Novel approaches for the evaluation and symptomatic treatment of Huntington disease (HD) were presented at the 59th Annual Meeting of the American Academy of Neurology held April 29 to May 5 in Boston. Interventions included use of tetrabenazine (TBZ) (as yet unapproved for the symptomatic treatment of hyperkinetic movement disorders in the United States but granted orphan drug status in 2004) and deep brain stimulation (DBS) of the globus pallidus externus (GPe).
Novel approaches for the evaluation and symptomatic treatment of Huntington disease (HD) were presented at the 59th Annual Meeting of the American Academy of Neurology held April 29 to May 5 in Boston. Interventions included use of tetrabenazine (TBZ) (as yet unapproved for the symptomatic treatment of hyperkinetic movement disorders in the United States but granted orphan drug status in 2004) and deep brain stimulation (DBS) of the globus pallidus externus (GPe). Studies also showed that patients could be evaluated for HD motor function loss with the use of simple biomarkers such as grip force and tongue protrusion force.
TREATMENT WITH TETRABENAZINE
Researchers from the Huntington Study Group examined the long-term safety and effectiveness of TBZ for chorea in patients with HD and found that the therapy suppressed chorea for up to 80 weeks.1 These results, which represented an update of a previous study2 of TBZ in patients with HD, were presented by Samuel A. Frank, MD, assistant professor at the Boston University School of Medicine. The previous study showed that TBZ effectively suppressed chorea and had a favorable short-term safety profile.
Previous studies have shown that medications that treat chorea may be beneficial in select patients with HD.3,4 Patients are usually treated with neuroleptics, which may cause adverse effects, including parkinsonism, decreased balance, akathisia, neuroleptic malignant syndrome, acute dystonic reactions, tardive dyskinesia, blunting of affect, and generalized apathy. TBZ has been shown to reversibly bind to the type-2 vesicular monoamine transporter, which selectively depletes central monoamines, and a limited number of studies have shown that TBZ may improve movement disorders.5-7 The drug is available in Canada, Australia, New Zealand, and Europe, but as yet is only available for experimental use in the United States.
Of 75 participants, 45 completed the 80-week study and received TBZ-up to a maximum dosage of 200 mg/d-based on their response to the therapy. The mean dose at week 80 was 63.4 mg (range, 12.5 to 175 mg). By week 80, the patients' chorea had significantly improved from baseline, with a mean reduction in total maximal chorea (TMC) score of 4.6. When the patients stopped taking TBZ for 1 week, the mean TMC score increased by 5.3 units.
The most frequent adverse effects associated with TBZ therapy were depressed mood (37.8%), sedation (35.5%), anxiety (28.9%), chorea (24.4%), akathisia (20%), and insomnia (20%). The researchers concluded that TBZ effectively suppresses chorea for up to 80 weeks in HD; however, they recommended that patients be monitored for sleep disturbances, depression, anxiety, and akathisia.
One patient in the earlier study by the Huntington Study Group committed suicide, although he had scored within the normal range on the Hamilton Depression Scale 2 weeks before the event. The researchers were unsure whether treatment with TBZ contributed to the suicide and reminded fellow physicians that depression indexes and monoamine depleters cannot always predict which patients with HD may be suicidal. Studies have shown that patients with HD have an average suicide rate of 7.3%, and up to 25% of patients may attempt suicide at some point during the illness.8,9
DEEP BRAIN STIMULATION
DBS of the GPe can improve both cognitive and motor symptoms of HD, according to results of a study by a team from Centre Hospitalier Régional Universitaire de Lille in France.10 Inspired by studies in animal models that showed that HD leads to rapid loss of inhibitory striatal neurons that project to the GPe, the team treated 5 patients who had early HD with continuous bilateral, high-frequency stimulation to the GPe.
Each patient was evaluated before surgery and again 6 months after surgery. Motor and cognitive outcomes were evaluated using the Unified Huntington's Disease Rating Scale (UHDRS), UHDRS motor subscores (chorea and dystonia), and timed motor tests. Overall behavioral and cognitive tolerance as well as tolerance of the therapy was also assessed using the Mattis Dementia Rating Scale, Marins Apathy Scale, and Montgomery-Åsberg Depression Rating Scale. The treatment had a dramatically beneficial effect in all motor and cognitive tests in 1 patient. Another patient demonstrated a more heterogeneous improvement, and the other 3 patients remained stable.
Other small studies have shown the potential benefits of DBS to the globus pallidus in patients with HD. Moro and colleagues11 found that chorea and dystonia were reduced in a patient with bilateral globus pallidus internus (GPi) stimulation. Different stimulation levels caused varying effects in the patient studied; chorea and dystonia were reduced at 40 Hz, but parkinsonism was increased at 130 Hz. Hebb and colleagues12 also demonstrated that bilateral stimulation of the GPi dramatically reduced chorea in 1 patient. Overall motor function also improved, and the patient had a normalization of body weight, mood, and energy level, as well as improved performance of activities of daily living. These effects were sustained at 1-year follow-up after surgery.
MOTOR FUNCTION ASSESSMENT
Tongue protrusion force was shown to correlate with disease severity in patients with HD.13 A German investigative team examined 19 patients with HD and a control group of 20 persons without HD. Participants were instructed to protrude their tongue and push on a force transducer that was 2 cm in front of their mouths and, for 30 seconds, match force levels of 0.25, 0.5 and 1.0 N. Involuntary movements of the head and body were recorded. Patients with HD were shown to lose contact more often and did not reach 50% of the target force for significantly longer times than members of the control group. The researchers suggested that tongue protrusion ability can be quantified and that tongue protrusion force directly correlates with the severity of HD.
Grip force also may indicate motor dysfunction in asymptomatic carriers of the huntingtin gene before clinical manifestations of HD.14 Members of the same investigative team examined 13 carriers of the gene and 13 controls. Each person was instructed to grasp and lift an object weighing 250 or 500 g using the precision grip and hold it for 30 seconds. The grip and lift forces were recorded. The researchers found that grip force variability in the static holding phase was increased in carriers of the huntingtin gene compared with controls, specifically when holding objects weighing 250 g. The researchers concluded that this technique might act as a biological marker for HD.
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