Pichet Termsarasab

Isolated Focal Dystonia as a Disorder of Large-Scale Functional Networks

Abstract Isolated focal dystonias are a group of disorders with diverse symptomatology but unknown pathophysiology. Although recent neuroimaging studies demonstrated regional changes in brain connectivity, it remains unclear whether focal dystonia may be considered a disorder of abnormal networks. We examined topology as well as the global and local features of large‐scale functional brain networks across different forms of isolated focal dystonia, including patients with task‐specific (TSD) and nontask‐specific (NTSD) dystonias. Compared with healthy participants, all patients showed altered network architecture characterized by abnormal expansion or shrinkage of neural communities, such as breakdown of basal ganglia‐cerebellar community, loss of a pivotal region of information transfer (hub) in the premotor cortex, and pronounced connectivity reduction within the sensorimotor and frontoparietal regions. TSD were further characterized by significant connectivity changes in the primary sensorimotor and inferior parietal cortices and abnormal hub formation in insula and superior temporal cortex, whereas NTSD exhibited abnormal strength and number of regional connections. We suggest that isolated focal dystonias likely represent a disorder of large‐scale functional networks, where abnormal regional interactions contribute to network‐wide functional alterations and may underline the pathophysiology of isolated focal dystonia. Distinct symptomatology in TSD and NTSD may be linked to disorder‐specific network aberrations.

Neural correlates of abnormal sensory discrimination in laryngeal dystonia

Aberrant sensory processing plays a fundamental role in the pathophysiology of dystonia; however, its underpinning neural mechanisms in relation to dystonia phenotype and genotype remain unclear. We examined temporal and spatial discrimination thresholds in patients with isolated laryngeal form of dystonia (LD), who exhibited different clinical phenotypes (adductor vs. abductor forms) and potentially different genotypes (sporadic vs. familial forms). We correlated our behavioral findings with the brain gray matter volume and functional activity during resting and symptomatic speech production. We found that temporal but not spatial discrimination was significantly altered across all forms of LD, with higher frequency of abnormalities seen in familial than sporadic patients. Common neural correlates of abnormal temporal discrimination across all forms were found with structural and functional changes in the middle frontal and primary somatosensory cortices. In addition, patients with familial LD had greater cerebellar involvement in processing of altered temporal discrimination, whereas sporadic LD patients had greater recruitment of the putamen and sensorimotor cortex. Based on the clinical phenotype, adductor form-specific correlations between abnormal discrimination and brain changes were found in the frontal cortex, whereas abductor form-specific correlations were observed in the cerebellum and putamen. Our behavioral and neuroimaging findings outline the relationship of abnormal sensory discrimination with the phenotype and genotype of isolated LD, suggesting the presence of potentially divergent pathophysiological pathways underlying different manifestations of this disorder.

Intermediate Phenotypes of ATP1A3 Mutations: Phenotype-Genotype Correlations.

Background ATP1A3-related disorders include rapid-onset dystonia–parkinsonism (RDP or DYT12), alternating hemiplegia of childhood (AHC), and CAPOS syndrome (Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy, and Sensorineural hearing loss). Case Report We report two cases with intermediate forms between RDP and AHC. Patient 1 initially presented with the AHC phenotype, but the RDP phenotype emerged at age 14 years. The second patient presented with levodopa-responsive paroxysmal oculogyria, a finding never before reported in ATP1A3-related disorders. Genetic testing confirmed heterozygous changes in the ATP1A3 gene in both patients, one of them novel. Discussion Intermediate phenotypes of RDP and AHC support the concept that these two disorders are part of a spectrum. We add our cases to the phenotype–genotype correlations of ATP1A3-related disorders.

Spinal-generated movement disorders: a clinical review

Spinal-generated movement disorders (SGMDs) include spinal segmental myoclonus, propriospinal myoclonus, orthostatic tremor, secondary paroxysmal dyskinesias, stiff person syndrome and its variants, movements in brain death, and painful legs-moving toes syndrome. In this paper, we review the relevant anatomy and physiology of SGMDs, characterize and demonstrate their clinical features, and present a practical approach to the diagnosis and management of these unusual disorders.

The diagnostic value of saccades in movement disorder patients: a practical guide and review

Saccades are rapid eye movements designed to shift the fovea to objects of visual interest. Abnormalities of saccades offer important clues in the diagnosis of a number of movement disorders. In this review, we explore the anatomy of horizontal and vertical saccades, discuss practical aspects of their examination, and review how saccadic abnormalities in hyperkinetic and hypokinetic movement disorders aid in diagnosis, with video demonstration of classic examples. Documentation of the ease of saccade initiation, range of motion and conjugacy of saccades, speed and accuracy of saccades, dynamic saccadic trajectory, and the presence or absence of saccadic intrusions and oscillations are important components of this exam. We also provide a practical algorithm to demonstrate the value of saccades in the differential diagnosis of the movement disorders patient.

Medical treatment of dystonia

Therapeutic strategies in dystonia have evolved considerably in the past few decades. Three major treatment modalities include oral medications, botulinum toxin injections and surgical therapies, particularly deep brain stimulation. Although there has been a tremendous interest in the later two modalities, there are relatively few recent reviews of oral treatment. We review the medical treatment of dystonia, focusing on three major neurotransmitter systems: cholinergic, GABAergic and dopaminergic. We also provide a practical guide to medication selection, therapeutic strategy and unmet needs.

Evaluation of embouchure dysfunction: Experience of 139 patients at a single center

Our aims are to 1) illustrate the complexity and phenomenological richness of the embouchure; 2) delineate the main clinical features of non‐dystonic embouchure problems (NED) versus embouchure dystonia (ED); and 3) provide a practical framework for physicians who may encounter a patient with embouchure dysfunction.

The phenomenology and natural history of idiopathic lower cranial dystonia

BackgroundMany patients with lower cranial dystonia (LCrD) are misdiagnosed, and recognition of this condition by general practitioners and dental health professionals is limited.MethodsWe define the phenomenology and natural history of idiopathic LCrD, presenting in 41 patients with the disorder, the largest series of these patients reported to date.ResultsPhenomenology of dystonia included lower cranial and pharyngeal involvement, jaw opening and jaw closing dystonia, and tongue dystonia. Of 25 newly described patients, 72% (18) were female, average age at onset was 56 years, and delay before correct diagnosis was 3.8 years (0-25 years, median 2 years). Eleven patients (44%) reported a precipitating event, the most common of which was recent dental work. Geste antagonistes were found in 18 patients (72%). Response to treatment was mixed, indicating an unmet therapeutic need.ConclusionsIdiopathic LCrD is often missed and institution of effective therapy is often delayed. The clinical features and natural history of LCrD are similar to other forms of focal dystonia.

Paroxysmal Kinesigenic Dyskinesia Caused by 16p11.2 Microdeletion

Background Four cases of paroxysmal kinesigenic dyskinesia (PKD) have been reported in individuals with proximal 16p11.2 microdeletions that include PRRT2. Case Report We describe a fifth patient with PKD, features of Asperger’s syndrome, and mild language delays. Sanger sequencing of the PRRT2 gene did not identify any mutations implicated in PKD. However, microarray-based comparative genomic hybridization (aCGH) detected a 533.9-kb deletion on chromosome 16, encompassing over 20 genes and transcripts. Discussion This case underscores the importance of aCGH testing for individuals with PKD who do not have PRRT2 mutations, particularly when developmental delays, speech problems, intellectual disability, and/or autism spectrum disorder are present.

Alcohol-responsive Action Myoclonus of the Leg in Prostate Cancer: A Novel Paraneoplastic Syndrome?

Background Paraneoplastic movement disorders in prostate cancer are rare, and to our knowledge paraneoplastic myoclonus has not previously been reported. Case Report We report two men with adenocarcinoma of the prostate who developed isolated alcohol-responsive action myoclonus of one leg. Myoclonus was absent at rest but triggered by movement, standing, or walking. Evaluations excluded malignant invasion of the nervous system, and testing for commercial paraneoplastic antibodies in serum and cerebrospinal fluid were unrevealing. Both patients experienced significant improvement with alcohol, and sodium oxybate was used in one patient with good initial benefit. Discussion Alcohol-responsive leg myoclonus might be a novel paraneoplastic syndrome associated with prostate cancer. The nature of the syndrome and the source of the myoclonus are currently unknown.