A novel therapeutic agent, sodium oxybate, improves dystonic symptoms via reduced network-wide activity

Abstract

Oral medications for the treatment of dystonia are not established. Currently, symptoms of focal dystonia are managed with botulinum toxin injections into the affected muscles. However, the injection effects are short-lived and not beneficial for all patients. We recently reported significant clinical improvement of symptoms with novel investigational oral drug, sodium oxybate, in patients with the alcohol-responsive form of laryngeal focal dystonia. Understanding the mechanism of action of this promising oral agent holds a strong potential for the development of a scientific rationale for its use in dystonia. Therefore, to determine the neural markers of sodium oxybate effects, which may underlie dystonic symptom improvement, we examined brain activity during symptomatic speech production before and after drug intake in patients with laryngeal dystonia and compared to healthy subjects. We found that sodium oxybate significantly attenuated hyperfunctional activity of cerebellar, thalamic and primary/secondary sensorimotor cortical regions. Drug-induced symptom improvement was correlated with decreased-to-normal levels of activity in the right cerebellum. These findings suggest that sodium oxybate shows direct modulatory effects on disorder pathophysiology by acting upon abnormal neural activity within the dystonic network.

Alcohol-Responsive Hyperkinetic Movement Disorders—a Mechanistic Hypothesis

“…Investigations in patients with SD and SCGE-MD support a pivotal role of the cerebellum and Purkinje cells in these disorders. In an fMRI study of SD patients treated with a single dose of Xyrem, clinical improvement in dysphonia and reduction in vocal breaks correlated with normalization of cerebellar activation [72]. In a PET study, symptomatic SCGE-MD patients demonstrated activation of cerebellar cortex and dentate compared to non-manifesting SCGE carriers and healthy controls [70].…”

“…One hour after administration of two gm of Xyrem, myoclonus was improved. The final two patients, #s 12 and 13, participated in a study of the effects of Xyrem on SD with functional MRI [72].…”

Multimodal Quantitative MRI Reveals No Evidence for Tissue Pathology in Idiopathic Cervical Dystonia

“…As a matter of fact, it has been previously suggested that idiopathic focal dystonias may be considered as a purely functional disorder (10, 11, 24, 58, 59). Network-wide differences in brain activation that disappear with successful symptomatic treatment have been observed in functional MRI (60–62).…”

Mechanisms and Pharmacotherapy for Ethanol-Responsive Movement Disorders

“…When ingested orally, it could be quickly absorbed and cross the blood–brain barrier, converted into GHB within the brain ( 97 ). It is proved to be an agonist of most GABA B receptors as well ( 98 ), which also suggests that it might deliver a similar effect to ethanol.…”

“…When ingested orally, it could be quickly absorbed and cross the bloodbrain barrier, converted into GHB within the brain (97). It is proved to be an agonist of most GABA B receptors as well (98), which also suggests that it might deliver a similar effect to ethanol. Recent clinical trials showed that over half of patients with ethanol-responsive movement disorders achieved symptom improvement after administration of sodium oxybate, and the improvement of myoclonus at rest usually occurs earlier than that of myoclonus in action.…”