The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.
If you have any questions or comments, please contact us.
BACKGROUND - Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous disorder of the peripheral nervous system. Biallelic variants in have been associated with autosomal-recessive hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC). We identified heterozygous de novo variants in in three unrelated patients with intermediate CMT.
METHODS - We evaluated the clinical reports and electrophysiological data of three patients carrying de novo variants in identified by diagnostic trio exome sequencing. For functional characterisation of the identified variants, potassium influx of mutated KCC3 cotransporters was measured in oocytes.
RESULTS - We identified two different de novo missense changes (p.Arg207His and p.Tyr679Cys) in in three unrelated individuals with early-onset progressive CMT. All presented with axonal/demyelinating sensorimotor neuropathy accompanied by spasticity in one patient. Cognition and brain MRI were normal. Modelling of the mutant KCC3 cotransporter in oocytes showed a significant reduction in potassium influx for both changes.
CONCLUSION - Our findings expand the genotypic and phenotypic spectrum associated with variants from autosomal-recessive HMSN/ACC to dominant-acting de novo variants causing a milder clinical presentation with early-onset neuropathy.
© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.
BACKGROUND - Immune checkpoint inhibitors (ICI) produce durable antitumor responses but provoke autoimmune toxicities, including uncommon but potentially devastating neurologic toxicities. The clinical features, including the spectrum, timing, and outcomes, of ICI-induced neurologic toxicities are not well characterized.
METHODS - We performed disproportionality analysis using Vigibase, the World Health Organization pharmacovigilance database, comparing neurologic adverse event (AE) reporting in patients receiving ICIs vs. the full database. Neurologic AEs were classified by group queries using Medical Dictionary for Regulatory Activities, between database inception to September 28, 2018. Associations between ICIs and neurologic AEs were assessed using reporting odds ratios (ROR) and information component (IC). IC compares observed and expected values to find associations between drugs and AEs using disproportionate Bayesian reporting; IC (lower end of the IC 95% credibility interval) > 0 is considered statistically significant.
RESULTS - Among the full database, 18,518,994 AEs were reported, including 48,653 with ICIs. ICIs were associated with higher incidence of myasthenia gravis (0.47% of ICI reports vs. 0.04% of the full database, ROR 16.5 [95% CI 14.5-18.9]; IC 3.31), encephalitis (0.51% vs. 0.05%, ROR 10.4 [95% CI 9.2-11.8]; IC 3.15), peripheral neuropathy (1.16% vs. 0.67%, IC 0.68), and meningitis (0.15% vs. 0.06%, ROR 3.1 [95% CI 2.5-3.9]; IC 1.01). Myasthenia gravis and encephalitis were associated with anti-PD-1 whereas other neurologic AEs were associated with anti-CTLA-4. Myasthenia gravis was characterized by high fatality rates (~ 20%), early onset (median 29 days), and frequent concurrent myocarditis and myositis; whereas other neurologic AEs had lower fatality rates (6-12%), later onset (median 61-80 days), and were non-overlapping.
CONCLUSIONS - ICIs produce a spectrum of distinct classes of neurologic AEs that can cause significant morbidity and mortality and tend to occur early and with class-specific associations.
Enterovirus D68 (EV-D68) is a pathogen that causes outbreaks of respiratory illness across the world, mostly in children, and can be especially severe in those with asthma. Clusters of acute flaccid myelitis, a poliomyelitis-like neuromuscular weakness syndrome, often occur concurrent with EV-D68 respiratory outbreaks. Seroepidemiologic studies have found that the serum of nearly everyone older than 2 to 5 years contains anti-EV-D68 neutralizing antibodies, which suggests that EV-D68 is a ubiquitous pathogen of childhood. However, knowledge of the viral epitopes against which the humoral immune response is directed is only inferred from previous studies of related viruses. Although neutralizing antibodies protect newborn mice from lethal EV-D68 inoculation via nonphysiologic routes, cotton rats have a mixed phenotype of both benefit and possible exacerbation when inoculated intranasally. The human antibody response to EV-D68 needs to be studied further to clarify the role of antibodies in protection versus pathogenesis, which might differ among respiratory and neurologic disease phenotypes.
Hypophosphatasia (HPP) typically manifests with fractures, tooth loss, and muscle pain. Although mental health diagnoses and neurological symptoms have not been previously well documented in HPP, they occur commonly. The recognition of non-traditional symptoms may improve patient satisfaction, preempt costly evaluation and misdiagnosis, and lead to further treatment options.
INTRODUCTION - Hypophosphatasia (HPP) is an inborn error of metabolism due to deficiency of tissue non-specific alkaline phosphatase (TNSALP). It is traditionally characterized by rickets in children and osteomalacia in adults, along with fractures, tooth loss, and muscle pain. Neurological symptoms and mental health diagnoses have not been widely reported, and we therefore report their prevalence in a cohort of patients with HPP.
METHODS - A retrospective chart review was performed on a series of 82 HPP patients. Patient charts were reviewed to identify the possible presence and onset of 13 common neurological symptoms.
RESULTS - Median age was 36 years (2 to 79). Seventeen had adult onset HPP (> 18 years) and 65 had pediatric onset HPP (< 18 years). Median time from symptom onset to HPP diagnosis was 8 years (0 to 67). Seventy-four percent had a family history of bone disease, while 17% had a family history of neurologic disease. Bone problems occurred in 89%, dental problems in 77%, and muscle problems in 66%. Fatigue occurred in 66%, headache in 61%, sleep disturbance in 51%, gait change in 44%, vertigo in 43%, depression in 39%, anxiety in 35%, neuropathy in 35%, and hearing loss in 33%.
CONCLUSIONS - The extra-skeletal manifestations of HPP, specifically neurological symptoms, have not been previously well documented. However, mental health diagnoses and neurological symptoms such as headache and sleep disturbance occur commonly in patients with HPP. The recognition of non-traditional symptoms in HPP may improve patient satisfaction, preempt costly evaluation and misdiagnosis, and may lead to further treatment options.
OBJECTIVES - The Society of Critical Care Medicine recommends routine delirium monitoring, based on data in critically ill patients without primary neurologic injury. We sought to answer whether there are valid and reliable tools to monitor delirium in neurocritically ill patients and whether delirium is associated with relevant clinical outcomes (e.g., survival, length of stay, functional independence, cognition) in this population.
DATA SOURCES - We systematically reviewed Cumulative Index to Nursing and Allied Health Literature, Web of Science, and PubMed.
STUDY SELECTION AND DATA EXTRACTION - Inclusion criteria allowed any study design investigating delirium monitoring in neurocritically ill patients (e.g., neurotrauma, ischemic, and/or hemorrhagic stroke) of any age. We extracted data relevant to delirium tool sensitivity, specificity, negative predictive value, positive predictive value, interrater reliability, and associated clinical outcomes.
DATA SYNTHESIS - Among seven prospective cohort studies and a total of 1,173 patients, delirium was assessed in neurocritically patients using validated delirium tools after considering primary neurologic diagnoses and associated complications, finding a pooled prevalence rate of 12-43%. When able to compare against a common reference standard, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, the test characteristics showed a sensitivity of 62-76%, specificity of 74-98%, positive predictive value of 63-91%, negative predictive value of 70-94%, and reliability kappa of 0.64-0.94. Among four studies reporting multivariable analyses, delirium in neurocritically patients was associated with increased hospital length of stay (n = 3) and ICU length of stay (n = 1), as well as worse functional independence (n = 1) and cognition (n = 2), but not survival.
CONCLUSIONS - These data from studies of neurocritically ill patients demonstrate that patients with primary neurologic diagnoses can meet diagnostic criteria for delirium and that delirious features may predict relevant untoward clinical outcomes. There is a need for ongoing investigations regarding delirium in these complicated neurocritically ill patients.
Loss-of-function mutations in the potassium-chloride cotransporter KCC3 lead to Andermann syndrome, a severe sensorimotor neuropathy characterized by areflexia, amyotrophy and locomotor abnormalities. The molecular events responsible for axonal loss remain poorly understood. Here, we establish that global or neuron-specific KCC3 loss-of-function in mice leads to early neuromuscular junction (NMJ) abnormalities and muscular atrophy that are consistent with the pre-synaptic neurotransmission defects observed in patients. KCC3 depletion does not modify chloride handling, but promotes an abnormal electrical activity among primary motoneurons and mislocalization of Na/K-ATPase α1 in spinal cord motoneurons. Moreover, the activity-targeting drug carbamazepine restores Na/K-ATPase α1 localization and reduces NMJ denervation in Slc12a6 mice. We here propose that abnormal motoneuron electrical activity contributes to the peripheral neuropathy observed in Andermann syndrome.
Copyright © 2017 Elsevier Inc. All rights reserved.
Our purpose was to characterize the clinical influences, genetic risk factors, and gene mechanisms contributing to persistent cisplatin-induced peripheral neuropathy (CisIPN) in testicular cancer survivors (TCSs). TCS given cisplatin-based therapy completed the validated EORTC QLQ-CIPN20 questionnaire. An ordinal CisIPN phenotype was derived, and associations with age, smoking, excess drinking, hypertension, body mass index, diabetes, hypercholesterolemia, cumulative cisplatin dose, and self-reported health were examined for 680 TCS. Genotyping was performed on the Illumina HumanOmniExpressExome chip. Following quality control and imputation, 5.1 million SNPs in 680 genetically European TCS formed the input set. GWAS and PrediXcan were used to identify genetic variation and genetically determined gene expression traits, respectively, contributing to CisIPN. We evaluated two independent datasets for replication: Vanderbilt's electronic health database (BioVU) and the CALGB 90401 trial. Eight sensory items formed a subscale with good internal consistency (Cronbach α = 0.88). Variables significantly associated with CisIPN included age at diagnosis (OR per year, 1.06; = 2 × 10), smoking (OR, 1.54; = 0.004), excess drinking (OR, 1.83; = 0.007), and hypertension (OR, 1.61; = 0.03). CisIPN was correlated with lower self-reported health (OR, 0.56; = 2.6 × 10) and weight gain adjusted for years since treatment (OR per Δkg/m, 1.05; = 0.004). PrediXcan identified lower expressions of and and higher expression as associated with CisIPN ( value for each < 5 × 10) with replication of meeting significance criteria (Fisher combined = 0.0089). CisIPN is associated with age, modifiable risk factors, and genetically determined expression level of Further study of implicated genes could elucidate the pathophysiologic underpinnings of CisIPN. .
©2017 American Association for Cancer Research.
PURPOSE OF REVIEW - Manganese (Mn) is critical for neurodevelopment but also has been implicated in the pathophysiology of several neurological diseases. We discuss how Mn requirements intersect with Mn biology and toxicity, and how these requirements may be altered in neurological disease. Furthermore, we discuss the emerging evidence that the level of Mn associated with optimal overall efficiency for Mn biology does not necessarily coincide with optimal cognitive outcomes.
RECENT FINDINGS - Studies have linked Mn exposures with urea cycle metabolism and autophagy, with evidence that exposures typically neurotoxic may be able to correct deficiencies in these processes at least short term. The line between Mn-dependent biology and toxicity is thus blurred. Further, new work suggests that Mn exposures correlating to optimal cognitive scores in children are associated with cognitive decline in adults. This review explores relationships between Mn-dependent neurobiology and Mn-dependent neurotoxicity. We propose the hypothesis that Mn levels/exposures that are toxic to some biological processes are beneficial for other biological processes and influenced by developmental stage and disease state.
AIMS - To identify the prevalence of and risk factors for urinary retention and catheterization among female Medicare beneficiaries.
METHODS - We identified women with a diagnosis of urinary retention in a 5% sample of Medicare claims in 2012. Women were categorized into three groups based on the occurrence and duration of urinary catheterization within a 1 year period: 1) no catheterization; 2) short-term catheterization (ie, one or more catheterizations in less than 30 days); and 3) chronic catheterization (catheterizations in multiple 30 day periods within 1 year). We then identified a group of age-matched controls without catheterization or a diagnosis of urinary retention in 2012. Clinical and demographic data were collected for each patient, and risk factors for retention and catheterization were compared across groups. We assessed factors associated with urinary retention using multivariable logistic regression.
RESULTS - We estimated the rate of retention to be 1532 per 100 000 U.S. female Medicare beneficiaries in 2012, with rates of short term and chronic catheterization estimated to be 160 and 108 per 100 000 women, respectively. Prior diagnoses of neurologic condition, urinary tract infection, and pelvic organ prolapse were positively associated with retention and catheterization in multivariable analyses.
CONCLUSIONS - We estimated the prevalence of urinary retention diagnoses among female Medicare beneficiaries to be 1532 per 100 000 women. Retention and catheterization were significantly associated with comorbid disease, with the strongest associations identified with a concomitant diagnosis of neurologic condition, UTI, and POP.
© 2017 Wiley Periodicals, Inc.
Xanomeline (1) is an orthosteric muscarinic acetylcholine receptor (mAChR) agonist, often referred to as M/M-preferring, that received widespread attention for its clinical efficacy in schizophrenia and Alzheimer's disease (AD) patients. Despite the compound's promising initial clinical results, dose-limiting side effects limited further clinical development. While xanomeline, and related orthosteric muscarinic agonists, have yet to receive approval from the FDA for the treatment of these CNS disorders, interest in the compound's unique M/M-preferring mechanism of action is ongoing in the field of chemical neuroscience. Specifically, the promising cognitive and behavioral effects of xanomeline in both schizophrenia and AD have spurred a renewed interest in the development of safer muscarinic ligands with improved subtype selectivity for either M or M. This Review will address xanomeline's overall importance in the field of neuroscience, with a specific focus on its chemical structure and synthesis, pharmacology, drug metabolism and pharmacokinetics (DMPK), and adverse effects.