Correspondence

Failure of pallidal deep brain stimulation in DYT12-ATP1A3 dystonia

Dystonia is one of the most common pediatric movement disorders and can have a profound impact on the lives of children and their caregivers. Response to pharmacologic treatment is often unsatisfactory. Deep brain stimulation (DBS) has emerged as a promising treatment option for children with medically refractory dystonia. In this review we highlight the relevant literature related to DBS for pediatric dystonia, with emphasis on the background, indications, prognostic factors, challenges, and future directions of pediatric DBS.

Treatment of dystonia and tics continues to evolve. In dystonia, while oral agents such as benzodiazepines, baclofen and anticholinergics remain in use, botulinum toxin (BoNT) continues to be regarded as the treatment of choice for focal and segmental dystonia, but new preparations are being studied. While deep brain stimulation (DBS) has typically focused on targeting the globus pallidus internus (GPi) when treating dystonia, more recent research has expanded the targets to include subthalamic nucleus (STN) and other targets. In addition to DBS, thalamotomies continue to show therapeutic benefit in focal hand dystonias. Treatment of tics includes a growing armamentarium of options besides the three FDA-approved drugs, all dopamine receptor blockers (haloperidol, pimozide and aripiprazole). Because of lower risk of adverse effects, dopamine depleters (e.g. tetrabebazine, deutetrabenazine, and valbenazine), along with novel D1 receptor antagonists, are currently studied as treatment alternatives in patients with tics. Practice guidelines for the treatment of tics and Tourette syndrome have been recently updated. Data regarding the use of DBS in treatment of tics remains relatively sparse, but international registries have expanded our understanding of the effect of stimulation at several targets.

Rapid-onset dystonia-parkinsonism (RDP) is a rare form of hereditary dystonia caused by loss-of-function mutations of the Na⁺/K⁺-ATPase α3 isoform (ATP1α3). An acute onset of generalized dystonia and parkinsonism after exposure to stress and an incomplete disease penetrance is described in RDP, thereby suggesting a gene-environmental interaction in individuals with a genetic predisposition for dystonia development. Dystonia is considered a central motor network disease and in line with this concept, alterations in cerebellar neuronal firing have been described in RDP mouse models, but the pathogenic role of the basal ganglia remains unclear. We have mimicked RDP pharmacologically by simultaneous perfusion of the selective ATP1α3-blocker ouabain into the striatum and cerebellum of mice, followed by repeated exposure to mild motor stress. Ouabain-perfused RDP mice developed dystonia-like movements, which were exacerbated by exposure to sensorimotor stress. Compared to control mice, ouabain perfusion of the striatum led to dendritic spine loss of medium spiny neurons in addition to loss of cholinergic and GABAergic interneurons in the striatum. High-pressure liquid chromatography analyses revealed significant dopamine (DA) depletion and increased DA and serotonergic turnover, while qPCR analyses displayed reduction of glutamatergic receptors. Adding stress to the ouabain-predisposed brain, however, resulted in an elevation of the striatal DA metabolism back to the level of control animals. Our results indicate an ouabain-induced basal ganglia and cerebellar motor network dysfunction characterized by structural and neurochemical alterations of striatal dopaminergic, cholinergic and glutamatergic pathways that represent a motor endophenotype of RDP mutation carriers. Challenging the motor circuit by sensorimotor stress causes exacerbation of dystonia-like movements tightly linked to a hyperdopaminergic state in the striatum. Our observations support a gene-environment interaction or “second-hit” hypothesis in the symptomatogenesis of RDP.