Pallidal deep brain stimulation for patients with myoclonus-dystonia without SGCE mutations.

BACKGROUND: Pallidal deep brain stimulation (GPi-DBS) is effective for treating myoclonus and dystonia caused by SGCE mutations (DYT-SGCE, DYT11). However, it is unknown whether GPi-DBS is effective for the treatment of myoclonus-dystonia which is not associated with the SGCE gene mutations. In this study, we investigated the efficacy of GPi-DBS in treating myoclonus-dystonia in SGCE mutation-negative cases. METHODS: Three patients with myoclonus-dystonia without SGCE mutations who underwent GPi-DBS were evaluated preoperatively and 6 months postoperatively using the Unified Myoclonus Rating Scale (UMRS) and Fahn-Marsden Dystonia Rating Scale (FMDRS) for myoclonus and dystonia, respectively. In two of the three patients, myoclonus was more evident during action. Myoclonus was predominant at rest in the other patient, and he was unaware of his dystonia symptoms. The results were compared with those of the four DYT-SGCE cases. RESULTS: The mean UMRS score in patients with myoclonus-dystonia without SGCE mutations improved from 61.7 to 33.7 pre- and postoperatively, respectively, and the mean FMDRS score improved from 7.2 to 4.5. However, the degree of improvement in myoclonus-dystonia in patients without SGCE mutations was inferior to that in patients with DYT-SGCE (the UMRS score improved by 45% and 69%, respectively). CONCLUSIONS: GPi-DBS is effective for treating myoclonus-dystonia in patients with and without SGCE mutations. GPi-DBS should be considered as a treatment option for myoclonus-dystonia without SGCE mutations.

Dominant VPS16 Pathogenic Variants: Not Only Isolated Dystonia.

BACKGROUND: VPS16 pathogenic variants have been recently associated with inherited dystonia. Most patients affected by dominant VPS16-related disease display early-onset isolated dystonia with prominent oromandibular, bulbar, cervical, and upper limb involvement, followed by slowly progressive generalization. CASES: We describe six newly reported dystonic patients carrying VPS16 mutations displaying unusual phenotypic features in addition to dystonia, such as myoclonus, choreoathetosis, pharyngospasm and freezing of gait. Response to bilateral Globus Pallidus Internus Deep Brain Stimulation (GPi-DBS) is reported in three of them, associated with significant improvement of dystonia but only minor effect on other hyperkinetic movements. Moreover, five novel pathogenic/likely pathogenic variants are described. CONCLUSIONS: This case collection expands the genetic and clinical spectrum of VPS16-related disease, prompting movement disorder specialists to suspect mutations of this gene not only in patients with isolated dystonia.

GPi DBS treatment outcome in children with monogenic dystonia: a case series and review of the literature.

Introduction: Dystonia is the third most common pediatric movement disorder and is often difficult to treat. Deep brain stimulation (DBS) of the internal pallidum (GPi) has been demonstrated as a safe and effective treatment for genetic dystonia in adolescents and adults. The results of DBS in children are limited to individual cases or case series, although it has been proven to be an effective procedure in carefully selected pediatric cohorts. The aim of our study was to present the treatment outcome for 7- to 9-year-old pediatric patients with disabling monogenic isolated generalized DYT-THAP1 and DYT-KMT2B dystonia after bilateral GPi-DBS. Patients and results: We present three boys aged <10 years; two siblings with disabling generalized DYT-THAP1 dystonia and a boy with monogenic-complex DYT-KMT2B. Dystonia onset occurred between the ages of 3 and 6. Significantly disabled children were mostly dependent on their parents. Pharmacotherapy was inefficient and patients underwent bilateral GPi-DBS. Clinical signs of dystonia improved significantly in the first month after the implantation and continued to maintain improved motor functions, which were found to have improved further at follow-up. These patients were ambulant without support and included in everyday activities. All patients had significantly lower Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) values, indicating >25% improvement over the first 15 months. However, there was a decline in speech and upper limb function, manifesting with bradylalia, bradykinesia, and dysphonia, which decreased after treatment with trihexyphenidyl. Conclusion: Although reports of patients with monogenic dystonia, particularly DYT-THAP1, treated with DBS are still scarce, DBS should be considered as an efficient treatment approach in children with pharmacoresistent dystonia, especially with generalized monogenic dystonia and to prevent severe and disabling symptoms that reduce the quality of life, including emotional and social aspects. Patients require an individual approach and parents should be properly informed about expectations and possible outcomes, including relapses and impairments, in addition to DBS responsiveness and related improvements. Furthermore, early genetic diagnosis and the provision of appropriate treatments, including DBS, are mandatory for preventing severe neurologic impairments.

Differential Effects of Subthalamic Nucleus and Globus Pallidus Internus Deep Brain Stimulation on Motor Subtypes in Parkinson's Disease.

OBJECTIVE: We investigated the differences in motor symptom change outcomes after bilateral subthalamic nucleus (STN) and globus pallidus internus (GPi) deep brain stimulation (DBS) in well-defined motor subtypes of Parkinson's disease (PD) to improve clinical decision making. METHODS: We included 114 patients who had undergone STN-DBS and 65 patients who had undergone GPi-DBS. The patients were classified as having akinetic-rigid type (ART), tremor-dominant type (TDT), and mixed type (MT) using the preoperative Movement Disorder Society Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS-III) scores in the no-medication state. The outcome measures included the no-medication MDS-UPDRS-III scores and subscore changes at the last follow-up after surgery. The outcomes were compared among the different motor subtypes and between STN-DBS and GPi-DBS. RESULTS: At the last follow-up (14.92 ± 8.35 months), the TDT patients had had a greater median overall motor improvement in the no-medication MDS-UPDRS-III scores compared with the ART patients (62.90% vs. 46.67%; P < 0.001), regardless of the stimulation target. The ART patients showed greater improvement after STN-DBS than after GPi-DBS (54.44% vs. 37.21%; P < 0.001), with improvements in rigidity, akinesia, and posture and gait disorders accounting for the difference. CONCLUSIONS: Our results suggest that the different PD motor subtypes will have differential responses to STN-DBS and GPi-DBS, that TDT patients will experience greater improvement than ART patients, and that STN-DBS provides better effects for ART patients than does GPi-DBS. In addition, different motor symptoms among the different motor subtypes might respond differently to STN-DBS than to GPi-DBS. All these factors could reflect the heterogeneity of PD. Longer-term outcomes across the different motor subtypes and stimulation targets should be studied further.

Case report: Pallidal deep brain stimulation for treatment of tardive dystonia/dyskinesia secondary to chronic metoclopramide medication.

Objectives: Tardive dystonia/dyskinesia (TDD) occurs as a side effect of anti-dopaminergic drugs, including metoclopramide, and is often refractory to medication. While pallidal deep brain stimulation (DBS) has become an accepted treatment for TDD secondary to neuroleptic medication, there is much less knowledge about its effects on metoclopramide-induced TDD. Methods: We present the case of a woman with metoclopramide-induced TDD, whose symptoms were initially misjudged as "functional." After 8 years of ineffective medical treatments, she received bilateral implantation of quadripolar electrodes into the posteroventral lateral globus pallidus internus (GPi). Results: GPi DBS led to significant symptom reduction [Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) motor score 24/44 at admission and 7/44 at discharge]. Chronic stimulation led to full recovery from TDD symptoms 9 years after surgery. The BFMDRS motor score decreased to 0.5 (98% improvement). Discussion: Pallidal DBS may result in sustained improvement of TDD secondary to chronic metoclopramide intake in the long term.

Pallidal Deep Brain Stimulation for KMT2B Related Dystonia in An Indian Patient.

Outcomes of pallidal stimulation in KMT2B dystonia have been infrequently reported prospectively. We report the six-month outcomes of bilateral GPi DBS in an Asian Indian patient with early-onset generalized dystonia associated with a novel heterozygous variant in the KMT2B gene.

Long term follow-up results of deep brain stimulation of the Globus pallidus interna in pediatric patients with DYT1-positive dystonia.

OBJECTIVES: Primary generalized dystonia (PGD) due to heterozygous torsin 1A (TOR1A) gene mutation (DYT1) is a childhood onset dystonia with rapid deterioration of symptoms, leading to severe disability in adolescence. Globus pallidus interna deep brain stimulation (GPi-DBS) has been shown to provide significant improvement in these cases. METHODS: This was a retrospective study of TOR1A mutation positive dystonia patients, conducted at a university hospital from 2006 to 2018. Burke-Fahn-Marsden Dystonia Rating Scale (BFM-DRS) was used to evaluate dystonia severity before and after surgery. Emergence of postsurgical parkinsonian symptoms was evaluated using the Unified Parkinson Disease Rating Scale (UPDRS) part III. Montreal Cognitive Assessment (MOCA) was applied to assess cognitive dysfunction. SPSS version 18 was used for data analysis. RESULTS: Eleven patients entered for analysis with an average age of 22.36 (±3.35) years (range: 18-28). Seven patients (63.6 %) were female. Mean follow-up period was 8.72 (±0.87). Difference between baseline and most recent BFM scores was significant (disability: 10.5 ±4.52 versus 2.09 (±3.20), P: 0.001; severity: 48.45 (±17.88) versus 9.36 (±10.47), P<0.001). The mean MOCA and UPDRS III scores after 7-9 years of DBS were 27.18 (±2.99), and 6.09 (±4.15), respectively. CONCLUSION: Our experience confirms that GPi-DBS in pediatric patients with DYT1 dystonia is overall successful, with significant and long-lasting positive effects on motor and cognitive functions. There was no prominent side effect in long-term follow up.

Neurophysiological insights in dystonia and its response to deep brain stimulation treatment.

Dystonia is a movement disorder characterised by involuntary muscle contractions resulting in abnormal movements, postures and tremor. The pathophysiology of dystonia is not fully understood but loss of neuronal inhibition, excessive sensorimotor plasticity and defective sensory processing are thought to contribute to network dysfunction underlying the disorder. Neurophysiology studies have been important in furthering our understanding of dystonia and have provided insights into the mechanism of effective dystonia treatment with pallidal deep brain stimulation. In this article we review neurophysiology studies in dystonia and its treatment with Deep Brain Stimulation, including Transcranial magnetic stimulation studies, studies of reflexes and sensory processing, and oscillatory activity recordings including local field potentials, micro-recordings, EEG and evoked potentials.

Pallidal Deep Brain Stimulation Reduces Sensorimotor Cortex Activation in Focal/Segmental Dystonia.

BACKGROUND: Although deep brain stimulation of the globus pallidus internus (GPi-DBS) is an established treatment for many forms of dystonia, including generalized as well as focal forms, its effects on brain (dys-)function remain to be elucidated, particularly for focal and segmental dystonia. Clinical response to GPi-DBS typically comes with some delay and lasts up to several days, sometimes even weeks, once stimulation is discontinued. OBJECTIVE: This study investigated how neural activity during rest and motor activation is affected by GPi-DBS while excluding the potential confound of altered feedback as a result of therapy-induced differences in dystonic muscle contractions. METHODS: Two groups of patients with focal or segmental dystonia were included in the study: 6 patients with GPi-DBS and 8 without DBS (control group). All 14 patients had cervical dystonia. Using H215 O PET, regional cerebral blood flow was measured at rest and during a motor task performed with a nondystonic hand. RESULTS: In patients with GPi-DBS (stimulation ON and OFF), activity at rest was reduced in a prefrontal network, and during the motor task, sensorimotor cortex activity was lower than in patients without DBS. Within-group contrasts (tapping > rest) showed less extensive task-induced motor network activation in GPi-DBS patients than in non-DBS controls. Reduced sensorimotor activation amounted to a significant group-by-task interaction only in the stimulation ON state. CONCLUSIONS: These findings support previous observations in generalized dystonia that suggested that GPi-DBS normalizes dystonia-associated sensorimotor and prefrontal hyperactivity, indicating similar mechanisms in generalized and focal or segmental dystonia. Evidence is provided that these effects extend into the OFF state, which was not previously demonstrated by neuroimaging. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Postoperative symptoms of psychosis after deep brain stimulation in patients with Parkinson's disease.

OBJECT: Cases of postoperative psychosis in Parkinson's disease patients receiving deep brain stimulation (DBS) treatment have previously been published. However, the magnitude of symptom incidence and the clinical risk factors are currently unknown. This retrospective study sheds light on these issues by investigating psychosis in a group of 128 Parkinson's disease patients who received DBS implants. METHODS: A retrospective chart review was performed to obtain surgery dates, follow-up clinic visit dates, and associated stimulation parameter settings (contacts in use and the polarity of each along with stimulation voltage, frequency, and pulse width) for each patient. Unified Parkinson's Disease Rating Scale II Thought Disorder scores, used as a clinical assessment tool to evaluate the presence of psychosis at each visit, were also collected. The data were compiled into a database and analyzed. RESULTS: The lifetime incidence of psychosis in this cohort of patients was 28.1%. The data suggest that risk of psychosis remains fairly constant throughout the first 5 years after implantation of a DBS system and that patients older at the time of receiving the first DBS implant are not only more likely to develop psychosis, but also to develop symptoms sooner than their younger counterparts. Further analysis provides evidence that psychosis is largely independent of the clinically used electrode contact and of stimulation parameters prior to psychosis onset. CONCLUSIONS: Although symptoms of psychosis are widely seen in patients with Parkinson's disease in the years following stimulator placement, results of the present suggest that most psychoses occurring postoperatively are likely independent of implantation and stimulation settings.