Summary The neurodevelopmental disabilities of those who were born prematurely have been well described, yet the underlying alterations in brain development that lead to these changes remain poorly ...understood. Processes that are vulnerable to injury in the developing brain include maturation of oligodendrocyte precursors and genetically programmed changes in cortical connectivity; recent data have indicated that diffuse injury of the white matter accompanied by neuronal and axonal disruption is common in prematurely born infants. Recent advances in MRI include diffusion tensor imaging and sophisticated image analysis tools, such as functional connectivity, voxel-based morphometry, and mathematical morphology-based cortical folding strategies. These advanced techniques have shown that white matter structure is dependent on gestational age and have started to provide important information about the dynamic interactions between development, injury, and functional recovery in the preterm brain. Identification of early biomarkers for outcome could enable physicians and scientists to develop targeted pharmacological and behavioural therapies to restore functional connectivity.
In this randomized trial of three common treatments for childhood absence epilepsy, ethosuximide and valproic acid were more effective than lamotrigine, and adverse effects on attention were less ...frequent with ethosuximide than with valproic acid. These findings suggest that ethosuximide has the best efficacy and safety profile.
The findings of this randomized trial of three common treatments for childhood absence epilepsy suggest that ethosuximide has the best efficacy and safety profile.
Childhood absence epilepsy accounts for 10 to 17% of all cases of childhood-onset epilepsy, making it the most common form of pediatric epilepsy.
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The syndrome is characterized by daily frequent but brief staring spells, typically beginning at 4 to 8 years of age, in an otherwise apparently healthy child.
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The classic electroencephalogram (EEG) shows generalized spike-wave bursts (of 3 Hz) with normal background activity.
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Often misperceived as a benign form of epilepsy, childhood absence epilepsy is associated with variable remission rates; affected children have cognitive deficits and long-term psychosocial difficulties.
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Three medications are commonly used as initial . . .
Summary
Purpose: Determine the optimal initial monotherapy for children with newly diagnosed childhood absence epilepsy (CAE) based on 12 months of double‐blind therapy.
Methods: A double‐blind, ...randomized controlled clinical trial compared the efficacy, tolerability, and neuropsychological effects of ethosuximide, valproic acid, and lamotrigine in children with newly diagnosed CAE. Study medications were titrated to clinical response, and subjects remained in the trial unless they reached a treatment failure criterion. Maximal target doses were ethosuximide 60 mg/kg/day or 2,000 mg/day, valproic acid 60 mg/kg/day or 3,000 mg/day, and lamotrigine 12 mg/kg/day or 600 mg/day. Original primary outcome was at 16–20 weeks and included a video–electroencephalography (EEG) assessment. For this report, the main effectiveness outcome was the freedom from failure rate 12 months after randomization and included a video‐EEG assessment; differential drug effects were determined by pairwise comparisons. The main cognitive outcome was the percentage of subjects experiencing attentional dysfunction at the month 12 visit.
Key Findings: A total of 453 children were enrolled and randomized; 7 were deemed ineligible and 446 subjects comprised the overall efficacy cohort. There were no demographic differences between the three cohorts. By 12 months after starting therapy, only 37% of all enrolled subjects were free from treatment failure on their first medication. At the month 12 visit, the freedom‐from‐failure rates for ethosuximide and valproic acid were similar (45% and 44%, respectively; odds ratio ORwith valproic acid vs. ethosuximide 0.94; 95% confidence interval CI 0.58–1.52; p = 0.82) and were higher than the rate for lamotrigine (21%; OR with ethosuximide vs. lamotrigine 3.08; 95% CI 1.81–5.33; OR with valproic acid vs. lamotrigine 2.88; 95% CI 1.68–5.02; p < 0.001 for both comparisons). The frequency of treatment failures due to lack of seizure control (p < 0.001) and intolerable adverse events (p < 0.037) was significantly different among the treatment groups. Almost two thirds of the 125 subjects with treatment failure due to lack of seizure control were in the lamotrigine cohort. The largest subgroup (42%) of the 115 subjects discontinuing due to adverse events was in the valproic acid group. The previously reported higher rate of attentional dysfunction seen at 16–20 weeks in the valproic acid group compared with the ethosuximide or lamotrigine groups persisted at 12 months (p < 0.01).
Significance: As initial monotherapy, the superior effectiveness of ethosuximide and valproic acid compared to lamotrigine in controlling seizures without intolerable adverse events noted at 16–20 weeks persisted at 12 months. The valproic acid cohort experienced a higher rate of adverse events leading to drug discontinuation as well as significant negative effects on attentional measures that were not seen in the ethosuximide cohort. These 12‐month outcome data coupled with the study’s prespecified decision‐making algorithm indicate that ethosuximide is the optimal initial empirical monotherapy for CAE. This is the first randomized controlled trial meeting International League Against Epilepsy (ILAE) criteria for class I evidence for CAE (or for any type of generalized seizure in adults or children). (NCT00088452.)
OBJECTIVE:To determine the neurocognitive deficits associated with newly diagnosed untreated childhood absence epilepsy (CAE), develop a model describing the factorial structure of items measuring ...academic achievement and 3 neuropsychological constructs, and determine short-term differential neuropsychological effects on attention among ethosuximide, valproic acid, and lamotrigine.
METHODS:Subjects with newly diagnosed CAE entering a double-blind, randomized controlled clinical trial had neuropsychological testing including assessments of general intellectual functioning, attention, memory, executive function, and achievement. Attention was reassessed at the week 16–20 visit.
RESULTS:At study entry, 36% of the cohort exhibited attention deficits despite otherwise intact neurocognitive functioning. Structural equation modeling of baseline neuropsychological data revealed a direct sequential effect among attention, memory, executive function, and academic achievement. At the week 16–20 visit, attention deficits persisted even if seizure freedom was attained. More subjects receiving valproic acid (49%) had attention deficits than subjects receiving ethosuximide (32%) or lamotrigine (24%) (p = 0.0006). Parental assessment did not reliably detect attention deficits before or after treatment (p < 0.0001).
CONCLUSIONS:Children with CAE have a high rate of pretreatment attentional deficits that persist despite seizure freedom. Rates are disproportionately higher for valproic acid treatment compared with ethosuximide or lamotrigine. Parents do not recognize these attentional deficits. These deficits present a threat to academic achievement. Vigilant cognitive and behavioral assessment of these children is warranted.
CLASSIFICATION OF EVIDENCE:This study provides Class I evidence that valproic acid is associated with more significant attentional dysfunction than ethosuximide or lamotrigine in children with newly diagnosed CAE.
Summary
Evidence‐based guidelines, or recommendations, for the management of infants with seizures are lacking. A Task Force of the Commission of Pediatrics developed a consensus document addressing ...diagnostic markers, management interventions, and outcome measures for infants with seizures. Levels of evidence to support recommendations and statements were assessed using the American Academy of Neurology Guidelines and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. The report contains recommendations for different levels of care, noting which would be regarded as standard care, compared to optimal care, or “state of the art” interventions. The incidence of epilepsy in the infantile period is the highest of all age groups (strong evidence), with epileptic spasms the largest single subgroup and, in the first 2 years of life, febrile seizures are the most commonly occurring seizures. Acute intervention at the time of a febrile seizure does not alter the risk for subsequent epilepsy (class 1 evidence). The use of antipyretic agents does not alter the recurrence rate (class 1 evidence), and there is no evidence to support initiation of regular antiepileptic drugs for simple febrile seizures (class 1 evidence). Infants with abnormal movements whose routine electroencephalography (EEG) study is not diagnostic, would benefit from video‐EEG analysis, or home video to capture events (expert opinion, level U recommendation). Neuroimaging is recommended at all levels of care for infants presenting with epilepsy, with magnetic resonance imaging (MRI) recommended as the standard investigation at tertiary level (level A recommendation). Genetic screening should not be undertaken at primary or secondary level care (expert opinion). Standard care should permit genetic counseling by trained personal at all levels of care (expert opinion). Genetic evaluation for Dravet syndrome, and other infantile‐onset epileptic encephalopathies, should be available in tertiary care (weak evidence, level C recommendation). Patients should be referred from primary or secondary to tertiary level care after failure of one antiepileptic drug (standard care) and optimal care equates to referral of all infants after presentation with a seizure (expert opinion, level U evidence). Infants with recurrent seizures warrant urgent assessment for initiation of antiepileptic drugs (expert opinion, level U recommendation). Infantile encephalopathies should have rapid introduction and increment of antiepileptic drug dosage (expert opinion, level U recommendation). There is no high level evidence to support any particular current agents for use in infants with seizures. For focal seizures, levetiracetam is effective (strong evidence); for generalized seizures, weak evidence supports levetiracetam, valproate, lamotrigine, topiramate, and clobazam; for Dravet syndrome, strong evidence supports that stiripentol is effective (in combination with valproate and clobazam), whereas weak evidence supports that topiramate, zonisamide, valproate, bromide, and the ketogenic diet are possibly effective; and for Ohtahara syndrome, there is weak evidence that most antiepileptic drugs are poorly effective. For epileptic spasms, clinical suspicion remains central to the diagnosis and is supported by EEG, which ideally is prolonged (level C recommendation). Adrenocorticotropic hormone (ACTH) is preferred for short‐term control of epileptic spasms (level B recommendation), oral steroids are probably effective in short‐term control of spasms (level C recommendation), and a shorter interval from the onset of spasms to treatment initiation may improve long‐term neurodevelopmental outcome (level C recommendation). The ketogenic diet is the treatment of choice for epilepsy related to glucose transporter 1 deficiency syndrome and pyruvate dehydrogenase deficiency (expert opinion, level U recommendation). The identification of patients as potential candidates for epilepsy surgery should be part of standard practice at primary and secondary level care. Tertiary care facilities with experience in epilepsy surgery should undertake the screening for epilepsy surgical candidates (level U recommendation). There is insufficient evidence to conclude if there is benefit from vagus nerve stimulation (level U recommendation). The key recommendations are summarized into an executive summary. The full report is available as Supporting Information. This report provides a comprehensive foundation of an approach to infants with seizures, while identifying where there are inadequate data to support recommended practice, and where further data collection is needed to address these deficits.
IMPORTANCE Prenatal folic acid supplements reduce the risk of neural tube defects in children, but it has not been determined whether they protect against other neurodevelopmental disorders. ...OBJECTIVE To examine the association between maternal use of prenatal folic acid supplements and subsequent risk of autism spectrum disorders (ASDs) (autistic disorder, Asperger syndrome, pervasive developmental disorder–not otherwise specified PDD-NOS) in children. DESIGN, SETTING, AND PATIENTS The study sample of 85 176 children was derived from the population-based, prospective Norwegian Mother and Child Cohort Study (MoBa). The children were born in 2002-2008; by the end of follow-up on March 31, 2012, the age range was 3.3 through 10.2 years (mean, 6.4 years). The exposure of primary interest was use of folic acid from 4 weeks before to 8 weeks after the start of pregnancy, defined as the first day of the last menstrual period before conception. Relative risks of ASDs were estimated by odds ratios (ORs) with 95% CIs in a logistic regression analysis. Analyses were adjusted for maternal education level, year of birth, and parity. MAIN OUTCOME MEASURE Specialist-confirmed diagnosis of ASDs. RESULTS At the end of follow-up, 270 children in the study sample had been diagnosed with ASDs: 114 with autistic disorder, 56 with Asperger syndrome, and 100 with PDD-NOS. In children whose mothers took folic acid, 0.10% (64/61 042) had autistic disorder, compared with 0.21% (50/24 134) in those unexposed to folic acid. The adjusted OR for autistic disorder in children of folic acid users was 0.61 (95% CI, 0.41-0.90). No association was found with Asperger syndrome or PDD-NOS, but power was limited. Similar analyses for prenatal fish oil supplements showed no such association with autistic disorder, even though fish oil use was associated with the same maternal characteristics as folic acid use. CONCLUSIONS AND RELEVANCE Use of prenatal folic acid supplements around the time of conception was associated with a lower risk of autistic disorder in the MoBa cohort. Although these findings cannot establish causality, they do support prenatal folic acid supplementation.
Two placebo-controlled trials involving pregnant women with subclinical hypothyroidism or hypothyroxinemia showed that levothyroxine beginning between 8 and 20 weeks of gestation did not ...significantly improve cognitive outcomes in children through 5 years of age.
Observational studies spanning almost three decades suggest that subclinical thyroid disease during pregnancy is associated with adverse outcomes.
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In 1999, interest in undiagnosed maternal thyroid dysfunction was heightened by studies suggesting an association between subclinical thyroid hypofunction and impaired fetal neuropsychological development.
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In one report, children of women whose serum thyrotropin levels during pregnancy were greater than the 98th percentile had a lower IQ than children of matched controls who had a normal thyrotropin level.
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In another study, children whose mothers had a serum free thyroxine (T
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A randomized trial of transfusion therapy versus standard therapy showed a reduction in cerebral infarcts among children with sickle cell anemia whose hemoglobin S levels were kept below 30%. ...Transfusion risks seem to be outweighed by the neurologic benefits.
Sickle cell anemia affects 1 of every 396
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black newborns and approximately 100,000 persons in the United States.
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Among children with sickle cell anemia (defined as homozygous hemoglobin S or hemoglobin S-β
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thalassemia), silent cerebral infarcts are the most common neurologic injury.
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In contrast to overt stroke (hereinafter referred to as stroke), a silent cerebral infarct is not associated with obvious neurologic impairment and cannot be detected on neurologic examination.
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However, children with a silent cerebral infarct are at increased risk for stroke, new or enlarged silent cerebral infarcts,
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poor academic achievement,
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and lower IQ, as compared either with . . .
Summary Background On the basis of mixed results from previous trials, we assessed whether therapeutic hypothermia for 48–72 h with slow rewarming improved mortality in children after brain injury. ...Methods In this phase 3, multicenter, multinational, randomised controlled trial, we included patients with severe traumatic brain injury who were younger than 18 years and could be enrolled within 6 h of injury. We used a computer-generated randomisation sequence to randomly allocate patients (1:1; stratified by site and age <6 years, 6–15 years, 16–17 years) to either hypothermia (rapidly cooled to 32–33°C for 48–72 h, then rewarmed by 0·5–1·0°C every 12–24 h) or normothermia (maintained at 36·5–37·5°C). The primary outcome was mortality at 3 months, assessed by intention-to-treat analysis; secondary outcomes were global function at 3 months after injury using the Glasgow outcome scale (GOS) and the GOS-extended pediatrics, and the occurrence of serious adverse events. Investigators assessing outcomes were masked to treatment. This trial is registered with ClinicalTrials.gov , number NCT00222742. Findings The study was terminated early for futility after an interim data analysis on data for 77 patients (enrolled between Nov 1, 2007, and Feb 28, 2011): 39 in the hypothermia group and 38 in the normothermia group. We detected no between-group difference in mortality 3 months after injury (6 15% of 39 patients in the hypothermia group vs two 5% of 38 patients in the normothermia group; p=0·15). Poor outcomes did not differ between groups (in the hypothermia group, 16 42% patients had a poor outcome by GOS and 18 47% had a poor outcome by GOS-extended paediatrics; in the normothermia group, 16 42% patients had a poor outcome by GOS and 19 51% of 37 patients had a poor outcome by GOS-extended paediatrics). We recorded no between-group differences in the occurrence of adverse events or serious adverse events. Interpretation Hypothermia for 48 h with slow rewarming does not reduce mortality of improve global functional outcome after paediatric severe traumatic brain injury. Funding National Institute of Neurological Disorders and Stroke and National Institutes of Health.
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