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Background: Most cases of pediatric epistaxis are spontaneous and self-resolve. However, a subset of children may experience significant bleeding and require procedural or medical intervention., Objective: We aim to identify risk factors associated with moderate and severe epistaxis in the emergency department (ED) and explore management outcomes., Methods: We retrospectively reviewed all patients under 22 years old with epistaxis who presented to our ED between 2013 and 2022. Epistaxis severity was defined as mild (required nasal compression or intranasal medications), moderate (required cautery or packing), or severe (required factor replacement, transfusion, hospital admission, or surgery). We performed univariable and multinomial regression analyses, with risk factors and outcomes analyzed according to severity., Results: Of 858 visits, 41 (5%) patients had moderate and 67 (8%) had severe epistaxis. Patients with moderate epistaxis were older than those with mild and severe epistaxis (median 15.6 vs. 8.3 vs. 10.7 years, p < 0.001). In regression analysis, moderate epistaxis was associated with older age, prior ED visit within 72 h, and antiplatelet medication use (p < 0.01). Severe epistaxis was associated with bleeding disorders, nasal procedures within 30 days, and anticoagulation medication use (p ≤ 0.001). Bleeding over 30 min prior to arrival was associated with both moderate and severe epistaxis (p < 0.05). Of the 67 patients with severe epistaxis, 10 (15%) required factor replacement, 28 (42%) required transfusion, 52 (77%) required hospital admission, and 5 (7%) underwent surgery., Conclusion: Epistaxis severity is associated with certain risk factors. However, most cases of pediatric epistaxis are mild and do not require intervention or ED evaluation., Competing Interests: Declaration of competing interest The authors report no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Heterozygous KMT2B variants are a common cause of dystonia. A novel synonymous KMT2B variant, c.5073C>T (p.Gly1691=) was identified in an individual with childhood-onset progressive dystonia., Methods: The splicing impact of c.5073C>T was assessed using an in vitro exon-trapping assay. The genomic region of KMT2B exons 23-26 was cloned into the pSpliceExpress plasmid between exon 2 and 3 of the rat Ins2 gene. The c.5073C>T variant was then introduced through site-directed mutagenesis. The KMT2B wild-type and c.5073C>T plasmids were transfected separately into HeLa cells and RNA was extracted 48 hours after transfection. The RNA was reverse transcribed to produce cDNA, which was PCR amplified using primers annealing to the flanking rat Ins2 sequences., Results: Sanger sequencing of the PCR products revealed that c.5073C>T caused a novel splice donor site and therefore a 5-bp deletion of KMT2B exon 23 in mature mRNA, leading to a coding frameshift and premature stop codon (p.Lys1692AsnfsTer7)., Conclusion: To our knowledge, this is the first report of a KMT2B synonymous variant associated with dystonia. Reassessment of synonymous variants may increase diagnostic yield for inherited disorders including monogenic dystonia. This is of clinical importance, given the generally favourable response to deep brain stimulation for KMT2B-related dystonia., (© 2022 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Background: Poor oral care may lead to systemic disease, and there is evidence that assisted living (AL) residents lack quality oral care; in AL, poor care may be due to staff knowledge and attitudes, as well as organizational barriers to providing care., Objectives: Determine AL staff knowledge and attitudes regarding mouth care and barriers to changing care., Design: Self-administered repeated-measures questionnaires completed before and after oral care training., Setting and Participants: A total of 2012 direct care staff and administrators from 180 AL communities., Methods: Nine knowledge questions and 8 attitude and practice intention questions, and open-ended questions regarding training and obstacles to providing oral care., Results: Overall, 2012 participants completed pretraining questionnaires, and 1977 completed posttraining questionnaires. Baseline knowledge was high, but staff were not uniformly aware of the systemic-oral link whereby mouth care affects pneumonia and diabetes. Almost all staff reported learning a new technique (96%), including for residents who resist care (95%). Suggested areas to improve mouth care included having more hands-on experience. The primary perceived obstacles to care centered around residents who resist care and a lack of time., Conclusions and Implications: Based on reports of having benefitted from training, AL staff overwhelmingly noted that new knowledge was helpful, suggesting the benefit of skills-based training, especially in dementia care. Mouth care in AL has been sorely understudied, and merits additional attention., (Copyright © 2021. Published by Elsevier Inc.)

Objective: To improve understanding of disease pathophysiology in anti-myelin-associated glycoprotein (anti-MAG) neuropathy to guide further treatment approaches., Methods: Anti-MAG neuropathy patients underwent clinical assessments, nerve conduction and excitability studies, and ultrasound assessment., Results: Patients demonstrated a distinctive axonal excitability profile characterised by a reduction in superexcitability [MAG: -14.2 ± 1.6% vs healthy controls (HC): -21.8 ± 1.2%; p < 0.01] without alterations in most other excitability parameters. Mathematical modelling of nerve excitability recordings suggested that changes in axonal function could be explained by a 72.5% increase in juxtaparanodal fast potassium channel activation and an accompanying hyperpolarization of resting membrane potential (by 0.3 mV) resulting in a 94.2% reduction in discrepancy between anti-MAG data and the healthy control model. Superexcitability changes correlated strongly with clinical and neurophysiological parameters. Furthermore, structural assessments demonstrated a proximal pattern of nerve enlargement (C6 nerve root cross-sectional area: 15.9 ± 8.1 mm 2 vs HC: 9.1 ± 2.3 mm 2 ; p < 0.05)., Conclusions: The imaging and neurophysiological results support the pathogenicity of anti-MAG IgM. Widening between adjacent loops of paranodal myelin due to antibodies would expand the pathway from the node to the juxtaparanode, increasing activation of juxtaparanodal fast potassium channels, thereby impairing saltatory conduction., Significance: Potassium channel blockers may prove beneficial in restoring conduction closer to its normal state and improving nerve function in anti-MAG neuropathy., (Copyright © 2018 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

With the rapid evolution of understanding of neurological channelopathies comes a need for sensitive tools to evaluate patients in clinical practice. Neurological channelopathies with a single-gene basis can manifest as seizures, headache, ataxia, vertigo, confusion, weakness and neuropathic pain and it is likely that other genetic factors contribute to the phenotype of many of these disorders. Ion channel dysfunction can result in abnormal cell membrane excitability but utilisation of advanced neurophysiology techniques has lagged behind developments in clinical, genetic and imaging evaluation of channelopathies. However, momentum in the application of in vivo axonal excitability testing sees these tests emerging as valuable tools, with the capacity to provide sensitive and specific insights into the mechanism of disease. While single-channel function cannot be directly measured in vivo, evaluation of subjects with single-gene channelopathies has provided insights into the effects of mutation-related alterations of membrane excitability, as well as compensatory adaptive changes. By showing how ion channel dysfunction can affect axonal excitability in vivo, studies of the excitability of peripheral nerve axons complement in vitro analysis of single channel activity. The interpretation of results is enhanced by mathematical modelling of axonal function and insights provided by in vitro work. This article is part of the Special Issue entitled 'Channelopathies.', (Copyright © 2017. Published by Elsevier Ltd.)

Background Migraine is highly prevalent in women (18%). Peak morbidity affects their most productive years, coinciding with peak fertility. Hormonal contraception is often tailored for migraine prevention. Estrogen-containing contraceptives may be contraindicated in women experiencing migraine with aura due to the risk of vascular events. While improvements in migraine with a progestin-only pill (POP), which inhibits ovulation are documented, the strength and quality of evidence has not been formally evaluated. Objectives To determine the effectiveness of progestin-only contraceptives for migraine treatment by systematic review and meta-analysis. Data sources and selection MEDLINE, EMBASE and Cochrane Libraries were searched (1980 to September 2016) for studies on progestin-only treatments for migraine. Studies in English on >4 non-menopausal women aged 18-50 with migraine diagnosed by formal criteria were included. Data extraction and analysis Data were quality-assessed using the GRADE system. A random effects model was used for pooled analyses. Results Pooled analyses of four studies demonstrated that desogestrel 75 mcg/day, POP significantly but modestly reduced the number of migraine attacks and migraine days. Reduced intensity and duration, reduced analgesic and triptan use were observed, along with improved headache-related quality of life. GRADE analysis indicated evidence was low to very low for each outcome measure. Adverse effects resulted in treatment cessation for <10% of participants. Two studies compared desogestrel POP to a combined oral contraceptive, demonstrating similar migraine outcomes for both treatments. Conclusions The desogestrel POP shows promise in improving migraine in women. Current evidence is observational and based on small samples of women using only one oral progestin-only formulation. Further randomized trials on additional progestin-only contraceptives are required to confirm their role in migraine management.

Ion channel dysfunction causes a range of neurological disorders by altering transmembrane ion fluxes, neuronal or muscle excitability, and neurotransmitter release. Genetic neuronal channelopathies affecting peripheral axons provide a unique opportunity to examine the impact of dysfunction of a single channel subtype in detail in vivo. Episodic ataxia type 2 is caused by mutations in CACNA1A, which encodes the pore-forming subunit of the neuronal voltage-gated calcium channel Cav2.1. In peripheral motor axons, this channel is highly expressed at the presynaptic neuromuscular junction where it contributes to action potential-evoked neurotransmitter release, but it is not expressed mid-axon or thought to contribute to action potential generation. Eight patients from five families with genetically confirmed episodic ataxia type 2 underwent neurophysiological assessment to determine whether axonal excitability was normal and, if not, whether changes could be explained by Cav2.1 dysfunction. New mutations in the CACNA1A gene were identified in two families. Nerve conduction studies were normal, but increased jitter in single-fibre EMG studies indicated unstable neuromuscular transmission in two patients. Excitability properties of median motor axons were compared with those in 30 age-matched healthy control subjects. All patients had similar excitability abnormalities, including a high electrical threshold and increased responses to hyperpolarizing (P < 0.00007) and depolarizing currents (P < 0.001) in threshold electrotonus. In the recovery cycle, refractoriness (P < 0.0002) and superexcitability (P < 0.006) were increased. Cav2.1 dysfunction in episodic ataxia type 2 thus has unexpected effects on axon excitability, which may reflect an indirect effect of abnormal calcium current fluxes during development., (© The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.)

Introduction: Human immunodeficiency virus (HIV) can affect the frontal-striatal brain regions, which are known to subserve decision-making functions. Previous studies have reported impaired decision making among HIV+ individuals using the Iowa Gambling Task, a task that assesses decision making under ambiguity. Previous study populations often had significant comorbidities such as past or present substance use disorders and/or hepatitis C virus coinfection, complicating conclusions about the unique contributions of HIV-infection to decision making. Decision making under explicit risk has very rarely been examined in HIV+ individuals and was tested here using the Game of Dice Task (GDT)., Method: We examined decision making under explicit risk in the GDT in 20 HIV+ individuals without substance use disorder or HCV coinfection, including a demographically matched healthy control group (n = 20). Groups were characterized on a standard neuropsychological test battery. For the HIV+ group, several disease-related parameters (viral load, current and nadir CD4 T-cell count) were included. Analyses focused on the GDT and spanned between-group (t-tests; analysis of covariance, ANCOVA) as well as within-group comparisons (Pearson/Spearman correlations)., Results: HIV+ individuals were impaired in the GDT, compared to healthy controls (p = .02). Their decision-making impairments were characterized by less advantageous choices and more random choice strategies, especially towards the end of the task. Deficits in the GDT in the HIV+ group were related to executive dysfunctions, slowed processing/motor speed, and current immune system status (CD4+ T-cell levels, ps < .05)., Conclusions: Decision making under explicit risk in the GDT can occur in HIV-infected individuals without comorbidities. The correlational patterns may point to underlying fronto-subcortical dysfunctions in HIV+ individuals. The GDT provides a useful measure to assess risky decision making in this population and should be tested in larger studies.

Background and Objective: Heterozygous mutations in KCNA1 cause episodic ataxia type 1 (EA1), an ion channel disorder characterised by brief paroxysms of cerebellar dysfunction and persistent neuromyotonia. This paper describes four previously unreported families with EA1, with the aim of understanding the phenotypic spectrum associated with different mutations., Methods: 15 affected individuals from four families underwent clinical, genetic and neurophysiological evaluation. The functional impact of new mutations identified in the KCNA1 gene was investigated with in vitro electrophysiology and immunocytochemistry., Results: Detailed clinical documentation, dating back to 1928 in one family, indicates that all patients manifested episodic ataxia of varying severity. Four subjects from three families reported hearing impairment, which has not previously been reported in association with EA1. New mutations (R167M, C185W and I407M) were identified in three out of the four families. When expressed in human embryonic kidney cells, all three new mutations resulted in a loss of K(v)1.1 channel function. The fourth family harboured a previously reported A242P mutation, which has not been previously described in association with ataxia., Conclusions: The genetic basis of EA1 in four families is established and this report presents the earliest documented case from 1928. All three new mutations caused a loss of K(v)1.1 channel function. The finding of deafness in four individuals raises the possibility of a link between K(v)1.1 dysfunction and hearing impairment. Our findings broaden the phenotypic range associated with mutations in KCNA1.

Background: The myopathy associated with mutations in the nuclear-encoded mitochondrial DNA maintenance gene POLG, coding for the catalytic subunit of DNA polymerase, is typically proximal with early ophthalmoplegia., Results: We report two unrelated patients in whom a distal, mainly upper limb, myopathy was the predominant and early clinical feature. One patient also suffered with marked cachexia. DNA genomic sequence analysis identified novel dominant heterozygous missense POLG mutations (Leu896Arg and Tyr951His) located within the conserved catalytic polymerase domain of the protein in both cases., Conclusions: Distal upper limb myopathy/cachexia is not previously described with dominant POLG mutations and our observations further highlight the diverse clinical spectrum of POLG-related mitochondrial disorders. These data indicate that dominant POLG mutations should be considered in the differential diagnosis of distal upper limb predominant myopathy.

Benign familial neonatal epilepsy is a neuronal channelopathy most commonly caused by mutations in KCNQ2, which encodes the K(v)7.2 subunit of the slow K(+) channel. K(v)7.2 is expressed in both central and peripheral nervous systems. Seizures occur in the neonatal period, often in clusters within the first few days of life, and usually remit by 12 months of age. The mechanism of involvement of K(v)7.2 mutations in the process of seizure generation has not been established in vivo. In peripheral axons, K(v)7.2 contributes to the nodal slow K(+) current. The present study aimed to determine whether axonal excitability studies could detect changes in peripheral nerve function related to dysfunction or loss of slow potassium channel activity. Nerve excitability studies were performed on eight adults with KCNQ2 mutations and a history of benign familial neonatal epilepsy, now in remission. Studies detected distinctive changes in peripheral nerve, indicating a reduction in slow K(+) current. Specifically, accommodation to long-lasting depolarizing currents was reduced in mutation carriers by 24% compared with normal controls, and the threshold undershoot after 100 ms depolarizing currents was reduced by 22%. Additional changes in excitability included a reduction in the relative refractory period, an increase in superexcitability and a tendency towards reduced sub-excitability. Modelling of the nerve excitability changes suggested that peripheral nerve hyperexcitability may have been ameliorated by upregulation of other potassium channels. We conclude that subclinical dysfunction of K(v)7.2 in peripheral axons can be reliably detected non-invasively in adulthood. Related alterations in neuronal excitability may contribute to epilepsy associated with KCNQ2 mutations.

Episodic ataxia type 1 is a neuronal channelopathy caused by mutations in the KCNA1 gene encoding the fast K(+) channel subunit K(v)1.1. Episodic ataxia type 1 presents with brief episodes of cerebellar dysfunction and persistent neuromyotonia and is associated with an increased incidence of epilepsy. In myelinated peripheral nerve, K(v)1.1 is highly expressed in the juxtaparanodal axon, where potassium channels limit the depolarizing afterpotential and the effects of depolarizing currents. Axonal excitability studies were performed on patients with genetically confirmed episodic ataxia type 1 to characterize the effects of K(v)1.1 dysfunction on motor axons in vivo. The median nerve was stimulated at the wrist and compound muscle action potentials were recorded from abductor pollicis brevis. Threshold tracking techniques were used to record strength-duration time constant, threshold electrotonus, current/threshold relationship and the recovery cycle. Recordings from 20 patients from eight kindreds with different KCNA1 point mutations were compared with those from 30 normal controls. All 20 patients had a history of episodic ataxia and 19 had neuromyotonia. All patients had similar, distinctive abnormalities: superexcitability was on average 100% higher in the patients than in controls (P < 0.00001) and, in threshold electrotonus, the increase in excitability due to a depolarizing current (20% of threshold) was 31% higher (P < 0.00001). Using these two parameters, the patients with episodic ataxia type 1 and controls could be clearly separated into two non-overlapping groups. Differences between the different KCNA1 mutations were not statistically significant. Studies of nerve excitability can identify K(v)1.1 dysfunction in patients with episodic ataxia type 1. The simple 15 min test may be useful in diagnosis, since it can differentiate patients with episodic ataxia type 1 from normal controls with high sensitivity and specificity.

Clinical neurophysiology has become an invaluable tool in the diagnosis of muscle channelopathies, but the situation is less clear cut with neuronal channelopathies. The genetic episodic ataxias are a group of disorders with heterogeneous phenotype and genotype, but share in common the feature of intermittent cerebellar dysfunction. Episodic ataxia (EA) types 1 and 2 are the most widely recognised of the autosomal dominant episodic ataxias and are caused by dysfunction of neuronal voltage-gated ion channels. There are central and peripheral nervous system manifestations in both conditions, and they are therefore good models of neuronal channelopathies to study neurophysiologically. To date most work has focussed upon characterising the electrophysiological properties of mutant channels in vitro. This review summarises the role of voltage-gated potassium and calcium channels, mutations of which underlie the main types of episodic ataxia types 1 and 2. The clinical, genetic and electrophysiological features of EA1 and EA2 are outlined, and a protocol for the assessment of these patients is proposed.