Survival in a young child with out-of-hospital cardiac arrest: diagnostic dilemma and when to deviate from standard resuscitation guidelines.

A boy in early childhood presented in cardiac arrest. Care was provided out of hospital and in the emergency department as per standard paediatric resuscitation guidelines. Despite initial return of spontaneous circulation following cardiopulmonary resuscitation, two defibrillation shocks and epinephrine via intraosseous access, he had recurrent episodes of pulseless ventricular tachycardia and ventricular fibrillation. In total, 40 defibrillation shocks were administered, and he subsequently stabilised on combined treatment with intravenous esmolol, amiodarone and milrinone. He was transferred to the paediatric intensive care unit and had an automated implantable cardioverter-defibrillator inserted prior to discharge. Genetic testing has confirmed a diagnosis of catecholaminergic polymorphic ventricular tachycardia and it is hypothesised that the childhood excitement at a popular time of year, combined with caffeinated drinks, instigated his initial cardiac arrest which was propagated with iatrogenic epinephrine. He has remained stable since, with no neurological sequelae thus far from a significantly prolonged downtime.

Electroencephalography Quality and Application Times in a Pediatric Emergency Department Setting: A Feasibility Study.

BACKGROUND: Status epilepticus is the most common neurological emergency presenting to pediatric emergency departments. Nonconvulsive status epilepticus can be extremely challenging to diagnose, however, requiring electroencephalographic (EEG) confirmation for definitive diagnosis. We aimed to determine the feasibility of achieving a good-quality pediatric EEG recording within 20 minutes of presentation to the emergency department. METHODS: Single-center prospective feasibility study in Cork University Hospital, Ireland, between July 2021 and June 2022. Two-channel continuous EEG was recorded from children (1) aged <16 years and (2) with Glasgow Coma Scale <11 or a reduction in baseline Glasgow Coma Scale in the case of a child with a neurodisability. RESULTS: Twenty patients were included. The median age at presentation was 65.8 months (interquartile range, 23.2 to 119.0); 50% had a background diagnosis of epilepsy. The most common reason for EEG monitoring was status epilepticus (85%) followed by suspected nonconvulsive status (10%) and reduced consciousness of unknown etiology (5%). The mean length of recording was 93.1 minutes (S.D. 47.4). The mean time to application was 41.3 minutes (S.D. 11.7). The mean percent of artifact in all recordings was 19.3% (S.D. 15.9). Thirteen (65%) EEGs had <25% artifact. Artifact was higher in cases in which active airway management was ongoing. CONCLUSIONS: EEG monitoring can be achieved in a pediatric emergency department setting within one hour of presentation. Overall, artifact percentage was low outside of periods of airway manipulation. Future studies are required to determine its use in early seizure detection and its support role in clinical decision-making in these patients.

Late-Onset Tay-Sachs Disease in an Irish Family.

BACKGROUND: Late-onset Tay-Sachs disease (LOTS) is an autosomal-recessive lysosomal storage disease caused by deficient ß-hexosaminidase A activity. LOTS is rare in the Ashkenazi Jews, but even rarer in the non-Jewish population. CASES: We report an Irish family expanding the LOTS phenotype (ataxia, diffuse muscle wasting, dystonia, chorea, belly dancer's dyskinesia, and neuropsychiatric features) associated with the known HEXA variant 1073 + 1G > A and a novel variant c.459 + 24G > C. CONCLUSIONS: LOTS should be considered in patients with similar symptoms and cerebellar atrophy on brain imaging.

Varicella Zoster Reactivation Causing Aseptic Meningitis in Healthy Adolescents: A Case Series And Review Of The Literature.

We describe 3 cases of adolescent varicella-zoster virus reactivation, complicated by aseptic meningitis, presenting to our institution in a 3-year period. These cases highlight varicella-zoster virus reactivation as an important cause of aseptic meningitis in the differential diagnosis of healthy adolescents, even in the absence of a characteristic exanthem. Evidence-based management recommendations are needed.

Impact of therapeutic hypothermia on infantile spasms: an observational cohort study.

AIM: To establish the incidence of infantile spasms in children in the southern region of the Republic of Ireland and to compare the incidence of infantile spasms before and after the introduction of therapeutic hypothermia in infants with hypoxic-ischemic encephalopathy (HIE). METHOD: Children born between 2003 and 2015 and diagnosed with infantile spasms (epileptic spasms with or without hypsarrhythmia) in the first 2 years of life were identified through audits of electroencephalography reports and paediatric neurology patient lists. Data on live births were obtained from the regional hospital statistics databases. Medical charts of infantile spasm cases were reviewed for demographic information, diagnostic workup results, treatment response, disease course, and developmental outcome. RESULTS: Forty-two infants with infantile spasms were identified. The cumulative incidence of infantile spasms up to the age of 2 years was 4.01 per 10 000 live births. Difference due to sex was minimal (22 males, 20 females) and most infants were delivered at or near term with gestational ages ranging between 30.0 and 41.8 weeks (median [interquartile range] 39.6wks [38.1-40.0wks]). The aetiology for infantile spasms was identified in almost two-thirds of cases, with HIE being the single most common cause (n=7). Other causes included chromosomal and monogenetic abnormalities (n=8). Infantile spasms occurred in moderate and severe grades of HIE, with a significantly higher incidence in those with severe HIE (p=0.029). Infants with severe HIE who did not receive therapeutic hypothermia were six times more likely to develop infantile spasms compared to those who did, but the difference was not statistically significant (4 out of 16 vs 1 out of 24, p=0.138). INTERPRETATION: This study provides detailed information about infantile spasms before and after the introduction of therapeutic hypothermia. HIE severity is a risk factor for the development of infantile spasms. The introduction of therapeutic hypothermia may have had an impact, but the effect was hard to ascertain in this cohort due to the small number of infants. WHAT THIS PAPER ADDS: The incidence of infantile spasms and patient characteristics in the southern region of the Republic of Ireland is similar to internationally published data. None of the infants with a history of mild hypoxic-ischemic encephalopathy (HIE) developed infantile spasms. The risk of infantile spasms was higher in infants with severe HIE. Infantile spasms were more frequent in infants with severe HIE not treated with therapeutic hypothermia.

IMPACTO DE LA HIPOTERMIA COMO TRATAMIENTO EN LOS ESPASMOS INFANTILES: UN ESTUDIO DE COHORTE OBSERVACIONAL: OBJETIVO: Establecer la incidencia de los espasmos infantiles en niños de la República de Irlanda y comparar la incidencia de los espasmos infantiles antes y después de la introducción de la hipotermia terapéutica en niños con encefalopatía hipóxico-isquémica (EHI). MÉTODO: Niños nacidos entre 2003 y 2015 y diagnosticados con espasmos infantiles (espasmos epilépticos con o sin hipsarritmia) en los primeros 2 años de vida fueron identificados por medio de auditorías de reportes de electroencefalográficos y listas de pacientes de neurólogos infantiles. Datos sobre los nacidos vivos se obtuvieron de la base de datos estadística del hospital regional. Las historias clínicas de los casos de espasmos infantiles fueron revisadas para obtener datos demográficos, resultados diagnósticos, respuesta a tratamiento, curso de la enfermedad y resultados del desarrollo. RESULTADOS: Fueron identificados 42 niños con espasmos infantiles. La incidencia acumulada de los espasmos infantiles por encima de los 2 años fue de 4,01 por 10.000 nacidos vivos. La diferencia debida al sexo fue mínima (22 masculinos, 20 femeninos) y la mayoría nacieron en o cercano a término, con edad gestacional entre 30,0 y 41,8 semanas (media (rango Intercuartil) 39,6 semanas (38,1-40,0 semanas). La etiología de espasmos infantiles fue identificada en dos tercios de los casos, siendo EHI la causa más común (7 de 42). Otras causas incluyeron anormalidades cromosómicas y monogénicas (8 de 42). Los espasmos infantiles ocurrieron en los grados moderados y severos de EHI con incidencia significativamente mayor en aquellos casos severos de EHI (p=0,029). Los niños con EHI severo que no recibieron hipotermia terapéutica tuvieron una probabilidad seis veces mayor de desarrollar espasmos infantiles comparados con aquellos quienes la recibieron, pero la diferencia no era estadísticamente significativa (4 de 16 vs 1 de 14, p=0,138). INTERPRETACIÓN: Este estudio proporciona información detallada acerca de los espasmos infantiles antes y después de la introducción de la hipotermia terapéutica. La severidad de la EHI es un factor de riesgo para el desarrollo de los espasmos infantiles. La introducción de la hipotermia terapéutica puede haber tenido un impacto, pero el efecto fue difícil de determinar en esta cohorte debido al pequeño número de recién nacidos.

IMPACTO DA HIPOTERMIA TERAPÊUTICA NOS ESPASMOS INFANTIS: UM ESTUDO DE COORTE OBSERVACIONAL: OBJETIVO: Estabelecer a incidência de espasmos infantis em crianças da República da Irlanda e comparar a incidência de espasmos infantis antes e após a introdução da hipotermia terapêutica em lactentes com encefalopatia hipóxica-isquêmica (EHI). MÉTODO: Crianças nascidas entre 2003 e 2015 e diagnosticadas com espasmos infantis (espasmos epilépticos com ou sem hipsarritmia) nos primeiros 2 anos de vida foram identificadas por meio de checagem dos relatórios de eletroencefalografia e listas de pacientes de neurologia pediátrica. Dados sobre nascidos vivos foram obtidos nas bases de dados estatísticas dos hospitais regionais. Prontuários médicos sobre casos de espasmos infantis foram revisados quanto a dados demográficos, resultados diagnósticos, resposta ao tratamento, curso da doença, e resultado desenvolvimental. RESULTADOS: Quarenta e dois lactentes com espasmos infantis foram identificados. A incidência cumulativa de espasmos infantis até os dois anos de idade foi 4,01 por 10.000 nascidos vidos. Diferenças devida ao sexo foram mínimas (22 meninos, 20 meninas) e a maior parte dos lactentes nasceu próximo ao termo, com idades gestacionais variando de 30,0 41,8 semanas (mediana [intervalo interquartil] 39,6 sem [38,1-40,0sem]). A etiologia dos espasmos infantis foi identificada em dois terços dos casos, com a EHI sendo a causa mais comum (7 em cada 42). Outras causas incluíram anormalidades cromossômicas e monogenéticas (8 em 42). Os espasmos infantis aconteceram em graus moderados a severos de EHI, com incidência significantemente maior naqueles com EHI severa (p=0,029). Lactentes com EHI severa que não receberam hipotermia terapêutica tinham seis vezes mais probabilidade de desenvolver espasmos infantis comparados com os que receberam, mas a diferença não foi estatisticamente significativa. (4 em16 vs 1 em 24, p=0,138). INTERPRETAÇÃO: Este esudo fornece informação detalhada sobre espasmos infantis antes e após a introdução de hipotermia terapêutica. A severidade da EHI é um fator de risco para o desenvolvimento de espasmos infantis. A introdução de hiportermia terapêutica por ter tido um impacto, mas o efeito foi difícil de assegurar nesta coorte devido ao pequeno número de lactentes.

Familial Hemiplegic Migraine With Asymmetric Encephalopathy Secondary to ATP1A2 Mutation: A Case Series.

INTRODUCTION: Familial hemiplegic migraine (FHM) is a genetic disease with a variable clinical phenotype. The imaging and electroencephalogram (EEG) correlates of FHM are not well described. CASE SERIES: We describe a case series of five young women aged 12 to 32 years. Each case presented with headache, encephalopathy, and hemiparesis of varying severity. One patient developed seizures. All patients improved spontaneously. INVESTIGATIONS: Asymmetric slow-wave activity was seen on electroencephalogram in each case. One patient developed marked unilateral cortical edema on MR imaging. Cerebro-spinal fluid (CSF) studies were normal for all patients. Genetic testing in each case showed a mutation of the ATP1A2 gene. One of the mutations identified is a novel mutation. DISCUSSION: Genetic mutation of the ATP1A2 gene results in a channelopathy which is thought to predispose to spreading depolarization, the probable physiologic correlate of migraine aura. We hypothesize that widespread prolonged depolarization accounts for the characteristic electroencephalogram findings in these cases. Familial hemiplegic migraine should be considered in the differential diagnosis of an asymmetric encephalopathy, particularly when CSF and imaging studies are normal.

Pathogenic mtDNA mutations causing mitochondrial myopathy: The need for muscle biopsy.

Pathogenic mitochondrial tRNA (mt-tRNA) gene mutations represent a prominent cause of primary mitochondrial DNA (mtDNA)-related disease despite accounting for only 5%-10% of the mitochondrial genome.(1,2) Although some common mt-tRNA mutations, such as the m.3243A>G mutation, exist, the majority are rare and have been reported in only a small number of cases.(3) The MT-TP gene, encoding mt-tRNA(Pro), is one of the less polymorphic mt-tRNA genes, and only 5 MT-TP mutations have been reported as a cause of mitochondrial muscle disease to date (table e-1 at Neurology.org/ng, P6-10). We report 5 patients with myopathic phenotypes, each harboring different pathogenic mutations in the MT-TP gene, highlighting the importance of MT-TP mutations as a cause of mitochondrial muscle disease and the requirement to study clinically relevant tissue.

Synthesis, characterization, and monoamine transporter activity of the new psychoactive substance 3',4'-methylenedioxy-4-methylaminorex (MDMAR).

The recent occurrence of deaths associated with the psychostimulant cis-4,4'-dimethylaminorex (4,4'-DMAR) in Europe indicated the presence of a newly emerged psychoactive substance on the market. Subsequently, the existence of 3,4-methylenedioxy-4-methylaminorex (MDMAR) has come to the authors' attention and this study describes the synthesis of cis- and trans-MDMAR followed by extensive characterization by chromatographic, spectroscopic, mass spectrometric platforms and crystal structure analysis. MDMAR obtained from an online vendor was subsequently identified as predominantly the cis-isomer (90%). Exposure of the cis-isomer to the mobile phase conditions (acetonitrile/water 1:1 with 0.1% formic acid) employed for high performance liquid chromatography analysis showed an artificially induced conversion to the trans-isomer, which was not observed when characterized by gas chromatography. Monoamine release activities of both MDMAR isomers were compared with the non-selective monoamine releasing agent (+)-3,4-methylenedioxymethamphetamine (MDMA) as a standard reference compound. For additional comparison, both cis- and trans-4,4'-DMAR, were assessed under identical conditions. cis-MDMAR, trans-MDMAR, cis-4,4'-DMAR and trans-4,4'-DMAR were more potent than MDMA in their ability to function as efficacious substrate-type releasers at the dopamine (DAT) and norepinephrine (NET) transporters in rat brain tissue. While cis-4,4'-DMAR, cis-MDMAR and trans-MDMAR were fully efficacious releasing agents at the serotonin transporter (SERT), trans-4,4'-DMAR acted as a fully efficacious uptake blocker. Currently, little information is available about the presence of MDMAR on the market but the high potency of ring-substituted methylaminorex analogues at all three monoamine transporters investigated here might be relevant when assessing the potential for serious side-effects after high dose exposure.

Characterization of a novel and potentially lethal designer drug (±)-cis-para-methyl-4-methylaminorex (4,4'-DMAR, or 'Serotoni').

During the second half of 2013, a total of 26 deaths involving para-methyl-4-methylaminorex (4,4'-DMAR) were reported to the European Monitoring Centre for Drugs and Drug Addiction. While aminorex and 4-methylaminorex (4-MAR) are known psychostimulants, nothing is known about the comparatively new para-methyl analog. Analytical characterization of two independent samples obtained from online vendors confirmed the presence of the (±)-cis isomer that also appeared to be associated with at least 18 of the 26 deaths. Extensive characterizations included crystal structure analysis, single, tandem, and high-resolution mass spectrometry, liquid and gas chromatography, and nuclear magnetic resonance spectroscopy. For the work described here, both the (±)-cis and (±)-trans racemates were also synthesized, confirming that the differentiation between these two forms was straight-forward. Monoamine transporter activity was studied using rat brain synaptosomes which included the comparison with d-amphetamine, aminorex and (±)-cis-4-MAR. (±)-cis-4,4'-DMAR was a potent, efficacious substrate-type releaser at transporters for dopamine, norepinephrine and serotonin with EC50 values of 8.6 ± 1.1 nM (DAT), 26.9 ± 5.9 nM (NET) and 18.5 ± 2.8 nM (SERT), respectively. The potency of (±)-cis-4,4'-DMAR at DAT and NET rivalled that of other psychomotor stimulant drugs like d-amphetamine and aminorex. However, (±)-cis-4,4'-DMAR had much more potent actions at SERT and activity at SERT varied more than 100-fold across the four drugs. The potent releasing activity of (±)-cis-4,4'-DMAR at all three monoamine transporters predicts a potential for serious side-effects such as psychotic symptoms, agitation, hyperthermia and cardiovascular stimulation, especially after high-dose exposure or following combination with other psychostimulants.

Genotype-phenotype correlation in a large population of muscular dystrophy patients with LAMA2 mutations.

Merosin deficient congenital muscular dystrophy 1A (MDC1A) results from mutations in the LAMA2 gene. We report 51 patients with MDC1A and examine the relationship between degree of merosin expression, genotype and clinical features. Thirty-three patients had absence of merosin and 13 showed some residual merosin. Compared to the residual merosin group, patients with absent merosin had an earlier presentation (<7days) (P=0.0073), were more likely to lack independent ambulation (P=0.0215), or require enteral feeding (P=0.0099) and ventilatory support (P=0.0354). We identified 33 novel LAMA2 mutations; these were distributed throughout the gene in patients with absent merosin, with minor clusters in exon 27, 14, 25 and 26 (55% of mutations). Patients with residual merosin often carried at least one splice site mutation and less frequently frameshift mutations. This large study identified novel LAMA2 mutations and highlights the role of immunohistochemical studies for merosin status in predicting clinical severity of MDC1A.