Why monitor the neonatal brain-that is the important question

A key goal of neonatal neurocritical care is improved outcomes, and brain monitoring plays an essential role. The recent NEST trial(1) reported no outcome benefits using aEEG monitoring compared to clinical seizure identification among neonates treated for seizures. However, the study failed to prove the effects of monitoring on seizure treatment in the first place.Non peer reviewe

The impact of hypsarrhythmia on infantile spasms treatment response: Observational cohort study from the National Infantile Spasms Consortium

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141801/1/epi13937_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141801/2/epi13937.pd

Crisis Standard of Care: Management of Infantile Spasms during COVID‐19

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156180/2/ana25792_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156180/1/ana25792.pd

Treatment of seizures in the neonate: Guidelines and consensus-based recommendations—Special report from the ILAE Task Force on Neonatal Seizures

Seizures are common in neonates, but there is substantial management variability. The Neonatal Task Force of the International League Against Epilepsy (ILAE) developed evidence-based recommendations about antiseizure medication (ASM) management in neonates in accordance with ILAE standards. Six priority questions were formulated, a systematic literature review and meta-analysis were performed, and results were reported following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 standards. Bias was evaluated using the Cochrane tool and risk of Bias in non-randomised studies - of interventions (ROBINS-I), and quality of evidence was evaluated using grading of recommendations, assessment, development and evaluation (GRADE). If insufficient evidence was available, then expert opinion was sought using Delphi consensus methodology. The strength of recommendations was defined according to the ILAE Clinical Practice Guidelines development tool. There were six main recommendations. First, phenobarbital should be the first-line ASM (evidence-based recommendation) regardless of etiology (expert agreement), unless channelopathy is likely the cause for seizures (e.g., due to family history), in which case phenytoin or carbamazepine should be used. Second, among neonates with seizures not responding to first-line ASM, phenytoin, levetiracetam, midazolam, or lidocaine may be used as a second-line ASM (expert agreement). In neonates with cardiac disorders, levetiracetam may be the preferred second-line ASM (expert agreement). Third, following cessation of acute provoked seizures without evidence for neonatal-onset epilepsy, ASMs should be discontinued before discharge home, regardless of magnetic resonance imaging or electroencephalographic findings (expert agreement). Fourth, therapeutic hypothermia may reduce seizure burden in neonates with hypoxic–ischemic encephalopathy (evidence-based recommendation). Fifth, treating neonatal seizures (including electrographic-only seizures) to achieve a lower seizure burden may be associated with improved outcome (expert agreement). Sixth, a trial of pyridoxine may be attempted in neonates presenting with clinical features of vitamin B6-dependent epilepsy and seizures unresponsive to second-line ASM (expert agreement). Additional considerations include a standardized pathway for the management of neonatal seizures in each neonatal unit and informing parents/guardians about the diagnosis of seizures and initial treatment options

Treatment of seizures in the neonate: Guidelines and consensus-based recommendations-Special report from the ILAE Task Force on Neonatal Seizures

Seizures are common in neonates, but there is substantial management variability. The Neonatal Task Force of the International League Against Epilepsy (ILAE) developed evidence-based recommendations about antiseizure medication (ASM) management in neonates in accordance with ILAE standards. Six priority questions were formulated, a systematic literature review and meta-analysis were performed, and results were reported following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 standards. Bias was evaluated using the Cochrane tool and risk of Bias in non-randomised studies - of interventions (ROBINS-I), and quality of evidence was evaluated using grading of recommendations, assessment, development and evaluation (GRADE). If insufficient evidence was available, then expert opinion was sought using Delphi consensus methodology. The strength of recommendations was defined according to the ILAE Clinical Practice Guidelines development tool. There were six main recommendations. First, phenobarbital should be the first-line ASM (evidence-based recommendation) regardless of etiology (expert agreement), unless channelopathy is likely the cause for seizures (e.g., due to family history), in which case phenytoin or carbamazepine should be used. Second, among neonates with seizures not responding to first-line ASM, phenytoin, levetiracetam, midazolam, or lidocaine may be used as a second-line ASM (expert agreement). In neonates with cardiac disorders, levetiracetam may be the preferred second-line ASM (expert agreement). Third, following cessation of acute provoked seizures without evidence for neonatal-onset epilepsy, ASMs should be discontinued before discharge home, regardless of magnetic resonance imaging or electroencephalographic findings (expert agreement). Fourth, therapeutic hypothermia may reduce seizure burden in neonates with hypoxic-ischemic encephalopathy (evidence-based recommendation). Fifth, treating neonatal seizures (including electrographic-only seizures) to achieve a lower seizure burden may be associated with improved outcome (expert agreement). Sixth, a trial of pyridoxine may be attempted in neonates presenting with clinical features of vitamin B6-dependent epilepsy and seizures unresponsive to second-line ASM (expert agreement). Additional considerations include a standardized pathway for the management of neonatal seizures in each neonatal unit and informing parents/guardians about the diagnosis of seizures and initial treatment options

Pharmacotherapy for Seizures in Neonates with Hypoxic Ischemic Encephalopathy

Seizures are common in neonates with moderate and severe hypoxic ischemic encephalopathy (HIE) and are associated with worse outcomes, independent of HIE severity. In contrast to adults and older children, no new drugs have been licensed for treatment of neonatal seizures over the last 50 years, because of a lack of controlled clinical trials. Hence, many antiseizure medications licensed in older children and adults are used off-label for neonatal seizure, which is associated with potential risks of adverse effects during a period when the brain is particularly vulnerable. Phenobarbital is worldwide the first-line drug and is considered standard of care, although there is a limited evidence base for its efficacy. Second-line agents include phenytoin, benzodiazepines, levetiracetam, and lidocaine. These drugs are discussed in more detail along with two emerging drugs (bumetanide and topiramate). More safety, pharmacokinetic, and efficacy data are needed from well-designed clinical trials to develop safe and effective antiseizure regimes for the treatment of neonatal seizures in HIE

A HOX Gene Mutation in a Family with Isolated Congenital Vertical Talus and Charcot-Marie-Tooth Disease

Congenital vertical talus (CVT), also known as “rocker-bottom foot” deformity, is a dislocation of the talonavicular joint, with rigid dorsal dislocation of the navicular over the neck of the talus. This condition is usually associated with multiple other congenital deformities and only rarely is an isolated deformity. The reported familial cases are consistent with an autosomal dominant mode of inheritance with incomplete penetrance. In contrast, Charcot-Marie-Tooth disease (CMT) is thought to be a completely distinct heterogeneous group of disorders, with foot abnormalities that typically develop a high-arched “claw foot” appearance later in life. In the present study, DNA was isolated from 36 members of a single upstate (northern) New York white family of Italian descent in which both CVT and CMT were segregating. Whole-genome linkage analysis with Affymetrix GeneChip Mapping 10K Array defined a 7-Mb critical region on chromosome 2q31, which led to candidate-gene sequencing of six HOX genes and detection of a single missense mutation, M319K (956T→A), in the HOXD10 gene. In the study family, this mutation was fully penetrant and exhibited significant evidence of linkage (LOD 6.33; θ=0), and it very likely accounts for both CVT and CMT in heterozygotes

Multicenter Assessment of Sturge-Weber Syndrome: A Retrospective Study of Variations in Care and Use of Natural History Data

BACKGROUND: We summarize the history of individuals with Sturge-Weber syndrome (SWS) to inform clinical trial design and identify variations in care. METHODS: We performed retrospective chart review of individuals with SWS from centers in New York City. We characterized data quality using a novel scoring system. For 13 clinical concepts, we evaluated if data were present and if they were of high quality. RESULTS: We included 26 individuals with SWS (58% female; median age at initial visit 7 years; absolute range 1 month to 56 years]). Twenty-two had nevus flammeus, 13 glaucoma, four homonymous hemianopia, and 15 hemiparesis. Nineteen of 21 had at least one confirmed seizure with a known first seizure date, all before 24 months. Most (18 of 26, 69%) epilepsy was controlled. A plurality (10 of 23, 43%) had either normal cognitive function or mild cognitive delays. Aspirin use varied by site (P = 0.02)-at four sites, use was 0% (zero of three), 0% (zero of four), 80% (four of five), and 64% (nine of 14). Data were present for more than 75% of cases for 11 of 13 clinical concepts (missing: age of diagnosis, age of glaucoma onset). There were gaps in level of detail for motor impairments, glaucoma severity, seizure history, cognition, and medication history. CONCLUSIONS: Clinical charts have important gaps in the level of detail around core SWS clinical features, limiting value for some natural history studies. Any clinical trial in SWS designed to prevent epilepsy should begin in the first year of life. Variations in use of aspirin suggest de facto clinical equipoise and warrant a comparative effectiveness study

Association of Time to Clinical Remission With Sustained Resolution in Children With New-Onset Infantile Spasms

Background and objectivesStandard therapies (adrenocorticotropic hormone [ACTH], oral steroids, or vigabatrin) fail to control infantile spasms in almost half of children. Early identification of nonresponders could enable rapid initiation of sequential therapy. We aimed to determine the time to clinical remission after appropriate infantile spasms treatment initiation and identify predictors of the time to infantile spasms treatment response.MethodsThe National Infantile Spasms Consortium prospectively followed children aged 2-24 months with new-onset infantile spasms at 23 US centers (2012-2018). We included children treated with standard therapy (ACTH, oral steroids, or vigabatrin). Sustained treatment response was defined as having the last clinically recognized infantile spasms on or before treatment day 14, absence of hypsarrhythmia on EEG 2-4 weeks after treatment, and persistence of remission to day 30. We analyzed the time to treatment response and assessed clinical characteristics to predict sustained treatment response.ResultsAmong 395 infants, clinical infantile spasms remission occurred in 43% (n = 171) within the first 2 weeks of treatment, of which 81% (138/171) responded within the first week of treatment. There was no difference in the median time to response across standard therapies (ACTH: median 4 days, interquartile range [IQR] 3-7; oral steroids: median 3 days, IQR 2-5; vigabatrin: median 3 days, IQR 1-6). Individuals without hypsarrhythmia on the pretreatment EEG (i.e., abnormal but not hypsarrhythmia) were more likely to have early treatment response than infants with hypsarrhythmia at infantile spasms onset (hazard ratio 2.23, 95% CI 1.39-3.57). No other clinical factors predicted early responders to therapy.DiscussionRemission after first infantile spasms treatment can be identified by treatment day 7 in most children. Given the importance of early and effective treatment, these data suggest that children who do not respond to standard infantile spasms therapy within 1 week should be reassessed immediately for additional standard treatment. This approach could optimize outcomes by facilitating early sequential therapy for children with infantile spasms