Comparison of Oropharyngeal Dysphagia Before and After Botulinum Toxin Injection in Cervical Dystonia.

Cervical dystonia (CD) is the most common form of focal dystonia with Botulinum neurotoxin (BoNT) being a frequent method of treatment. Dysphagia is a common side effect of BoNT treatment for CD. Instrumental evaluation of swallowing in CD using standardized scoring for the videofluoroscopic swallowing study (VFSS) and validated and reliable patient-reported outcomes measures is lacking in the literature. (1) to determine if BoNT injections change instrumental findings of swallowing function using the Modified Barium Swallow Impairment Profile (MBSImP) in individuals with CD; (2) to determine if BoNT injections change self-perception of the psychosocial handicapping effects of dysphagia in individuals with CD, using the Dysphagia Handicap Index (DHI); (3) to determine the effect of BoNT dosage on instrumental swallowing evaluation and self-reported swallowing outcomes measures. 18 subjects with CD completed a VFSS and the DHI before and after BoNT injection. There was a significant increase in pharyngeal residue for pudding consistency after BoNT injection, p = 0.015. There were significant positive associations between BoNT dosage and self-perception of the physical attributes of the handicapping effect of dysphagia, the grand total score and patient self-reported severity of dysphagia on the DHI; p = 0.022; p = 0.037; p = 0.035 respectively. There were several significant associations between changes in MBSImP scores and BoNT dose. Pharyngeal efficiency of swallowing may be affected by BoNT for thicker consistencies. Individuals with CD perceive greater physical handicapping effects of dysphagia with increased amounts of BoNT units and have greater self-perceptions of dysphagia severity with increased amounts of BoNT units.

Clinical diagnostic exome sequencing in dystonia: Genetic testing challenges for complex conditions.

Patients with dystonia are particularly appropriate for diagnostic exome sequencing (DES), due to the complex, diverse features and genetic heterogeneity. Personal and family history data were collected from test requisition forms and medical records from 189 patients with reported dystonia and available family members received for clinical DES. Of them, 20.2% patients had a positive genetic finding associated with dystonia. Detection rates for cases with isolated and combined dystonia were 22.4% and 25.0%, respectively. 71.4% of the cohort had co-occurring non-movement-related findings and a detection rate of 24.4%. Patients with childhood-onset dystonia trended toward higher detection rates (31.8%) compared to infancy (23.6%), adolescence (12.5%), and early-adulthood onset (16%). Uncharacterized gene findings were found in 6.7% (8/119) of cases that underwent analysis for genes without an established disease relationship. Patients with intellectual disability/developmental delay, seizures/epilepsy and/or multifocal dystonia were more likely to have positive findings (P = .0093, .0397, .0006). Four (2.1%) patients had findings in two genes, and seven (3.7%) had reclassification after the original report due to new literature, new clinical information or reanalysis request. Pediatric patients were more likely to have positive findings (P = .0180). Our observations show utility of family-based DES in patients with dystonia and illustrate the complexity of testing.

A mechanistic review on GNAO1-associated movement disorder.

Mutations in the GNAO1 gene cause a complex constellation of neurological disorders including epilepsy, developmental delay, and movement disorders. GNAO1 encodes Gαo, the α subunit of Go, a member of the Gi/o family of heterotrimeric G protein signal transducers. Go is the most abundant membrane protein in the mammalian central nervous system and plays major roles in synaptic neurotransmission and neurodevelopment. GNAO1 mutations were first reported in early infantile epileptic encephalopathy 17 (EIEE17) but are also associated with a more common syndrome termed neurodevelopmental disorder with involuntary movements (NEDIM). Here we review a mechanistic model in which loss-of-function (LOF) GNAO1 alleles cause epilepsy and gain-of-function (GOF) alleles are primarily associated with movement disorders. We also develop a signaling framework related to cyclic AMP (cAMP), synaptic vesicle release, and neural development and discuss gene mutations perturbing those mechanisms in a range of genetic movement disorders. Finally, we analyze clinical reports of patients carrying GNAO1 mutations with respect to their symptom onset and discuss pharmacological/surgical treatments in the context of our mechanistic model.

Long-term double-blinded unilateral pedunculopontine area stimulation in Parkinson's disease.

BACKGROUND: Gait-related symptoms are often refractory to current available treatment options with a significant reduction in quality of life in Parkinson's disease. OBJECTIVES: The objective of this study was to determine the long-term efficacy and safety of unilateral pedunculopontine area stimulation for refractory gait and balance impairment in Parkinson's disease. METHODS: This study used periodic randomized double-blinded assessments until 4 years postoperatively. The primary outcomes were gait-related items of the UPDRS part II and the MDS-UPDRS part III. RESULTS: At baseline, the median age and disease duration was 63 years (interquartile range: 62, 65) and 15 years (interquartile range: 11, 20). At 2 years, patient-reported freezing (UPDRS part II, off-time) was significantly better when compared with baseline (P =.028), with 62.5% of responders. At 4 years, there was no significant change in the used outcomes, but 66.7 % (n = 4 of 6) were responders for off-time patient-reported freezing and falling. CONCLUSIONS: Pedunculopontine area stimulation has an initial but not sustained benefit for gait-related symptoms. © 2016 International Parkinson and Movement Disorder Society.

Bilateral pallidal stimulation in cervical dystonia: blinded evidence of benefit beyond 5 years.

The local injection of botulinum toxin is accepted as the first-line treatment of primary cervical dystonia. This approach provides adequate symptomatic relief for most patients, but up to one-third will have an unsatisfactory response. Deep brain stimulation of the globus pallidus internus has been increasingly used in dystonic syndromes that are refractory to best pharmacological approaches. Although cervical dystonia is the most common idiopathic focal dystonia, evidence for long-term responsiveness to pallidal stimulation is limited. The primary objective of this study was to prospectively collect outcome data from baseline to last clinical follow-up on patients with idiopathic cervical dystonia treated with bilateral pallidal stimulation. Blinded video assessment of examinations performed preoperatively and at last video assessment were performed. Ten patients had complete prospective clinical follow-up. Baseline total Toronto Western Spasmodic Torticollis Rating Scale score (±standard deviation) was 54.5 ± 12.4 (range, 35.0-70.3). Comparison of the blinded severity sub-score on baseline video and at last video assessment at a mean of 7.7 years postoperatively demonstrated a mean improvement of 47.6% (P = 0.002) and strong inter-observer correlation between blinded raters (Spearman r = 0.78, 95% confidence interval 0.49-0.92, P = 0.0001). All 10 patients had 5 years of open prospective follow-up, documenting a 47.4 ± 26.4% (P < 0.01) mean improvement with respect to baseline. This was maintained at a mean of 7.8 years at last follow-up after surgery (range, 4.9-10.7 years) with a 54.4 ± 27.4% mean improvement (P < 0.01). Deep brain stimulation of the globus pallidus is an effective and long-lasting second-line treatment of cervical dystonia, with benefit in some of our patients extending to >10 years. More data are needed to explain variations in individual responses and to guide individual programming parameters.

Motor and Non-motor Outcomes of Deep Brain Stimulation across the Genetic Panorama of Parkinson's Disease: A Multi-Scale Meta-Analysis.

BACKGROUND: In the era of modern medicine, where high-throughput sequencing techniques are readily available, it is desirable to elucidate the role of genetic background in patients with Parkinson's Disease (PD) undergoing Deep Brain Stimulation (DBS). Genetic stratification of PD patients undergoing DBS may assist in patient selection and prediction of clinical outcomes and complement existing selection procedures such as levodopa challenge testing. OBJECTIVE: To capture a broad spectrum of motor and non-motor DBS outcomes in genetic PD patients with data from the recently updated literature. METHODS: A multi-scale meta-analysis with 380 genetic PD cases was conducted using the Cochrane Review Manager, JASP software and R. RESULTS: This meta-analysis revealed that overall, patients with genetic PD are good candidates for DBS but the outcomes might differ depending on the presence of specific mutations. PRKN carriers benefited the most regarding motor function, daily dose medication and motor complications. However, GBA carriers appeared to be more prone to cognitive decline after subthalamic nucleus DBS accompanied by a low quality of life with variable severity depending on genetic variants and concomitant alterations in other genes. Apart from GBA, cognitive worsening was also observed in SNCA carriers. Pre-operative levodopa responsiveness and a younger age of onset are associated with a favorable motor outcome. CONCLUSION: A personalized approach with a variant-based risk stratification within the emerging field of surgicogenomics is needed. Integration of polygenic risk scores in clinical-decision making should be encouraged.

Trigeminal neuralgia, demyelinating polyneuropathy, and central nervous system involvement in a patient with an SH3TC2 mutation.

BACKGROUND: Charcot-Marie-Tooth type 4C (CMT4C) is a slowly progressive, autosomal recessive, sensorimotor polyneuropathy characterized by demyelination and distinct clinical features, including cranial nerve involvement. CMT4C is associated with pathogenic mutations in the SH3TC2 gene. METHODS: A patient presenting with gait instability due to demyelinating polyneuropathy and refractory trigeminal neuralgia underwent comprehensive evaluation. Nerve conduction studies, magnetic resonance imaging (MRI) of the brain, cervical spine, and thoracic spine, lumbar puncture, and genetic test through next generation sequencing were performed. RESULTS: The genetic test found an Arg1109Stop mutation in the SH3TC2 gene, associated with demyelinating polyneuropathy and cranial neuropathy. Interestingly, brain MRI showed multiple, nonenhancing white matter hyperintensities. This is the first case of CMT4C associated with white matter lesions. CONCLUSION: Any patient with slowly progressive peripheral nervous system symptoms and disproportionally abnormal nerve conduction study findings should be tested for an inherited polyneuropathy and brain imaging for screening of possible central nervous system involvement should be performed. Further investigation is needed to elucidate the pathogenetic basis of CMT4C and a possible association with white matter lesions.

Paradigm shift in Parkinson's disease: using continuous telemonitoring to improve symptoms control. Results from a 2-years journey.

Introduction: Conventional care in Parkinson's disease (PD) faces limitations due to the significant time and location commitments needed for regular assessments, lacking quantitative measurements. Telemonitoring offers clinicians an opportunity to evaluate patient symptomatology throughout the day during activities of daily living. Methods: The progression of PD symptoms over a two-year period was investigated in patients undergoing traditional evaluation, supplemented by insights from ambulatory measurements. Physicians integrated a telemonitoring device, the PDMonitor®, into daily practice, using it for informed medication adjustments. Results: Statistical analyses examining intra-subject changes for 17 subjects revealed a significant relative decrease of -43.9% in the device-reported percentage of time spent in "OFF" state (from 36.2 to 20.3%). Following the 24-month period, the majority of the subjects improved or exhibited stable symptom manifestation. In addition to positively impacting motor symptom control, telemonitoring was found to enhance patient satisfaction about their condition, medication effectiveness, and communication with physicians. Discussion: Considering that motor function is significantly worsened over time in patients with PD, these findings suggest a positive impact of objective telemonitoring on symptoms control. Patient satisfaction regarding disease management through telemonitoring can potentially improve adherence to treatment plans. In conclusion, remote continuous monitoring paves the way for a paradigm shift in PD, focusing on actively managing and potentially improve symptoms control.

Bilateral pallidal stimulation for Wilson's disease.

BACKGROUND: To report on the clinical efficacy of bilateral globus pallidus internus deep brain stimulation in a 29-year-old patient with severe generalized dystonia secondary to Wilson's disease. METHODS: The primary outcome measure was the Burke-Fahn-Marsden Dystonia Scale motor severity score (blinded assessment) and the secondary outcome measures were the Abnormal Involuntary Movement Scale (blinded assessment) and the Zaritt Caregiver Burden Interview score, at 20-week postoperative follow up. RESULTS: There was a 14% improvement in the Burke-Fahn-Marsden Dystonia Scale motor severity score. Abnormal Involuntary Movement Scale score remained unchanged while the Zaritt Caregiver Burden Interview score improved by 44.4%. CONCLUSIONS: Bilateral globus pallidus deep brain stimulation can be effective in ameliorating dystonia and caregiver burden in Wilson's disease. Outcomes may depend on the stage of the disease at which the surgical procedure is completed. © 2013 Movement Disorder Society.

A Bayesian Network Meta-Analysis and Systematic Review of Guidance Techniques in Botulinum Toxin Injections and Their Hierarchy in the Treatment of Limb Spasticity.

Accurate targeting of overactive muscles is fundamental for successful botulinum neurotoxin (BoNT) injections in the treatment of spasticity. The necessity of instrumented guidance and the superiority of one or more guidance techniques are ambiguous. Here, we sought to investigate if guided BoNT injections lead to a better clinical outcome in adults with limb spasticity compared to non-guided injections. We also aimed to elucidate the hierarchy of common guidance techniques including electromyography, electrostimulation, manual needle placement and ultrasound. To this end, we conducted a Bayesian network meta-analysis and systematic review with 245 patients using the MetaInsight software, R and the Cochrane Review Manager. Our study provided, for the first time, quantitative evidence supporting the superiority of guided BoNT injections over the non-guided ones. The hierarchy comprised ultrasound on the first level, electrostimulation on the second, electromyography on the third and manual needle placement on the last level. The difference between ultrasound and electrostimulation was minor and, thus, appropriate contextualization is essential for decision making. Taken together, guided BoNT injections based on ultrasound and electrostimulation performed by experienced practitioners lead to a better clinical outcome within the first month post-injection in adults with limb spasticity. In the present study, ultrasound performed slightly better, but large-scale trials should shed more light on which modality is superior.

Brain Connectivity in Dystonia: Evidence from Magnetoencephalography.

Magnetoencephalography (MEG) detects synchronized activity within a neuronal network by measuring the magnetic field changes generated by intracellular current flow. Using MEG data, we can quantify brain region networks with similar frequency, phase, or amplitude of activity and thereby identify patterns of functional connectivity seen with specific disorders or disease states. In this review, we examine and summarize MEG-based literature on functional networks in dystonias. Specifically, we inspect literature evaluating the pathogenesis of focal hand dystonia, cervical dystonia, embouchure dystonia, the effects of sensory tricks, treatment with botulinum toxin and deep brain stimulation, and rehabilitation approaches. This review additionally highlights how MEG has potential for application to clinical care of patients with dystonia.

How Parkinson's patients in the USA perceive deep brain stimulation in the 21st century: Results of a nationwide survey.

Research on attitudes regarding the use and timing of deep brain stimulation (DBS) has been mostly qualitative to this date. In this study, we aim to examine attitudes and perceptions about the use and timing of DBS in patients with Parkinson's disease (PD) who have not had DBS. We designed an online survey comprising Likert-type, multiple choice, and rank-order questions and distributed it to PD patients. We recruited participants via flyers, the Michael J. Fox Foundation Trial Finder, and the Parkinson Alliance website. We analyzed considerations for choosing or rejecting DBS and when participants would consider such a decision to be premature. Data were analyzed using descriptive and inferential statistics, including a multinomial logistic regression model. Among the 285 participants who reported not having undergone DBS, the most frequent concerns were related to the efficacy of DBS and not having exhausted medication alternatives. DBS was viewed as less convenient, effective, and safe when PD symptoms were still manageable by medication. Our regression model suggests that having fewer concerns over technical problems was a positive predictor of preferring early DBS, while concerns over DBS interfering with friendships and relationships was a negative predictor. Our results suggest that patients with PD who have not undergone DBS have a wide variety of attitudes regarding DBS and its timing. Given the increasing number of therapeutic options for PD, future work should compare perceptions and preferences regarding different PD treatment modalities to provide the best counseling for patients regarding their therapeutic options.

Efficacy of a 5-day, intensive, multidisciplinary, outpatient physical and occupational therapy protocol in the treatment of functional movement disorders: A retrospective study.

BACKGROUND: The use of rehabilitation services has been shown to be beneficial for patients with functional movement disorders (FMD). However, there is great variability in the type of rehabilitation services utilized. In the present study we aimed at determining the efficacy of an intense outpatient physical rehabilitation program as a treatment modality for patients with FMD. METHODS: Eighteen participants underwent treatment in a specialized outpatient rehabilitation program utilizing a multidisciplinary approach for the treatment of FMD. Participants completed a series of tests on day one and day five of the program. RESULTS: Results indicated statistically significant improvements in all but one motor and gait outcomes in patients with functional movement disorders treated with physical rehabilitation. CONCLUSION: These results provide support for the continued use of physical and occupational therapy for functional movement disorder patients. Further research is needed to fully validate these findings and there remains a need for further study into multidisciplinary approaches that may be even more efficacious.

Adjuvant medical therapy in cervical dystonia after deep brain stimulation: A retrospective analysis.

Background: There is limited information on optimization of symptomatic management of cervical dystonia (CD) after implantation of pallidal deep brain stimulation (DBS). Objectives: To describe the long-term, "real-world" management of CD patients after DBS implantation and the role of reintroduction of pharmacologic and botulinum toxin (BoNT) therapy. Methods: A retrospective analysis of patients with focal cervical or segmental craniocervical dystonia implanted with DBS was conducted. Results: Nine patients were identified with a mean follow-up of 41.7 ± 15.7 months. All patients continued adjuvant oral medication(s) to optimize symptom control post-operatively. Three stopped BoNT and four reduced BoNT dose by an average of 22%. All patients remained on at least one medication used to treat dystonia post-operatively. Conclusion: Optimal symptom control was achieved with DBS combined with either BoNT and/or medication. We suggest utilization of adjuvant therapies such as BoNT and/or medications if DBS monotherapy does not achieve optimal symptom control.

Influence of brain-derived neurotrophic-factor and apolipoprotein E genetic variants on hippocampal volume and memory performance in healthy young adults.

Unravelling the impact of genetic variants on clinical phenotypes is a challenging task. Apolipoprotein E (ApoE) and brain-derived neurotrophic factor (BDNF) play an important role in cell growth, regeneration, synaptic plasticity, learning and memory processes. The aim of the present study was to examine the impact of BDNF Val66Met- and ApoE-polymorphisms and their interactions on hippocampal morphology and memory functions in healthy young adults. Hippocampal volume and memory performance of 135 healthy individuals, aged 24.6 ± 3.2 years, were assessed, using magnetic resonance imaging and the Inventory for Memory diagnostics. The performance of BDNF-Met66 carriers was significantly lower in working memory (P = 0.03) compared with non carriers, whereas no further differences were observed either in cognitive performance or in hippocampal volumes between the groups. Age, BDNF Val66 Met polymorphism and the interaction factor BDNF genotype x age were significantly associated with the variation of working memory scores (P = 0.01, 0.01, 0.02 respectively). No statistically significant differences were detected in the volumes of hippocampi and in memory phenotypes between individuals carrying the ApoE E4 allele and those without it. The analysis did not reveal an impact of gene-gene interaction between BDNF and ApoE genes on hippocampal volumes or memory performance. BDNF Val66Met polymorphism seems to influence working memory function and modulate the effects of ageing on working memory in healthy young adults.

Therapeutic Applications of Botulinum Neurotoxin for Autonomic Symptoms in Parkinson's Disease: An Updated Review.

Parkinson's disease is the most common age-related motoric neurodegenerative disease. In addition to the cardinal motor symptoms of tremor, rigidity, bradykinesia, and postural instability, there are numerous non-motor symptoms as well. Among the non-motor symptoms, autonomic nervous system dysfunction is common. Autonomic symptoms associated with Parkinson's disease include sialorrhea, hyperhidrosis, gastrointestinal dysfunction, and urinary dysfunction. Botulinum neurotoxin has been shown to potentially improve these autonomic symptoms. In this review, the varied uses of botulinum neurotoxin for autonomic dysfunction in Parkinson's disease are discussed. This review also includes discussion of some additional indications for the use of botulinum neurotoxin in Parkinson's disease, including pain.

Heterozygous VPS13A and PARK2 Mutations in a Patient with Parkinsonism and Seizures.

Neuroacanthocytosis (NA) is a diverse group of disorders in which nervous system abnormalities co-occur with irregularly shaped red blood cells called acanthocytes. Chorea-acanthocytosis is the most common of these syndromes and is an autosomal recessive disease caused by mutations in the vacuolar protein sorting 13A (VPS13A) gene. We report a case of early onset parkinsonism and seizures in a 43-year-old male with a family history of NA. Neurologic examinations showed cognitive impairment and marked parkinsonian signs. MRI showed bilateral basal ganglia gliosis. He was found to have a novel heterozygous mutation in the VPS13A gene, in addition a heterozygous mutation in the PARK2 gene. His clinical picture was atypical for typical chorea-acanthocytosis (ChAc). The compound heterozygous mutations of VPS13A and PARK2 provide the most plausible explanation for this patient's clinical symptoms. This case adds to the phenotypic diversity of ChAc. More research is needed to fully understand the roles of epistatic interactions on phenotypic expression of neurodegenerative diseases.

Results of the First GNAO1-Related Neurodevelopmental Disorders Caregiver Survey.

BACKGROUND: We sought to expand our knowledge of the clinical spectrum of GNAO1-related neurodevelopmental disorders through a caregiver survey reviewing medical and developmental history and development of epilepsy and movement disorders. METHODS: An online survey was administered to caregivers of individuals diagnosed with GNAO1 pathogenic variants. RESULTS: Eighty-two surveys were completed. Nearly all (99%) reported the first symptom of concern by age one year with the most frequently identified concerns as hypotonia (68%), developmental delay (67%), seizures (29%), difficulty feeding (23%), and abnormal movements (20%). All caregivers reported developmental delays with a spectrum of severity. Movement disorders (76%) were more common than epilepsy (52%), although 33% reported both. The onset of seizures tended to be earlier than abnormal movements. Nearly half (48%) of those with any seizures, reported they were no longer having recurrent seizures. No single most effective medication for movement disorders or epilepsy was noted. Ten participants have had deep brain stimulator for their movement disorder, and all indicated positive effects. CONCLUSIONS: GNAO1-related neurodevelopmental disorders most often present within the first year of life with nonspecific symptoms of hypotonia or developmental delay. Although associated epilepsy and movement disorders can be severe, GNAO1-associated epilepsy may not always be medically refractory or lifelong.

Self-Perception of Voice and Swallowing Handicap in Parkinson's Disease.

BACKGROUND: Hypokinetic dysarthria and dysphagia are known features of Parkinson's disease; however, self-perception of their handicapping effects on emotional, physical, and functional aspects of quality of life over disease duration is less understood. OBJECTIVE: 1) Based upon patient self-perception, to determine the relationship of the handicapping effects of dysphagia and dysphonia with time since diagnosis in individuals with Parkinson's disease; 2)To determine if there is a relationship between voice and swallowing handicap throughout the course of Parkinson's disease. METHOD: 277 subjects completed the Dysphagia Handicap Index and the Voice Handicap Index. Subjects were divided into three groups based on disease duration: 0-4 years, 5-9 years, and 10 + years. RESULTS: Subjects in the longer duration group identified significantly greater perceptions of voice and swallowing handicap compared to the shorter duration groups. There was a significant positive correlation between the DHI and VHI. CONCLUSION: Self-perception of swallowing and voice handicap in Parkinson's disease are associated with later stages of disease and progress in a linear fashion. Self-perception of voice and swallowing handicap parallel each other throughout disease progression in Parkinson's disease. Individuals may be able to compensate for changes in voice and swallowing early while sensory perceptual feedback is intact. Results support early targeted questioning of patient self-perception of voice and swallowing handicap as identification of one problem indicates awareness of the other, thus creating an opportunity for early treatment and maintenance of swallowing and communication quality of life for as long as possible.