Transient reduced diffusion in the cortex in a child with prolonged febrile seizures

We report on a 4-year-old boy with transient reduced diffusion in the cortex, thalamus, and hippocampus on diffusion-weighted imaging (DWI) performed after prolonged febrile seizures (PFS). He had experienced intermittent right hemiconvulsions lasting about 90 min during the febrile illness, but his neurological symptom resolved completely after several hours. DWI performed immediately after the PFS showed abnormally high signal intensities in the left extended cortex and pulvinar of the ipsilateral thalamus. Two days later, these DWI lesions resolved completely, but abnormally high signal intensities were observed in the left hippocampus. Three months later, the DWI was normal, and no atrophy or gliosis was seen. This patient had unique lesions on DWI after PFS, but it is nevertheless important to attend to such lesions on the DWI of patients with PFS.     

Hippocampal damage after prolonged febrile seizure: one case in a consecutive prospective series

The factors that contribute to hippocampal damage as a sequela, and its frequency, in patients experiencing febrile status epilepticus, remain unknown. Of the 472 patients with febrile seizures admitted to our hospital between February 2004 and August 2008, 77 had prolonged seizures. Among them, 59 underwent magnetic resonance imaging (MRI). A 21-month-old girl showed hippocampal changes after her first episode of febrile status epilepticus. The seizure lasted about 35 min, with eye deviation to the right and ictal rhythmic discharges in the left hemisphere. MRI at 72 h after the seizure revealed high-signal intensities in T(2) and fluid-attenuated inversion recovery (FLAIR) images of the left hippocampus. Left hippocampal volume diminished over the next several months suggesting the occurrence of neuronal cell death. In no other cases, not even those with longer seizure durations, did significant hippocampal changes develop. The frequency of hippocampal damage was 1.7% in this case series. The involvement of factors other than seizure duration merits further study.     

Clinical profile and treatment outcome of febrile infection-related epilepsy syndrome in South Indian children

Purpose:To describe the clinical features and outcome of febrile infection-related epilepsy syndrome (FIRES), a catastrophic epileptic encephalopathy, in a cohort of South Indian children.Significance:This study reports one of the largest single center cohorts from India, with an adverse long-term developmental and seizure outcome. The duration and severity of seizures in the acute period correlated directly with the short-term and long-term clinical outcomes. There is an urgent need for developing new effective therapeutic strategies to treat this acute catastrophic epileptic syndrome.     

Febrile seizures and genetic epilepsy with febrile seizures plus (GEFS+)

Aim. To review the literature about febrile seizures and GEFS plus with special emphasis on management and outcome. Methods. Selected literature review. Results. Febrile seizures are the most common convulsive event in humans, occurring in 2–6% of the population. The aetiology is complex with strong evidence for a heterogeneous genetic predisposition interacting with fever of any cause, with certain viral infections having a greater effect. A large amount of literature has established that febrile seizures have no long‐term consequences on cognition or behaviour. Unfortunately, about 40% of children with a first febrile seizure will have a recurrence. The strongest predictor of recurrence is age <14–16 months at the time of the first febrile seizure. Epilepsy follows febrile seizures in ～3% cases, with the concepts of simple and complex febrile seizures providing relatively weak prediction. Very prolonged febrile seizures may lead to mesial temporal sclerosis and temporal lobe epilepsy although the degree of risk remains uncertain. Investigations beyond establishing the cause of the provoking fever are nearly always unnecessary. Treatment is mainly reassurance and there is some evidence that parents eventually “come to grips” with the fear that their children are dying during a febrile seizure. Antipyretic medications are remarkably ineffective to prevent recurrences. Daily and intermittent prophylactic medications are ineffective or have unacceptable side effects or risks. “Rescue” benzodiazepines may prevent prolonged recurrences for selected patients with a first prolonged febrile seizure although this has not been proven. Genetic epilepsy with febrile seizures plus (GEFS+) is a complex autosomal dominant disorder usually caused by mutations in SCN1A (a voltage‐gated sodium channel). One third of patients have febrile seizures only; two thirds have a variety of epilepsy syndromes, both focal and generalized. Conclusions. Febrile seizures may distress parents but rarely have any long‐term consequences. Reassurance is the only treatment for the vast majority. Identifying patients with GEFS plus may lead to further investigations and counselling.     

Prolonged febrile seizures are associated with hippocampal vasogenic edema and developmental changes

PURPOSE: There is mounting evidence that a prolonged febrile seizure (PFS) can cause acute hippocampal edema although the nature of that edema remains uncertain. The principal aims of the current study were: (1) to use apparent diffusion coefficient (ADC) measurements to further characterize the hippocampal edema previously identified within 5 days of a PFS, and (2) to determine whether the age dependency of ADC in the hippocampus is different in patients when compared to a control population following a PFS. METHODS: Diffusion weighted imaging was acquired in 23 children within 5 days of a PFS, and in 14 of these children a mean of 5.5 months later. Twenty-four control children were enrolled. RESULTS: There was a reduction in ADC between the acute and follow-up investigations [mean reduction = 0.0072 mm2/s/month since PFS (95% confidence interval; 0.0001-0.014 mm2/s/month since PFS), p = 0.048] consistent with early vasogenic edema, followed by recovery in children investigated within 2 days of a PFS. In addition, the behavior of ADC with respect to age was different in patients when compared to control subjects [mean difference in slope =-0.155 mm2/s/log10 age (95% confidence interval; -0.290-0.0203 mm2/s/log10 age), p = 0.029], in that the expected age dependence was observed only in the control subjects. CONCLUSION: We suggest that these latter findings are most consistent with a preexisting developmental hippocampal abnormality that may predispose individuals to having a PFS.     

Acute encephalopathy with biphasic seizures and late reduced diffusion: Predictive EEG findings

BackgroundAcute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is a common type of acute encephalopathy in Japan; the condition is clinically characterized by prolonged seizures as the initial neurological symptom, followed by late seizures 4–6 days later. It is difficult to differentiate AESD from prolonged febrile seizures (PFSs). Here, we explored the use of electroencephalography to differentiate AESD from PFSs.MethodsWe studied the electroencephalograms (EEGs) of children <6 years of age diagnosed with AESD or PFSs; all EEGs were recorded within 48 h of seizure onset (i.e., before the late seizures of AESD). Two pediatric neurologists evaluated all EEGs, focusing on the basic rhythm, slowing during wakefulness/arousal by stimuli, spindles, fast waves, and slowing during sleep.ResultsThe EEGs of 14 children with AESD and 31 children with PFSs were evaluated. Spindles were more commonly reduced or absent in children with AESD than in those with PFSs (71% vs. 31%, p = 0.021). Fast waves were also more commonly reduced or absent in children with AESD (21% vs. 0%, p = 0.030). The rates of all types of slowing did not differ between children with AESD and those with PFSs, but continuous or frequent slowing during sleep was more common in the former (50% vs. 17%, p = 0.035).ConclusionsEEG findings may usefully differentiate AESD from PFSs. Reduced or absent spindles/fast waves and continuous or frequent slowing during sleep are suggestive of AESD in children with prolonged seizures associated with fever.     

Incidence and risk factors of acute encephalopathy with biphasic seizures in febrile status epilepticus

ObjectiveTo clarify the incidence and risk factors of acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) in pediatric patients with febrile status epilepticus (FSE).MethodsWe retrospectively surveyed patients with FSE (≥20 min and ≥40 min) who were younger than 6 years by mailing a questionnaire to 1123 hospitals in Japan. The survey period was 2 years. We then collected clinical data on patients with prolonged febrile seizures (PFS) ≥40 min and those with AESD, and compared clinical data between the PFS and AESD groups.ResultsThe response rate for the primary survey was 42.3%, and 28.0% of hospitals which had applicable cases responded in the secondary survey. The incidence of AESD was 4.3% in patients with FSE ≥20 min and 7.1% in those with FSE ≥40 min. In the second survey, a total of 548 patients had FSE ≥40 min (AESD group, n = 93; PFS group, n = 455). Univariate analysis revealed significant between-group differences in pH, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, creatine kinase, NH₃, procalcitonin (PCT), uric acid, blood urea nitrogen, creatinine (Cr), and lactate. Multivariate analysis using stratified values showed that high PCT was an only risk factor for AESD. A prediction score of ≥3 was indicative of AESD, as determined using the following indexes: HCO3^? < 20 mmol/L (1 point), Cl <100 mEq/L (1 point), Cr ≥0.35 mg/dL (1 point), glucose ≥200 mg/dL (1 point), and PCT ≥1.7 pg/mL (2 points). The scoring system had sensitivity of 84.2% and specificity of 81.0%.ConclusionIncidence data and prediction scores for AESD will be useful for future intervention trials for AESD.     

Respiratory alkalosis in children with febrile seizures

Purpose: Febrile seizures (FS) are the most common type of convulsive events in children. FS are suggested to result from a combination of genetic and environmental factors. However, the pathophysiologic mechanisms underlying FS remain unclear. Using an animal model of experimental FS, it was demonstrated that hyperthermia causes respiratory alkalosis with consequent brain alkalosis and seizures. Here we examine the acid–base status of children who were admitted to the hospital for FS. Children who were admitted because of gastroenteritis (GE), a condition known to promote acidosis, were examined to investigate a possible protective effect of acidosis against FS. Methods: We enrolled 433 age‐matched children with similar levels of fever from two groups presented to the emergency department. One group was admitted for FS (n = 213) and the other for GE (n = 220). In the FS group, the etiology of fever was respiratory tract infection (74.2%), otitis media (7%), GE (7%), tonsillitis (4.2%), scarlet fever (2.3%) chickenpox (1.4%), urinary tract infection (1.4%), postvaccination reaction (0.9%), or unidentified (1.4%). In all patients, capillary pH and blood Pco₂ were measured immediately on admission to the hospital. Key Findings: Respiratory alkalosis was found in children with FS (pH 7.46 ± 0.04, [mean ± standard deviation] Pco₂ 29.5 ± 5.5 mmHg), whereas a metabolic acidosis was seen in all children admitted for GE (pH 7.31 ± 0.03, Pco₂ 37.7 ± 4.3 mmHg; p < 0.001 for both parameters). No FS were observed in the latter group. A subgroup (n = 15; 7%) of the patients with FS had GE and, notably, their blood pH was more alkaline (pH 7.44 ± 0.04) than in the GE‐admitted group. During the enrollment period, eight of the patients were admitted on separate occasions because of FS or GE. Consistent with the view that generation of FS requires a genetic susceptibility in addition to acute seizure triggering factors, each of these patients had an alkalotic blood pH when admitted because of FS, whereas they had an acidotic pH (and no FS) when admitted because of GE (pH 7.47 ± 0.05 vs. pH 7.33 ± 0.03, p < 0.005). Significance: The results show that FS are associated with a systemic respiratory alkalosis, irrespective of the severity of the underlying infection as indicated by the level of fever. The lack of FS in GE patients is attributable to low pH, which also explains the fact that children with a susceptibility to FS do not have seizures when they have GE‐induced fever that is associated with acidosis. The present demonstration of a close link between FS and respiratory alkalosis may pave the way for further clinical studies and attempts to design novel therapies for the treatment of FS by controlling the systemic acid–base status.     

中国10个全面性癫痫伴热性惊厥附加症家系的临床特征分析

目的探讨中国全面性癫痫伴热性惊厥附加症(generalized epilepsy with febrile seizure plus,GEFS+)家系的临床特征。方法通过门诊就诊、个人访视、电话等方式,对10个GEFS+家系所有成员进行详细临床资料收集,包括家系图谱、有无发作、发作形式以及检查结果等。结果10个家系共有140名成员接受了调查(其中3名去世,由亲属提供病史),发现受累者80例,其中74例符合GEFS+临床发作谱,2例为特发性全面性癫痫,4例不能明确分类。其中有两个家系较为特殊(家系I和家系H),2个家系受累者绝大部分仅表现为热性惊厥(febrile seizure,FS),每个家系仅有先症者1人表现为热性惊厥附加症(febrile seizure plus,FS+)。此外还发现3例FS+伴局灶性发作,2例为FS+伴儿童良性癫痫伴中央颞部棘波,1例为FS+伴颞叶癫痫。结论GEFS+是一种常见的、儿童时期起病的遗传性癫痫综合征,GEFS+最常见的表型为FS和FS+,其次是FS+伴局灶性发作、FS伴IGE、FS+伴失神发作以及FS+伴肌阵挛发作,我们的10个GEFS+家系中未发现FS+伴失张力发作、肌阵挛站立不能性癫痫和婴儿严重肌阵挛癫痫,说明这些表型为临床少见表型;此外我们还发现了GEFS+合并IGE以及在FS遗传背景上仅个别患者为FS+的较特殊家系,这些将进一步扩展GEFS+的概念。     

Hippocampal and amygdala volumes in children and adults with childhood maltreatment-related posttraumatic stress disorder: a meta-analysis

Little work has directly examined the course of hippocampal volume in children and adults with childhood maltreatment-related posttraumatic stress disorder (PTSD). Data from adults suggest that hippocampal volume deficits are associated with PTSD, whereas findings from children with PTSD generally show no hippocampal volume deficits in PTSD. Additionally, the role of the amygdala in emotional response makes it a possible region for investigation in children and adults with childhood maltreatment-related PTSD. The objectives of this study were 2-fold: (1) to meta-analytically determine whether hippocampal and amygdala volumes in children and adults with PTSD from childhood maltreatment differ from those in healthy controls, and (2) to use cross-sectional findings performed with meta-analyses as a proxy for longitudinal studies to estimate the course of hippocampal and amygdala volumes in child and adult subjects with PTSD from childhood maltreatment. Using electronic databases, we identified articles containing hippocampal and amygdala data for children with PTSD and adults with PTSD from childhood maltreatment. Data were extracted and effect sizes were calculated using Comprehensive Meta-Analysis Version 2.0. Reduced bilateral hippocampal volume was found in adults with childhood maltreatment-related PTSD compared with healthy controls, but this deficit was not seen in children with maltreatment-related PTSD, suggesting hippocampal volume deficits from childhood maltreatment may not be apparent until adulthood. Greater left than right hippocampal volume was found in the adult healthy control group but not in the PTSD group. Amygdala volume in children with maltreatment-related PTSD did not differ from that in healthy controls. Hippocampal volume is normal in children with maltreatment-related PTSD but not in adults with PTSD from childhood maltreatment, suggesting an initially volumetrically normal hippocampus with subsequent abnormal volumetric development occurring after trauma exposure. However, longitudinal studies are needed to support these preliminary findings.     

The value of early postictal EEG in children with complex febrile seizures

PURPOSE: To assess the usefulness of an early postictal EEG in neurologically normal children with complex febrile seizures. METHODS: We conducted a retrospective chart review of all neurologically normal children who were hospitalized over a period of 2.5 years after complex febrile seizures, and had an EEG up to 1 week after the seizure. RESULTS: Thirty-three patients (mean age, 17.8 months) qualified for inclusion into the study. Twenty-four patients were qualified as complex cases based on one factor (prolonged in 9, repetitive in 13, and focal in 2). Nine other patients had two complex factors: in six patients, the seizures were long and repetitive; in two patients, the seizures were focal and repetitive; and in one patient, the seizures were long, focal, and repetitive. Thirteen (39%) patients experienced prior febrile seizures. All 33 patients had a normal postictal sleep EEG. Our results indicate with a 95% probability that the true rate of abnormalities in an early postictal EEG performed on otherwise normal children with complex febrile seizures is 8.6% or less. CONCLUSIONS: The yield of abnormalities of an early postictal EEG in this population is low and similar to the reported rate of abnormalities in children with simple febrile seizures. The routine practice of obtaining an early EEG in neurologically normal children with complex febrile seizures is not justified.