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Memantine-induced Myoclonus in a Patient with Alzheimer Disease

Background: Myoclonus can be a clinical manifestation of numerous neurodegenerative disorders and an adverse drug reaction to medications used in their treatment. Case report: Herein, we report memantine-induced myoclonus in a patient with Alzheimer disease. The myoclonus seen in our patient was generalized (proximal limbs and trunk), present at rest and with action, and stimulus sensitive. A structured evaluation with the Unified Myoclonus Rating Scale showed that that myoclonus had no significant effect on functional capacity. After discontinuation of memantine, myoclonus slowly resolved over the course of several weeks. Discussion: Memantine may cause myoclonus in susceptible individuals.

Publication type: 
Author: 
Aditya A. Murgai
Mark S. LeDoux
Subjects: 
Neurosciences
Medicine
Health sciences
Title string: 
Memantine-induced Myoclonus in a Patient with Alzheimer Disease
GUID update: 
http://academiccommons.columbia.edu/catalog/ac:189747

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.

Publication type: 
Author: 
Pichet Termsarasab
Amy C. Yang
Steven J. Frucht
Subjects: 
Neurosciences
Medicine
Health sciences
Genetics
Title string: 
Intermediate Phenotypes of ATP1A3 Mutations: Phenotype–Genotype Correlations
GUID update: 
http://academiccommons.columbia.edu/catalog/ac:189777

The Role of Dopamine and Dopaminergic Pathways in Dystonia: Insights from Neuroimaging

Background: Dystonia constitutes a heterogeneous group of movement abnormalities, characterized by sustained or intermittent muscle contractions causing abnormal postures. Overwhelming data suggest involvement of basal ganglia and dopaminergic pathways in dystonia. In this review, we critically evaluate recent neuroimaging studies that investigate dopamine receptors, endogenous dopamine release, morphology of striatum, and structural or functional connectivity in cortico-basal ganglia-thalamo-cortical and related cerebellar circuits in dystonia. Method: A PubMed search was conducted in August 2014. Results: Positron emission tomography (PET) imaging offers strong evidence for altered D2/D3 receptor binding and dopaminergic release in many forms of idiopathic dystonia. Functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) data reveal likely involvement of related cerebello-thalamocortical and sensory-motor networks in addition to basal ganglia. Discussion: PET imaging of dopamine receptors or transmitter release remains an effective means to investigate dopaminergic pathways, yet may miss factors affecting dopamine homeostasis and related subcellular signaling cascades that could alter the function of these pathways. fMRI and DTI methods may reveal functional or anatomical changes associated with dysfunction of dopamine-mediated pathways. Each of these methods can be used to monitor target engagement for potential new treatments. PET imaging of striatal phosphodiesterase and development of new selective PET radiotracers for dopamine D3-specific receptors and Mechanistic target of rampamycin (mTOR) are crucial to further investigate dopaminergic pathways. A multimodal approach may have the greatest potential, using PET to identify the sites of molecular pathology and magnetic resonance methods to determine their downstream effects.

Publication type: 
Author: 
Morvarid Karimi
Joel S. Perlmutter
Subjects: 
Neurosciences
Medicine
Biochemistry
Title string: 
The Role of Dopamine and Dopaminergic Pathways in Dystonia: Insights from Neuroimaging
GUID update: 
http://academiccommons.columbia.edu/catalog/ac:189529

Uncommon Applications of Deep Brain Stimulation in Hyperkinetic Movement Disorders

Background: In addition to the established indications of tremor and dystonia, deep brain stimulation (DBS) has been utilized less commonly for several hyperkinetic movement disorders, including medication-refractory myoclonus, ballism, chorea, and Gilles de la Tourette (GTS) and tardive syndromes. Given the lack of adequate controlled trials, it is difficult to translate published reports into clinical use. We summarize the literature, draw conclusions regarding efficacy when possible, and highlight concerns and areas for future study. Methods: A Pubmed search was performed for English-language articles between January 1980 and June 2014. Studies were selected if they focused primarily on DBS to treat the conditions of focus. Results: We identified 49 cases of DBS for myoclonus-dystonia, 21 for Huntington’s disease, 15 for choreacanthocytosis, 129 for GTS, and 73 for tardive syndromes. Bilateral globus pallidus interna (GPi) DBS was the most frequently utilized procedure for all conditions except GTS, in which medial thalamic DBS was more common. While the majority of cases demonstrate some improvement, there are also reports of no improvement or even worsening of symptoms in each condition. The few studies including functional or quality of life outcomes suggest benefit. A limited number of studies included blinded on/off testing. There have been two double-blind controlled trials performed in GTS and a single prospective double-blind, uncontrolled trial in tardive syndromes. Patient characteristics, surgical target, stimulation parameters, and duration of follow-up varied among studies. Discussion: Despite these extensive limitations, the literature overall supports the efficacy of DBS in these conditions, in particular GTS and tardive syndromes. For other conditions, the preliminary evidence from small studies is promising and encourages further study.

Publication type: 
Author: 
Kara M. Smith
Meredith A. Spindler
Subjects: 
Neurosciences
Medicine
Health sciences
Title string: 
Uncommon Applications of Deep Brain Stimulation in Hyperkinetic Movement Disorders
GUID update: 
http://academiccommons.columbia.edu/catalog/ac:189538

Chorea: A Journey through History

The original descriptions of chorea date from the Middle Ages, when an epidemic of “dancing mania” swept throughout Europe. The condition was initially considered a curse sent by a saint, but was named “Saint Vitus’s dance” because afflicted individuals were cured if they touched churches storing Saint Vitus’s relics. Paracelsus coined the term chorea Sancti Viti and recognized different forms of chorea (imaginativa, lasciva, and naturalis). In the 17th century, Thomas Sydenham provided an accurate description of what he termed chorea minor. He also described rheumatic fever but did not associate it with chorea. It was only in 1850 that See established a relationship between chorea and rheumatic disease. A connection with cardiac involvement was soon recognized and in 1866 Roger postulated that chorea, arthritis, and heart disease had a common cause. The last quarter of the 19th century is marked by the works of Jean‐Martin Charcot, Silas Weir Mitchell, William Osler, and William Richard Gowers, all of paramount importance in the refinement of the definition of chorea, its causes, and differential diagnosis. In 1841, Charles Oscar Waters gave a concise account of a syndrome, likely to be Huntington’s disease (HD), later described further by George Huntington and named after him. In 1955, the Venezuelan physician Americo Negrette published a book describing communities in the State of Zulia in Venezuela, with unusual numbers of individuals with chorea. Negrette’s works culminated in the creation of the Venezuela project and the subsequent discovery of seminal findings in HD. We review the historical facts and outstanding physicians that mark both HD and Sydenham’s chorea’s history in various sections.

Publication type: 
Author: 
Thiago Cardoso Vale
Francisco Cardoso
Subjects: 
Health sciences
Neurosciences
Medicine
History
Title string: 
Chorea: A Journey through History
GUID update: 
http://academiccommons.columbia.edu/catalog/ac:189586

Reduced Number of Pigmented Neurons in the Substantia Nigra of Dystonia Patients? Findings from Extensive Neuropathologic, Immunohistochemistry, and Quantitative Analyses

Background: Dystonias (Dys) represent the third most common movement disorder after essential tremor (ET) and Parkinson’s disease (PD). While some pathogenetic mechanisms and genetic causes of Dys have been identified, little is known about their neuropathologic features. Previous neuropathologic studies have reported generically defined neuronal loss in various cerebral regions of Dys brains, mostly in the basal ganglia (BG), and specifically in the substantia nigra (SN). Enlarged pigmented neurons in the SN of Dys patients with and without specific genetic mutations (e.g., GAG deletions in DYT1 dystonia) have also been described. Whether or not Dys brains are associated with decreased numbers or other morphometric changes of specific neuronal types is unknown and has never been addressed with quantitative methodologies. Methods: Quantitative immunohistochemistry protocols were used to estimate neuronal counts and volumes of nigral pigmented neurons in 13 SN of Dys patients and 13 SN of age-matched control subjects (C). Results: We observed a significant reduction (∼20%) of pigmented neurons in the SN of Dys compared to C (p<0.01). Neither significant volumetric changes nor evident neurodegenerative signs were observed in the remaining pool of nigral pigmented neurons in Dys brains. These novel quantitative findings were confirmed after exclusion of possible co-occurring SN pathologies including Lewy pathology, tau-neurofibrillary tangles, β-amyloid deposits, ubiquitin (ubiq), and phosphorylated-TAR DNA-binding protein 43 (pTDP43)-positive inclusions. Discussion: A reduced number of nigral pigmented neurons in the absence of evident neurodegenerative signs in Dys brains could indicate previously unconsidered pathogenetic mechanisms of Dys such as neurodevelopmental defects in the SN.

Publication type: 
Author: 
Diego Iacono
Maria Geraci-Erck
Hui Peng
Marcie L. Rabin
Roger Kurlan
Subjects: 
Neurosciences
Medicine
Health sciences
Title string: 
Reduced Number of Pigmented Neurons in the Substantia Nigra of Dystonia Patients? Findings from Extensive Neuropathologic, Immunohistochemistry, and Quantitative Analyses
GUID update: 
http://academiccommons.columbia.edu/catalog/ac:189565

Comparable Botulinum Toxin Outcomes between Primary and Secondary Blepharospasm: A Retrospective Analysis

Background: Blepharospasm is a focal cranial dystonia, which could be idiopathic in origin or secondary to an underlying disorder that commonly impairs quality of life. Botulinum toxin (BoNT) injections have become the treatment of choice; however, a less favorable response to BoNT is expected in secondary blepharospasm. No studies have been conducted comparing outcomes between blepharospasm cohorts. We therefore aim to compare BoNT outcomes in primary and secondary blepharospasm subjects. Methods: A retrospective review of 64 blepharospasm subjects receiving BoNT therapy was conducted. Demographics, BoNT treatment schedules, duration of BoNT therapy, and side effects were recorded. Outcome measures were duration of benefit, peak-dose benefit recorded with the Clinical Global Impressions Scale (CGIS), and related side effects. Results: No difference was found between the two cohorts regarding duration of benefit from treatment (primary 9.47 weeks vs. secondary 9.63 weeks, p = 0.88). Perceived peak-dose benefit was more commonly reported as “very much improved” in secondary patients, but this was not significant (p = 0.13). Higher BoNT dosages were required in both groups over time, with a mean increase of 20.5% in primary and 26.5% in secondary blepharospasm. Ptosis (8%) and diplopia (6%) were the most common reported side effects. Mean follow-up in years was similar between groups, 3.6 years for primary vs. 2.4 years for secondary blepharospasm (p = 0.17). Discussion: BoNT injections were effective with comparable benefits seen in both primary and secondary blepharospasm populations. Clinicians should be aware of the similar benefit from BoNT reported in secondary blepharospasm patients. The average duration of benefit in this cohort was comparable with previous reports.

Publication type: 
Author: 
Juan C. Giugni
Erin Hastings
Aparna W. Shukla
Irene A. Malaty
Michael S. Okun
Ramon L. Rodriguez
Daniel Martinez-Ramirez
Subjects: 
Neurosciences
Medicine
Title string: 
Comparable Botulinum Toxin Outcomes between Primary and Secondary Blepharospasm: A Retrospective Analysis
GUID update: 
http://academiccommons.columbia.edu/catalog/ac:182322

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.

Publication type: 
Author: 
Pichet Termsarasab
Amy C. Yang
Jennifer Reiner
Hui Mei
Stuart A. Scott
Steven J. Frucht
Subjects: 
Neurosciences
Medicine
Title string: 
Paroxysmal Kinesigenic Dyskinesia Caused by 16p11.2 Microdeletion
GUID update: 
http://academiccommons.columbia.edu/catalog/ac:182259

Botulinum Toxin Therapy for Cervical Dystonia: The Science of Dosing

The first-line treatment for cervical dystonia (CD) is botulinum toxin type A (BoNT-A), which has been established as a highly effective and well-tolerated therapy. However, this treatment is also complex and challenging to apply in clinical practice. Approximately 20% of patients discontinue therapy due to treatment failure, adverse effects, and other reasons. In addition, expert consensus recommendations are lacking to guide physicians in the optimal use of BoNT-A for CD. Among the issues still to be clarified is the optimal dosing frequency. The generally accepted standard for intervals between BoNT-A injections is ≥12 weeks; however, this standard is based primarily on the methodology of pivotal trials for the BoNT-A products, rather than on evidence that it is optimal in comparison to other intervals. While some retrospective, observational studies of BoNT-A used in clinical practice appear to support the use of ≥12-week dosing intervals, it is often unclear in these studies how the need for reinjection was determined. In contrast, a prospective dose-ranging trial in which patients were allowed to request reinjection as early as 8 weeks showed that about half of patients receiving abobotulinumtoxinA, at the currently recommended initial dose of 500 U, requested reinjection at 8 weeks. Moreover, results from an open-label, 68-week extension phase of the pivotal trial of incobotulinumtoxinA showed that 47.1% of patients had received reinjection at ≤12 weeks. Ongoing studies, such as the Cervical Dystonia Patient Registry for Observation of BOTOXH Efficacy (CD PROBE), may help clarify this question of optimal dosing intervals for BoNT-A in CD.

Publication type: 
Author: 
Virgilio Gerald H. Evidente
Eric J. Pappert
Subjects: 
Neurosciences
Medicine
Title string: 
Botulinum Toxin Therapy for Cervical Dystonia: The Science of Dosing
GUID update: 
http://academiccommons.columbia.edu/catalog/ac:181698

Elucidating the Nature and Mechanism of Tic Improvement in Tourette Syndrome: A Pilot Study

Background: For unclear reasons, many Tourette syndrome (TS) children report near‐complete tic remission by young adulthood. Immature maturation of brain networks, observed with resting‐state functional MRI (rs‐fc‐MRI) in adolescents and adults with TS, might evolve to a mature pattern in adults who experience tic improvement or remission. We explored the feasibility of testing this hypothesis in our population of young adult TS males, each with prior clinical assessments completed during childhood as part of a separate TS Association Genetics Consortium study.

Methods: A total of 10 TS males (off tic suppressing drugs for at least 6 months) aged 19–32 years, mean follow‐up interval 7.5 (2 to 13) years, and 11 neurologically normal controls were enrolled and underwent 3‐Tesla structural and rs‐fc‐MRI sequences.

Results: The mean change in Yale Global Tic Severity Scale (YGTSS) was −31.5% (total) and −26.6% (YGTSS motor+vocal). Two subjects reported resolution of tic‐related disability, with drops from mean 45 to 16.5 (YGTSS‐total) and 25 to 11.5 (YGTSS motor+vocal.). Rs‐fc‐MRI revealed significantly increased connectivity between the ipsilateral anterior and mid cingulate cortex and striatum, increased connectivity between local connections, and decreased connectivity between more distant connections; representing an immature connectivity pattern.

Discussion: Similar to previous reports, we found immature patterns of functional connectivity in adult TS subjects. Despite a lack of complete tic remission, two subjects exhibited dramatic drops in tic severity that correlated with tic‐related disability improvement. More work is needed to elucidate the mechanism of such dramatic improvement in TS.

Publication type: 
Author: 
David R. Shprecher
Keenan Gannon
Nivedita Agarwal
Xianfeng Shi
Jeffrey S. Anderson
Subjects: 
Neurosciences
Title string: 
Elucidating the Nature and Mechanism of Tic Improvement in Tourette Syndrome: A Pilot Study
GUID update: 
http://academiccommons.columbia.edu/catalog/ac:179315

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