotonin reuptake inhibitors or tricyclic antidepressants, though the latter may be more likely to cause adverse effects. Anxiolytics may be considered for anxiety. (See 'Depression and anxiety' above.)

●Dementia – There is no known effective therapy for dementia associated with HD, and treatment is supportive. (See 'Cognitive impairment and dementia' above.)