It's not just the basal ganglia: Cerebellum as a target for dystonia therapeutics

Tewari, Ambika; Fremont, Rachel; Khodakhah, Kamran

doi:10.1002/mds.27123

Cited by 86 publications

(63 citation statements)

References 91 publications

(210 reference statements)

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“…Even though the pallidum is not a principal site of SGCE expression, it receives important outputs from the structures with higher expression of SGCE such as the cerebellum . Previous research supports the prominent implication of cerebellothalamic network dysfunction in M‐D and highlights the role of the cerebellum in dystonia per se . If the subcortical myoclonus in M‐D might be of cerebellar origin, why is GPi‐DBS so effective?…”

Section: Discussionsupporting

confidence: 52%

“…32 Previous research supports the prominent implication of cerebellothalamic network dysfunction in M-D 5 and highlights the role of the cerebellum in dystonia per se. 33 If the subcortical myoclonus in M-D might be of cerebellar origin, why is GPi-DBS so effective? This question is still under debate, but the answer may lie in the interconnectivity between the basal ganglia and cerebellar outflow with disynaptic projections from the cerebellum to the basal ganglia.…”

Section: Discussionmentioning

confidence: 99%

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Long‐term GPi‐DBS improves motor features in myoclonus‐dystonia and enhances social adjustment

et al. 2018

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Background Good short‐term results of pallidal deep brain stimulation have been reported in myoclonus‐dystonia. Efficacy and safety in the long term remain to be established. In addition, the actual impact of DBS treatment on social inclusion is unknown. The objective of this study was to assess the long‐term clinical outcome, quality of life, and social adjustment of GPi‐DBS in patients with ε‐sarcoglycan (DYT11)‐positive myoclonus‐dystonia. Methods Consecutive myoclonus‐dystonia patients with ε‐sarcoglycan mutations who underwent GPi‐DBS were evaluated at least 5 years postoperatively. Motor symptoms were assessed using the Burke‐Fahn‐Marsden Dystonia Rating Scale including the Disability Scale, a composite score combining the rest and action parts of the Unified Myoclonus Rating Scale and modified Abnormal Involuntary Movement Scale. Standardized video‐protocols were assessed by a blinded and external movement disorder specialist. Social adjustment, cognition, and mood were evaluated. Results Nine patients (5 women) with long‐term GPi‐DBS (8.7 ± 3.1 years) were included. There was significant improvement in the composite myoclonus score (94.1% ± 4% improvement; P = 0.008). Dystonia severity was also markedly improved (71.4% ± 28.33% improvement; P = 0.008) as well as motor disability (88.3% ± 20% improvement; P = 0.008) and abnormal involuntary movement score (71.1% ± 15.0% improvement; P = 0.008). No patients experienced postoperative speech or gait problems or any permanent adverse effects. Eight of the 9 patients had fully enhanced social adjustment and personal achievement, with little or no mood or behavioral disorders. Conclusions GPi‐DBS seems to be a safe and efficacious treatment for medically refractory ɛ‐sarcoglycan myoclonus‐dystonia, with sustained motor benefit, good quality of life, and social adjustment in long‐term follow‐up. © 2018 International Parkinson and Movement Disorder Society

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Section: Discussionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Long‐term GPi‐DBS improves motor features in myoclonus‐dystonia and enhances social adjustment

et al. 2018

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“…Although dystonia was classically thought to arise from basal ganglia pathology, increasing evidence supports a critical role of the cerebellum in its pathophysiology as well. 1 Through pharmacologic or genetic alteration of cerebellar output pathways, irregular cerebellar activity leads to high-frequency burst firing of the basal ganglia and is associated with dystonic posturing in mice. [2][3][4] Subsequent inhibition of cerebellar outflow, either electrically or pharmacologically, reduces the abnormal basal ganglia activity and improves dystonia.…”

Section: Resultsmentioning

confidence: 99%

Cerebellar Deep Brain Stimulation for Acquired Hemidystonia

Brown

Bledsoe

Luthra

et al. 2020

Movement Disord Clin Pract

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Background Background: The cerebellum's role in dystonia is increasingly recognized. Dystonia can be a disabling and refractory condition; deep brain stimulation can help many patients, but it is traditionally less effective in acquired dystonia. New surgical targets would be instrumental in providing treatment options and understanding dystonia further. Objective Objective: To evaluate the efficacy of deep brain stimulation of the cerebellum in acquired dystonia. Methods Methods: We report our management of a 37-year-old woman with severe left arm and leg dystonia, a complication of an ischemic stroke in childhood. She had already had 2 thalamotomies with only transient benefit. These procedures, in addition to her initial stroke that had damaged the basal ganglia, left traditional deep brain stimulation targets unavailable. ResultsResults: After implantation of bilateral deep cerebellar nuclei, dystonia improved with a 40% reduction in severity on scales and subjective reports of improved posturing, gait, and pain. This improvement has been maintained for almost 2 years after implantation. Conclusion Conclusion: Cerebellar stimulation has potential for therapeutic benefit in acquired dystonia and should be further explored.Although dystonia was classically thought to arise from basal ganglia pathology, increasing evidence supports a critical role of the cerebellum in its pathophysiology as well. 1 Through pharmacologic or genetic alteration of cerebellar output pathways, irregular cerebellar activity leads to high-frequency burst firing of the basal ganglia and is associated with dystonic posturing in mice. 2-4 Subsequent inhibition of cerebellar outflow, either electrically or pharmacologically, reduces the abnormal basal ganglia activity and improves dystonia. 3,4 Whereas classically the cerebellum and basal ganglia communicate through rubro-thalamo-cortical connections, rapid modulation may occur through a more direct, disynaptic pathway, with 1 relay in the thalamus. This pathway has recently been identified in rodents and nonhuman primates 5-8 and, in animal models, conveys the aberrant activity that underlies dystonic posturing. 3 In humans, structural abnormalities in the cerebellum or its afferent pathways have been implicated as the cause of dystonia in several cases. 9,10 Similarly, in a small autopsy study, a reduced density of cerebellar Purkinje cells was found in patients with cervical dystonia when compared with healthy controls. 11 The role of the cerebellum in dystonia indicates its potential as a therapeutic target for deep brain stimulation (DBS). In mouse models of dystonia, DBS of cerebellar output nuclei improved dystonic posturing and general mobility. 4 In humans, the invasive stimulation of the cerebellar hemispheres has been described previously for spasticity and dystonia with variable effect. 12,13 Recently, stimulation of the deep cerebellar nuclei has been employed for spasticity and dystonia as a result of cerebral palsy. 14,15 Identifying a new target would be clinically very use...

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“…Many of the genetic diseases reviewed here encompass complex phenotypes due to neurodegeneration of multiple systems and structures, including the alteration of both basal ganglia and cerebellum, which may explain the occurrence of dystonia in the setting of ataxia and other neurological features. There is growing evidence of an important role of the cerebellar dysfunction in dystonia . Animal models of generalized dystonia showed abnormal cerebellar activity, and dystonia can be independent of the basal ganglia and can be alleviated or abolished by inactivation of the cerebellum .…”

Section: Methodsmentioning

confidence: 99%

Genetic Dystonia‐ataxia Syndromes: Clinical Spectrum, Diagnostic Approach, and Treatment Options

Rossi

Balint

Vernetti

et al. 2018

Movement Disord Clin Pract

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Background Dystonia and ataxia are manifestations of numerous disorders, and indeed, an ever‐expanding spectrum of genes causing diseases that encompass dystonia and ataxia are discovered with the advances of genetic techniques. In recent years, a pathophysiological link between both clinical features and the role of the cerebellum in the genesis of dystonia, in some cases, has been proposed. In clinical practice, the genetic diagnosis of dystonia‐ataxia syndromes is a major issue for genetic counseling, prognosis and, occasionally, specific treatment. Methods For this pragmatic and educational review, we conducted a comprehensive and structured literature search in Pubmed, OMIM, and GeneReviews using the key words “dystonia” and “ataxia” to identify those genetic diseases that may combine dystonia with ataxia. Results There are a plethora of genetic diseases causing dystonia and ataxia. We propose a series of clinico‐radiological algorithms to guide their differential diagnosis depending on the age of onset, additional neurological or systemic features, and imaging findings. We suggest a sequential diagnostic approach to dystonia‐ataxia syndromes. We briefly highlight the pathophysiological links between dystonia and ataxia and conclude with a review of specific treatment implications. Conclusions The clinical approach presented in this review is intended to improve the diagnostic success of clinicians when faced with patients with dystonia‐ataxia syndromes.

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It's not just the basal ganglia: Cerebellum as a target for dystonia therapeutics

Cited by 86 publications

References 91 publications

Long‐term GPi‐DBS improves motor features in myoclonus‐dystonia and enhances social adjustment

Long‐term GPi‐DBS improves motor features in myoclonus‐dystonia and enhances social adjustment

Cerebellar Deep Brain Stimulation for Acquired Hemidystonia

Genetic Dystonia‐ataxia Syndromes: Clinical Spectrum, Diagnostic Approach, and Treatment Options

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