Approach

Optimal management of Huntington's disease requires a multidisciplinary approach. Patients usually benefit from a combination of pharmacological and non-pharmacological treatments.

Depression

The most serious treatable problem both in those at risk for the disease or in those who have been diagnosed is depression. Treatment of depression is vital and reduces the risk of suicide.

Evidence-based guidelines of pharmacological treatments specifically relating to Huntington's disease are very limited. The recommendations here are, therefore, primarily based on clinical consensus and expert opinion.[56][57][58][59][60][61][62] If there are adverse events or failure of response to any drug, trial of another medication or consideration of referral to a psychiatrist is recommended.

First-line treatments are antidepressant medicine and counselling. Depressive symptoms respond well to antidepressant medicine.[63][64][65] Treatment is similar to treating depression in the general population. However, given the increased risk of suicide, additional precaution about the potential of intentional medicine overdose needs to be considered while prescribing.

Comparative studies of antidepressants in Huntington's disease are not available, so choice of agents is based on clinical judgement relating to likely benefit and harms, suicide potential from overdose, and associated behavioural symptoms. Serotonin- and noradrenaline-reuptake inhibitors (e.g., fluoxetine, sertraline, escitalopram) are most commonly used. If one drug fails, others should be tried. In emergent or severe cases, drugs with a more rapid onset of action, such as mirtazapine, may be considered.[63] In patients with refractory depression, electroconvulsive therapy can be of significant benefit and does not aggravate other aspects of Huntington's disease.[66][67][68][69]

Counselling of patients with Huntington's disease involves recognition of impulsivity, and safety advice regarding driving, use of firearms, and discarding accumulated prescription medicines. Almost all patients benefit from counselling about behavioural and genetic aspects of the illness and carer demands. It is helpful to discuss variations in the disease. If there has been a particularly problematic experience in the family, such information can be comforting.

Anxiety

Anxiety is a common symptom and may respond to a variety of treatments, including selective serotonin reuptake inhibitors (SSRIs), buspirone, and benzodiazepines.[70][71]

Obsessive-compulsive behaviours and perseveration

Patients may become obsessive in ways that disrupt family life. Their obsessions may relate to other individuals (recurrent grudges, suspicions of infidelity) or may be self-orientated (obsessions with bowel or bladder habits or fluid intake) or ritualistic (insistence on routines, objects, or hand-washing). Family members usually find these disruptive and often have no choice but to comply as much as possible.

SSRIs, such as citalopram or fluoxetine, may have a role in the management of obsessive-compulsive symptoms.[72][73] Longer-duration and higher-dose therapy may be needed. Given the problematic nature of such symptoms in some patients, persistence is warranted. Clomipramine has a higher incidence of adverse events but may be considered if SSRIs fail.

Obsessive and compulsive symptoms may be responsive to antipsychotic medicine, such as olanzapine.[74][75] Choosing between antidepressant and antipsychotic medicines should be based on clinical experience and comorbidities. Antipsychotic agents are more likely to be helpful in patients with problematic chorea and agitation, whereas antidepressants are more appropriate for patients with apathy.

Cognitive behavioural therapy is also effective in the general population for obsessions and compulsions, either alone or in combination with medicines. It may also be of benefit in people with Huntington's disease, particularly in patients without significant cognitive impairment.

As dementia progresses, the obsessions often remit, perhaps because the patient becomes less able to retain the obsession in active memory. Psychiatric referral may be of benefit.

Behaviour and mood problems (e.g., irritability, mood swings, aggression, frequent temper outbursts)

One problematic behaviour is bad temper.[76][77] Patients become increasingly irritable as the disease progresses and can become outspoken and verbally or even physically abusive. Alienation of family can contribute to isolation, divorce, or abandonment, and this increases the likelihood of suicide, neglect, or accidental injury. Although evidence is limited, clinical experience suggests that irritability often responds to treatment with SSRIs, especially in the earlier stages; doses at the upper end of the manufacturer’s recommended range are usually necessary for this indication. Other standard approaches to managing temper and irritability include use of anticonvulsant agents with mood-stabilising properties (valproic acid, carbamazepine), propranolol, or typical or atypical antipsychotic drugs. Benzodiazepines may also be helpful, although these may have a disinhibiting effect in some patients. Choosing among these agents is difficult in the absence of definitive studies. However, antipsychotic drugs may be more suitable in circumstances where weight loss and chorea are prominent and symptoms need more acute management; benzodiazepines may be more suitable in situations where anxiety or insomnia is more prominent; and valproic acid more suitable in situations where symptoms are just evolving or where sedating side effects are of concern. In 2018, the European Medicines Agency recommended that valproate and its analogues are contraindicated during pregnancy due to the risk of congenital malformations and developmental problems in the infant/child.[78] In the US, standard practice is that valproate and its analogues are only prescribed during pregnancy if other alternative medications are not acceptable or not effective. In both Europe and the US, valproate medicines must not be used in female patients of childbearing potential unless there is a pregnancy prevention programme in place and certain conditions are met.[78]

Antipsychotic medicines have been used with success in managing irritability and aggression; however, few published studies are available for specific guidance.[79] The selection of antipsychotic agent is based on side-effect profile. For patients with behaviour problems co-existent with significant chorea, typical (first-generation) antipsychotics (e.g., sulpiride, haloperidol) may be helpful. Atypical antipsychotics (e.g., quetiapine, olanzapine) are more appropriate for people with co-existent bradykinesia and rigidity. Given the adverse effects of antipsychotic medicines, occasional dose reductions or holidays are appropriate.

Higher starting doses, or parenteral doses, of antipsychotic medicine can be considered for acute, severe behaviour problems. Olanzapine may also be administered parenterally if needed. Severe episodes of aggression or violent behaviour may require intervention by civil authorities, visits to the emergency department, or formal commitment.

Chorea

Chorea, when severe, interferes with function; when mild, it contributes to social isolation.[80][81] Treating chorea in Huntington's disease is somewhat problematic, and the evidence base for treatments is limited.[82] The drugs that reduce chorea typically have adverse effects on mood, concentration, and coordination, which are factors commonly responsible for functional disability in Huntington's disease.

Antipsychotics are among the most effective medicines available, especially agents such as haloperidol or trifluoperazine. However, atypical antipsychotics, such as risperidone or olanzapine, may be used. Side effects may aggravate underlying features of Huntington's disease, although on occasion they may also be beneficial, such as night sedation and weight gain. These medicines should be reserved for situations in which chorea is problematic.

Tetrabenazine is a selective reversible vesicular monoamine transport (VMAT) inhibitor that blocks the transport of dopamine into synaptic vesicles in the central nervous system.[83][84] It causes central adverse effects of sedation, bradykinesia, restlessness, and depression. Its action is similar to that of reserpine (not available in some countries), except that reserpine is non-selective and irreversible and therefore has central adverse effects of longer duration and peripheral adverse effects not seen with tetrabenazine, such as hypotension and gastric ulcers. Clinical trials have shown that tetrabenazine significantly reduces chorea.[61][84][85][86] Tetrabenazine has a shorter latency to effect and offset from the institution of therapy compared with antipsychotic agents, and it is free of any concerns of tardive dyskinesia. However, it is more likely to cause depression and sedation.[84] Patients with chorea in whom it is perceived as a significant problem are suitable candidates for treatment with tetrabenazine, particularly those who cannot tolerate antipsychotic medicines. It is a good first-line choice of medicine for those patients in whom chorea alone needs management (i.e., patients who do not need the side effects of weight gain or night sedation and/or management of irritation or agitation), but it is not suitable for patients with a history of psychiatric disease.

Amantadine may help with chorea.[87][88][89][90][91] Motor impersistence and abnormal eye movement, gait, speech, and coordination cannot be treated.

Predominant bradykinesia and rigidity

In general, such symptoms are difficult to treat.[92][93][94] Levodopa/carbidopa may be tried. A response should be apparent by 1 month. Amantadine may be used for 3 weeks, at which point a therapeutic response should be apparent.[87]

Cognitive impairment

While one small randomised controlled trial has suggested that anticholinesterase agents may have a beneficial effect on cognition in Huntington's disease, these findings have not been replicated.[95] One randomised, double-blind trial found no effect of citalopram on executive function in non-depressed patients.[96] Further studies are ongoing.

Other approaches

There is evidence that physical therapy interventions can improve fitness, motor function, and gait in people with HD.[97] Speech therapy and swallowing therapy have not been tested rigorously in Huntington's disease but may be of transient benefit.

The European Huntington’s Disease Network has published several best practice guidelines on the use of non-pharmacological interventions for Huntington's disease, such as occupational therapy, physiotherapy, speech and language therapy, and nutritional support.[98][99][100][101]

A driving assessment by an independent assessor can be helpful in deciding whether driving remains safe.

Carer support

A significant area of potential intervention by clinicians is carer support. The burden of caring for an affected patient is considerable and taxes families emotionally, physically, and financially. Directing families to community resources, Huntington's disease support groups, and relevant governmental agencies can be of benefit. Huntington’s Disease Association Opens in new window International Huntington Association Opens in new window Acknowledging the challenges faced by carers should be part of every clinic visit.

Palliative and end-of-life care

A palliative care approach, integrated through the multidisciplinary team, is appropriate throughout the disease course for patients with Huntington's disease.[102][103] Wishes for end-of-life care and advance directives should be discussed with the patient and family/carers once they are ready to do so, before such care is needed, and should be an ongoing conversation.[102]

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