Indications for drug treatment:
Drug treatment decisions for HD chorea have the goal of improving quality of life. However in practice, assessing the benefit of treatment on quality of life is difficult because there have been no chorea studies that have used quality of life as a measure, and lack of studies on chorea’s impact on stigma or motor dysfunction. Further, assessing side effects of chorea drugs, which include apathy, Parkinsonism, and worsening cognition are difficult to separate from signs of disease progression. There has also been general disagreement about the impact of chorea, citing the lack of patient awareness 
as a rationale to forgo treatment. However, subsequent studies have shown that lack of self-awareness occurs more broadly across the spectrum of HD symptoms including dyskinesia 
as well as cognitive, social, emotional and functional abilities 
, for which lack of awareness would not influence treatment decisions.
Impact of chorea on motor dysfunction:
Studies have shown that chorea negatively impacts motor function for accuracy of movement, reaction time, and gait regulation 
. However, HD is a mixed movement disorder with hypokinetic components that also negatively impact function. So it is difficult to assess the relative contribution of chorea and hypokinetic components in total motor dysfunction, particularly in early or middle stages of adult onset disease when chorea is more prominent 
. In contrast, bradykinesia begins early in adult onset disease 
, and correlates with decline in functional capacity over the entire course of disease 
. Bradykinesia and rigidity are the dominant motor impairments in juvenile onset 
and late-stage adult onset patients. Late stage bradykinesia is a strong predictor of nursing home placement 
Although direct clinical research is lacking on chorea’s functional impact as an isolated symptom, even in those with severe chorea, there are several studies suggesting that chorea may play an independent role in functional disability. The suppression of chorea improved writing speeds by 50% 
. Chorea score was a major factor in impairment of motor tracking, or of accurately completing a motor task 
. In a retrospective analysis of CARE-HD study participants, severity of chorea independently correlated with functional disability among a subgroup least affected by non-chorea symptoms 
. In very-early-disease subjects in the TRACK-HD study, motor scores were more highly associated with earliest functional decline in HD than cognitive or behavioral scores. Among the separate motor components, chorea scores showed the highest correlation with loss of function 
. In later-disease subjects, severity of chorea was an independent predictor of fall frequency and gait disturbance in HD, and more highly correlated to number of falls than voluntary motor impairment 
Survey results support a trial of drug treatment for motor component dysfunction when HD chorea causes difficulty performing motor tasks at the workplace, causes imbalance and falls, results in physical injury, or interferes with sleep.
Impact of chorea on HD stigma:
Though multiple factors are involved in HD stigma, chorea’s high visibility likely contributes to embarrassment and the social isolation of affected individuals and families. While there are no studies that have included quality of life measures in HD, related studies in other diseases suggest that stigma is high across the spectrum of chronic neurological disorders, particularly those that include visible motor components. Studies in epilepsy 
, multiple sclerosis 
, and Parkinson’s disease 
, indicate that stigma impacts quality of life in these disorders. Studies of the high stigma which occurs in Tourette Syndrome (TS) and related motor tics may more closely approximate the stigma related to chorea in HD 
. Further, in both HD and TS , the movement disorders are often mistaken for alcohol intoxication which in turn may further increase the level of stigma 
Stigma in HD can likely be assessed by use of a scale validated for use in other chronic neurologic disease 
, which suggests the type of interview question that might be asked: “Because of my illness: (1) I feel embarrassed in social situations, (2) people avoid me, (3) strangers tend to stare at me, (4) people seem to be uncomfortable with me.” The high frequency of stigma and discriminatory events that occur in individuals with a positive HD family history who have no symptoms has been documented in RESPOND-HD study 
. It is unclear how substantially chorea of the affected family member contributes to stigmatization of unaffected family members. However, it may be a factor to consider in treatment decisions.
Survey results strongly support drug treatment of chorea when stigma factors of embarrassment and social isolation affects the HD patient. In practice this type of information should regularly be elicited from patients. In contrast, there is minority support from the experts for treating the patient when HD stigma adversely affects family members.
Chorea drug treatments: For the indications listed, this survey supports the use of drugs for the treatment of chorea with the goal of reducing symptom severity. Though not addressed specifically in the survey, there is general agreement that pushing therapy to eliminate chorea will cause unacceptable levels of side effects. Because each drug alternative has significant side effects, a careful evaluation of risk-benefit must be assessed for each individual prior to initiating drug therapy, and reassessed frequently both during drug titration and over the course of treatment. Because chorea severity decreases with later progression of disease, the need for chorea treatment should be reassessed over time. Further, the presence of comorbid symptoms should greatly influence the choice of drug for treating chorea.
Antipsychotic drug treatment for HD chorea: Though it is an off-label use, the first choice of most international respondents for treatment of chorea is an APD. Importantly, APD use is strongly preferred when psychosis, depression, aggressive behaviors, or poor compliance are comorbid factors. Although the use of second generation APDs was generally preferred, tiapride a first generation APD was a frequent European choice, and the lower cost of haloperidol, a first generation APD was a factor in treatment choice for several respondents in all geographic areas. The choice of a specific APD was quite varied, which reflects the lack of evidence base to guide drug choice.
Only small studies and case reports are available; there are no large placebo-controlled or head-to-head comparison studies of APDs for treatment of HD chorea. Chorea benefit was demonstrated in a small placebo-controlled trial of haloperidol 
. Olanzapine has been used in small open label studies with variable benefit 
. A few reports note benefit with risperidone 
, and quetiapine 
. Benefit was shown in small open label 
and placebo-controlled 
trials of tiapride, available in most countries in Europe. A study with clozapine suggested minimal benefit, and significant side effects 
. Studies with aripiprazole, a third generation APD, found a reduction in chorea similar to that observed with TBZ 
. In the only study to compare functional capacity differences between a second generation APD (clotiapine) and TBZ for treatment of chorea 
, 38 participants were followed for a minimum of 2 years. Loss of functional capacity was greater in the APD group (N=10) than that in the TBZ group (N=28). However this study is retrospective and assignment to APD or TBZ was not randomized. This points out the important need to study and compare potential treatment-related functional losses in a prospective and randomized manner.
Importantly, survey respondents reported frequent APD side effects, including sedation, Parkinsonism, apathy, cognitive decline, and less frequently, akathisia, metabolic syndrome, and tardive dyskinesia. Though not specifically addressed in the survey, side effects may vary according to specific drug choice (Table 5). Because many of these symptoms occur as a consequence of disease progression, the contribution of drug side effects is difficult to assess. If APDs are used to treat chorea, it is important to reassess dose requirements as the disease progresses. Though dosage ranges for individual APDs were not addressed in the survey, respondents indicated that, in general, dosage less than that recommended for psychotic behaviors is preferred.
Table 5. Side effect profiles for APDs used for HD chorea.
Tetrabenazine treatment for HD chorea:
In North America, when choice was not influenced by other factors, TBZ was preferred almost as highly as APDs for chorea treatment. In both North America and Europe, TBZ was a consistent alternative monotherapy choice. TBZ is the only drug that the U.S. Federal Drug Administration has approved for the treatment of HD chorea. TBZ is also available in Canada, Australia, Denmark, France, Germany, Ireland, Israel, Italy, New Zealand, Portugal, Spain, Switzerland, and the UK. The efficacy of this drug was shown in a double-blinded, placebo-controlled study conducted by the HSG, in which drug was given as tolerated up to 100 mg/day 
. A 3.5 point change in chorea score, or a 23.5% reduction from baseline was demonstrated in the treated group (chorea score range is 0 to 28), with about 50% of the treated group achieving a 6-point or greater improvement compared to 7% showing this level of response in the placebo group. Importantly, however, more adverse events occurred in the treated group, including somnolence, insomnia, depressed mood, agitation, akathisia, and one suicide. However, after stable dosing was achieved, there was no significant difference in adverse events between the treated and placebo groups. During the 80-week open-label extension phase of this study, a similar side effect profile emerged 
. No quality of life issues were measured in this or any other TBZ chorea drug trial. In the present survey, the perceived frequency of TBZ side effects, except for depression, was similar to or slightly lower than those perceived for APDs in treating chorea. For HD in general, and particularly with the use of TBZ for HD chorea, it is imperative to have heightened caution regarding depression and suicide risk. While studies suggest that risk of depression with TBZ is more likely to occur in those with pre-existing depression, it can also occur in those with no history of depression prior to TBZ 
. As in the placebo controlled trial, survey responders reported more depression during the titration phase and first 2 months of stable dose TBZ treatment. However, functional capacity appeared to be better preserved in a small number of patients treated with TBZ than in those treated by an APD over a 2 year time period 
The dosage after titration for the majority of participants in the HSG trial and open label extension was 50-75 mg/day, which was the dosage range preferred by the majority of survey respondents. Lundbeck Inc. recommends and will provide reimbursement for testing CYP2D6 metabolizer levels prior to increasing TBZ dose above 50 mg/day. In CYP2D6-poor metabolizers, concomitant use of strong inhibitors (paroxetine, fluoxetine, fluxoxamine) should be avoided, or TBZ dosage decreased.
Benzodiazepine treatment for HD chorea:
In a single study, high doses of clonazepam (up to 5.5 mg/day) were required to suppress chorea 
. Survey respondents did not endorse use of BZDs as monotherapy, but thought BZDs an adjuctive therapy.
Amantadine treatment for HD chorea:
Two small placebo-controlled studies of amantadine for HD chorea provide conflicting results 
. When a meta-analysis of the combined trials was performed as part of the Cochrane review 
, the differences between treated and placebo groups did not reach significance. Similarly, survey respondents disagreed about the use of this drug. When chosen, amantadine’s most frequent use was as adjunctive therapy, though others thought its use inappropriate.
Based on the results of this international expert survey, a clinical practice algorithm for the treatment of chorea in HD was constructed. The authors do not mean to imply that following the steps most often chosen by experts will result in best outcomes. Treatment response varies greatly in HD, and is particularly hard to predict. The steps represented in the algorithm are meant to guide, not decide any individual's treatment. Only the clinician can address the complexities of any specific patient, where treatment must be tailored to fit individual needs.