Overview
The most common form of idiopathic dystonia is adult-onset cervical dystonia (CD), a focal form of dystonia affecting the muscles of the neck. CD is often associated with pain and limited range of motion, and frequently leads to reduced quality of life and disability. Effective long-term treatment options are extremely limited. Recurring botulinum neurotoxin (BoNT) injections can ease the symptoms of CD, but they frequently provide only partial relief and can be associated with intolerable side effects. Deep brain stimulation can be used to treat more severe cases of CD, but this neurosurgical procedure is invasive, on average only about 50% effective and may lead to serious adverse effects. Novel treatment approaches for CD are desperately needed to alleviate symptoms and improve the quality of life for the many who suffer from this chronic and disabling neurological disorder.
Description
The dopaminergic system has been implicated in the pathophysiology of hyperkinetic movement disorders including dystonia. For example, it is well established that acute and chronic dystonia syndromes can be caused by dopamine receptor-blocking drugs. Several animal and human imaging studies also support the presence of abnormal dopaminergic function in idiopathic forms of dystonia. Although historically dopamine receptor-blocking medications have been used to treat dystonia, early clinical trials have been limited and the results mixed. The atypical neuroleptic clozapine was found to be moderately effective in treating segmental and generalized dystonia, but its usefulness was limited by potential adverse effects. Another atypical neuroleptic risperidone has been reported to be effective in a 4-week trial of five patients with various forms of dystonia. Dopamine depleting medications such as the VMAT2 inhibitor tetrabenazine has also been found helpful in some patients with dystonia, particularly those with tardive dystonia, which has overlapping phenomenology with idiopathic dystonia. The more recently developed VMAT2 inhibitor valbenazine has demonstrated clear benefit in tardive dyskinesia, but their therapeutic benefit in idiopathic dystonia has not been evaluated in a placebo-controlled clinical trial. Off label uses and an open-label study of valbenazine suggest it could provide some benefit and be well tolerated in idiopathic CD patient populations.
Eligibility
Inclusion Criteria:
- Idiopathic CD (neck musculature first and most prominently affected)
- 18-75 years old (participants excluded if their dystonia symptoms began before age 18 as childhood-onset dystonia typically represents a genetic and/or primary generalized form of dystonia)
- Onset of dystonia ≥18 years old, no known hyperkinetic movement disorder-related genetic mutation
- Dystonia severity more than minimal and not very severe as defined by Toronto Western Spasmodic Torticollis Rating Scale-2 Motor Severity (TWSTRS-2-Severity) score ≥ 5 and ≤ 20.
- Stable on botulinum toxin injections last 90 days (BoNT dose change <10% and patient reported stability of response over last two injection cycles)
- Stable on other neuroactive medications.
Exclusion Criteria:
- History of deep brain stimulation
- History of uncontrolled or untreated depression in the prior 3 months, suicidality, or history of suicide attempts
- History of uncontrolled liver disease or failure
- History of tardive dyskinesia or tardive dystonia
- Currently taking dopaminergic and/or anti-dopaminergic medications including VMAT2 inhibitors or other antipsychotic medications
- Exposure to dopaminergic and/or anti-dopaminergic medications including VMAT2 inhibitors or other antipsychotic medications in the last 30 days -Presence of parkinsonism or other movement disorder other than dystonia on exam -Receiving botulinum toxin injections at a planned frequency other than every 3 months or typically receive injections at intervals <11 weeks or >13 weeks -Known history of long QT syndrome or cardiac tachyarrhythmia or any clinically significant cardiac abnormality.
- Prolonged QTc as defined by > 450 msec for men and > 470 msec for women