Hippocampal sclerosis and temporal lobe epilepsy following febrile status epilepticus: The FEBSTAT study.

OBJECTIVE: This study was undertaken to determine whether hippocampal T2 hyperintensity predicts sequelae of febrile status epilepticus, including hippocampal atrophy, sclerosis, and mesial temporal lobe epilepsy. METHODS: Acute magnetic resonance imaging (MRI) was obtained within a mean of 4.4 (SD = 5.5, median = 2.0) days after febrile status on >200 infants with follow-up MRI at approximately 1, 5, and 10 years. Hippocampal size, morphology, and T2 signal intensity were scored visually by neuroradiologists blinded to clinical details. Hippocampal volumetry provided quantitative measurement. Upon the occurrence of two or more unprovoked seizures, subjects were reassessed for epilepsy. Hippocampal volumes were normalized using total brain volumes. RESULTS: Fourteen of 22 subjects with acute hippocampal T2 hyperintensity returned for follow-up MRI, and 10 developed definite hippocampal sclerosis, which persisted through the 10-year follow-up. Hippocampi appearing normal initially remained normal on visual inspection. However, in subjects with normal-appearing hippocampi, volumetrics indicated that male, but not female, hippocampi were smaller than controls, but increasing hippocampal asymmetry was not seen following febrile status. Forty-four subjects developed epilepsy; six developed mesial temporal lobe epilepsy and, of the six, two had definite, two had equivocal, and two had no hippocampal sclerosis. Only one subject developed mesial temporal epilepsy without initial hyperintensity, and that subject had hippocampal malrotation. Ten-year cumulative incidence of all types of epilepsy, including mesial temporal epilepsy, was highest in subjects with initial T2 hyperintensity and lowest in those with normal signal and no other brain abnormalities. SIGNIFICANCE: Hippocampal T2 hyperintensity following febrile status epilepticus predicted hippocampal sclerosis and significant likelihood of mesial temporal lobe epilepsy. Normal hippocampal appearance in the acute postictal MRI was followed by maintained normal appearance, symmetric growth, and lower risk of epilepsy. Volumetric measurement detected mildly decreased hippocampal volume in males with febrile status.

Plasma cytokines associated with febrile status epilepticus in children: A potential biomarker for acute hippocampal injury.

OBJECTIVE: Our aim was to explore the association between plasma cytokines and febrile status epilepticus (FSE) in children, as well as their potential as biomarkers of acute hippocampal injury. METHODS: Analysis was performed on residual samples of children with FSE (n = 33) as part of the Consequences of Prolonged Febrile Seizures in Childhood study (FEBSTAT) and compared to children with fever (n = 17). Magnetic resonance imaging (MRI) was obtained as part of FEBSTAT within 72 h of FSE. Cytokine levels and ratios of antiinflammatory versus proinflammatory cytokines in children with and without hippocampal T2 hyperintensity were assessed as biomarkers of acute hippocampal injury after FSE. RESULTS: Levels of interleukin (IL)-8 and epidermal growth factor (EGF) were significantly elevated after FSE in comparison to controls. IL-1ß levels trended higher and IL-1RA trended lower following FSE, but did not reach statistical significance. Children with FSE were found to have significantly lower ratios of IL-1RA/IL-1ß and IL-1RA/IL-8. Specific levels of any one individual cytokine were not associated with FSE. However, lower ratios of IL-1RA/IL-1ß, IL-1RA/1L-6, and IL-1RA/ IL-8 were all associated with FSE. IL-6 and IL-8 levels were significantly higher and ratios of IL-1RA/IL-6 and IL-1RA/IL-8 were significantly lower in children with T2 hippocampal hyperintensity on MRI after FSE in comparison to those without hippocampal signal abnormalities. Neither individual cytokine levels nor ratios of IL-1RA/IL-1ß or IL-1RA/IL-8 were predictive of MRI changes. However, a lower ratio of IL-1RA/IL-6 was strongly predictive (odds ratio [OR] 21.5, 95% confidence interval [CI] 1.17-393) of hippocampal T2 hyperintensity after FSE. SIGNIFICANCE: Our data support involvement of the IL-1 cytokine system, IL-6, and IL-8 in FSE in children. The identification of the IL-1RA/IL-6 ratio as a potential biomarker of acute hippocampal injury following FSE is the most significant finding. If replicated in another study, the IL-1RA/IL-6 ratio could represent a serologic biomarker that offers rapid identification of patients at risk for ultimately developing mesial temporal lobe epilepsy (MTLE).

Disruption of Fgf13 causes synaptic excitatory-inhibitory imbalance and genetic epilepsy and febrile seizures plus.

We identified a family in which a translocation between chromosomes X and 14 was associated with cognitive impairment and a complex genetic disorder termed "Genetic Epilepsy and Febrile Seizures Plus" (GEFS(+)). We demonstrate that the breakpoint on the X chromosome disrupted a gene that encodes an auxiliary protein of voltage-gated Na(+) channels, fibroblast growth factor 13 (Fgf13). Female mice in which one Fgf13 allele was deleted exhibited hyperthermia-induced seizures and epilepsy. Anatomic studies revealed expression of Fgf13 mRNA in both excitatory and inhibitory neurons of hippocampus. Electrophysiological recordings revealed decreased inhibitory and increased excitatory synaptic inputs in hippocampal neurons of Fgf13 mutants. We speculate that reduced expression of Fgf13 impairs excitability of inhibitory interneurons, resulting in enhanced excitability within local circuits of hippocampus and the clinical phenotype of epilepsy. These findings reveal a novel cause of this syndrome and underscore the powerful role of FGF13 in control of neuronal excitability.

Risk factors for subsequent febrile seizures in the FEBSTAT study.

OBJECTIVES: To identify risk and risk factors for developing a subsequent febrile seizure (FS) in children with a first febrile status epilepticus (FSE) compared to a first simple febrile seizure (SFS). To identify home use of rescue medications for subsequent FS. METHODS: Cases included a first FS that was FSE drawn from FEBSTAT and Columbia cohorts. Controls were a first SFS. Cases and controls were classified according to established FEBSTAT protocols. Cumulative risk for subsequent FS over a 5-year period was compared in FSE versus SFS, and Cox proportional hazards regression was conducted. Separate analysis examined subsequent FS within FSE. The use of rescue medications at home was assessed for subsequent FS. RESULTS: Risk for a subsequent FSE was significantly increased in FSE versus SFS. Any magnetic resonance imaging (MRI) abnormality increased the risk 3.4-fold (p < 0.05), adjusting for age at first FS and FSE and in analyses restricted to children whose first FS was FSE (any MRI abnormality hazard ratio [HR] 2.9, p < 0.05). The risk for a second FS of any type or of subsequent FS lasting >10 min over the 5-year follow-up did not differ in FSE versus SFS. Rectal diazepam was administered at home to 5 (23.8%) of 21 children with subsequent FS lasting ≥10 min. SIGNIFICANCE: Compared to controls, FSE was associated with an increased risk for subsequent FSE, suggesting the propensity of children with an initial prolonged seizure to experience a prolonged recurrence. Any baseline MRI abnormality increased the recurrence risk when FSE was compared to SFS and when FSE was studied alone. A minority of children with a subsequent FS lasting 10 min or longer were treated with rectal diazepam at home, despite receiving prescriptions after the first FSE. This indicates the need to further improve the education of clinicians and parents in order to prevent subsequent FSE.

Hippocampal sclerosis after febrile status epilepticus: the FEBSTAT study.

OBJECTIVE: Whether febrile status epilepticus (FSE) produces hippocampal sclerosis (HS) and temporal lobe epilepsy (TLE) has long been debated. Our objective is to determine whether FSE produces acute hippocampal injury that evolves to HS. METHODS: FEBSTAT and 2 affiliated studies prospectively recruited 226 children aged 1 month to 6 years with FSE and controls with simple febrile seizures. All had acute magnetic resonance imaging (MRI), and follow-up MRI was obtained approximately 1 year later in the majority. Visual interpretation by 2 neuroradiologists informed only of subject age was augmented by hippocampal volumetrics, analysis of the intrahippocampal distribution of T2 signal, and apparent diffusion coefficients. RESULTS: Hippocampal T2 hyperintensity, maximum in Sommer's sector, occurred acutely after FSE in 22 of 226 children in association with increased volume. Follow-up MRI obtained on 14 of the 22 with acute T2 hyperintensity showed HS in 10 and reduced hippocampal volume in 12. In contrast, follow-up of 116 children without acute hyperintensity showed abnormal T2 signal in only 1 (following another episode of FSE). Furthermore, compared to controls with simple febrile seizures, FSE subjects with normal acute MRI had abnormally low right to left hippocampal volume ratios, smaller hippocampi initially, and reduced hippocampal growth. INTERPRETATION: Hippocampal T2 hyperintensity after FSE represents acute injury often evolving to a radiological appearance of HS after 1 year. Furthermore, impaired growth of normal-appearing hippocampi after FSE suggests subtle injury even in the absence of T2 hyperintensity. Longer follow-up is needed to determine the relationship of these findings to TLE.

Hippocampal Malrotation Is Associated With Prolonged Febrile Seizures: Results of the FEBSTAT Study.

OBJECTIVE: Hippocampal malrotation is characterized by incomplete hippocampal inversion with a rounded shape and blurred internal architecture. There is still debate about whether hippocampal malrotation has pathologic significance. We present findings from the Consequences of Prolonged Febrile Seizures in Childhood (FEBSTAT) study on the frequency of and risk factors for hippocampal malrotation. SUBJECTS AND METHODS: FEBSTAT is a prospective multicenter study investigating the consequences of febrile status epilepticus in childhood. MRI studies of 226 patients with febrile status epilepticus were analyzed visually by two board-certified neuroradiologists blinded to clinical details and were compared with MRI studies of 96 subjects with first simple febrile seizure. Quantitative analysis of hippocampal volume was performed by two independent observers. RESULTS: Hippocampal malrotation was present in 20 of 226 (8.8%) patients with febrile status epilepticus compared with two of 96 (2.1%) control subjects (odds ratio [OR], 4.56; 95% CI, 1.05-19.92). Hippocampal malrotation was exclusively left-sided in 18 of 22 (81.8%) patients and bilateral in the remaining four patients (18.2%). There was no case of exclusively right-sided hippocampal malrotation. Hippocampal malrotation was more common in boys than in girls (OR, 6.1; 95% CI, 1.7-21.5). On quantitative volumetric MRI analysis, the left hippocampal volume was smaller in patients with hippocampal malrotation than in control subjects with simple febrile seizure (p = 0.004), and the right-to-left hippocampal volume ratio was higher in the hippocampal malrotation group than in the simple febrile seizure group (p < 0.001). CONCLUSION: Hippocampal malrotation is a developmental malformation that predominantly affects the left hippocampus in male patients and is more frequently found in children with prolonged febrile status epilepticus than in control subjects. These data provide further evidence that hippocampal malrotation represents a pathologic error in brain development rather than a normal variant.

Risk factors for febrile status epilepticus: a case-control study.

OBJECTIVE: To identify risk factors for developing a first febrile status epilepticus (FSE) among children with a first febrile seizure (FS). STUDY DESIGN: Cases were children with a first FS that was FSE drawn from the Consequences of Prolonged Febrile Seizures in Childhood and Columbia cohorts. Controls were children with a first simple FS and separately, children with a first complex FS that was not FSE. Identical questionnaires were administered to family members of the 3 cohorts. Magnetic resonance imaging protocol and readings were consistent across cohorts, and seizure phenomenology was assessed by the same physicians. Risk factors were analyzed using logistic regression. RESULTS: Compared with children with simple FS, FSE was associated with younger age, lower temperature, longer duration (1-24 hours) of recognized temperature before FS, female sex, structural temporal lobe abnormalities, and first-degree family history of FS. Compared with children with other complex FS, FSE was associated with low temperature and longer duration (1-24 hours) of temperature recognition before FS. Risk factors for complex FS that was not FSE were similar in magnitude to those for FSE but only younger age was significant. CONCLUSIONS: Among children with a first FS, FSE appears to be due to a combination of lower seizure threshold (younger age and lower temperatures) and impaired regulation of seizure duration. Clinicians evaluating FS should be aware of these factors as many episodes of FSE go unnoticed. Further work is needed to develop strategies to prevent FSE.

Cerebrospinal fluid findings in children with fever-associated status epilepticus: results of the consequences of prolonged febrile seizures (FEBSTAT) study.

This prospective multicenter study of 200 patients with fever-associated status epilepticus (FSE), of whom 136 underwent a nontraumatic lumbar puncture, confirms that FSE rarely causes cerebrospinal fluid (CSF) pleocytosis. CSF glucose and protein levels were unremarkable. Temperature, age, seizure focality, and seizure duration did not affect results. CSF pleocytosis should not be attributed to FSE.

Human herpesvirus 6 and 7 in febrile status epilepticus: the FEBSTAT study.

PURPOSE: In a prospective study, Consequences of Prolonged Febrile Seizures in Childhood (FEBSTAT), we determined the frequency of human herpesvirus (HHV)-6 and HHV-7 infection as a cause of febrile status epilepticus (FSE). METHODS: Children ages 1 month to 5 years presenting with FSE were enrolled within 72 h and received a comprehensive assessment including specimens for HHV-6 and HHV-7. The presence of HHV-6A, HHV-6B, or HHV-7 DNA and RNA (amplified across a spliced junction) determined using quantitative polymerase chain reaction (qPCR) at baseline indicated viremia. Antibody titers to HHV-6 and HHV-7 were used in conjunction with the PCR results to distinguish primary infection from reactivated or prior infection. KEY FINDINGS: Of 199 children evaluated, HHV-6 or HHV-7 status could be determined in 169 (84.9%). HHV-6B viremia at baseline was found in 54 children (32.0%), including 38 with primary infection and 16 with reactivated infection. No HHV-6A infections were identified. HHV-7 viremia at baseline was observed in 12 children (7.1%), including eight with primary infection and four with reactivated infection. Two subjects had HHV-6/HHV-7 primary coinfection at baseline. There were no differences in age, characteristics of illness or fever, seizure phenomenology or the proportion of acute EEG or imaging abnormalities in children presenting with FSE with or without HHV infection. SIGNIFICANCE: HHV-6B infection is commonly associated with FSE. HHV-7 infection is less frequently associated with FSE. Together, they account for one third of FSE, a condition associated with an increased risk of both hippocampal injury and subsequent temporal lobe epilepsy.

Design and phenomenology of the FEBSTAT study.

PURPOSE: Febrile status epilepticus (FSE) has been associated with hippocampal injury and subsequent hippocampal sclerosis (HS) and temporal lobe epilepsy. The FEBSTAT study was designed to prospectively examine the association between prolonged febrile seizures and development of HS and associated temporal lobe epilepsy, one of the most controversial issues in epilepsy. We report on the baseline phenomenology of the final cohorts as well as detailed aims and methodology. METHODS: The "Consequences of Prolonged Febrile Seizures in Childhood" (FEBSTAT) study is a prospective, multicenter study. Enrolled are children, aged 1 month to 6 years of age, presenting with a febrile seizure lasting 30 min or longer based on ambulance, emergency department, and hospital records, and parental interview. At baseline, procedures included a magnetic resonance imaging (MRI) study and electroencephalography (EEG) recording done within 72 h of FSE, and a detailed history and neurologic examination. Baseline development and behavior are assessed at 1 month. The baseline assessment is repeated, with age-appropriate developmental testing at 1 and 5 years after enrollment as well as at the development of epilepsy and 1 year after that. Telephone calls every 3 months document additional seizures. Two other groups of children are included: a "control" group consisting of children with a first febrile seizure ascertained at Columbia University and with almost identical baseline and 1-year follow-up examinations and a pilot cohort of FSE from Duke University. KEY FINDINGS: The FEBSTAT cohort consists of 199 children with a median age at baseline of 16.0 months (interquartile range [IQR] 12.0-24.0) and a median duration of FSE of 70.0 min (IQR 47.0-110.0). Seizures were continuous in 57.3% and behaviorally intermittent (without recovery in between) in 31.2%; most were partial (2.0%) or secondary generalized (65.8%), and almost all (98.0%) culminated in a generalized tonic-clonic seizure. Of the 199 children, 86.4% had normal development and 20% had prior febrile seizures. In one third of cases, FSE was unrecognized in the emergency department. The Duke existing cohort consists of 23 children with a median age of FSE onset of 18.0 months (IQR 14.0-28.0) and median duration of FSE of 90.0 min (IQR 50.0-170.0). The Columbia control cohort consists of 159 children with a first febrile seizure who received almost the same workup as the FEBSTAT cohort at baseline and at 1 year. They were followed by telephone every 4 months for a median of 42 months. Among the control cohort, 64.2% had a first simple FS, 26.4% had a first complex FS that was not FSE, and 9.4% had FSE. Among the 15 with FSE, the median age at onset was 14.0 months (IQR 12.0-20.0) and the median duration of FSE was 43.0 min (IQR 35.0-75.0). SIGNIFICANCE: The FEBSTAT study presents an opportunity to prospectively study the relationship between FSE and acute hippocampal damage, the development of mesial temporal sclerosis, epilepsy (particularly temporal lobe epilepsy), and impaired hippocampal function in a large cohort. It is hoped that this study may illuminate a major mystery in clinical epilepsy today, and permit the development of interventions designed to prevent the sequelae of FSE.

A comparison of automated segmentation and manual tracing for quantifying hippocampal and amygdala volumes.

Large databases of high-resolution structural MR images are being assembled to quantitatively examine the relationships between brain anatomy, disease progression, treatment regimens, and genetic influences upon brain structure. Quantifying brain structures in such large databases cannot be practically accomplished by expert neuroanatomists using hand-tracing. Rather, this research will depend upon automated methods that reliably and accurately segment and quantify dozens of brain regions. At present, there is little guidance available to help clinical research groups in choosing such tools. Thus, our goal was to compare the performance of two popular and fully automated tools, FSL/FIRST and FreeSurfer, to expert hand tracing in the measurement of the hippocampus and amygdala. Volumes derived from each automated measurement were compared to hand tracing for percent volume overlap, percent volume difference, across-sample correlation, and 3-D group-level shape analysis. In addition, sample size estimates for conducting between-group studies were computed for a range of effect sizes. Compared to hand tracing, hippocampal measurements with FreeSurfer exhibited greater volume overlap, smaller volume difference, and higher correlation than FIRST, and sample size estimates with FreeSurfer were closer to hand tracing. Amygdala measurement with FreeSurfer was also more highly correlated to hand tracing than FIRST, but exhibited a greater volume difference than FIRST. Both techniques had comparable volume overlap and similar sample size estimates. Compared to hand tracing, a 3-D shape analysis of the hippocampus showed FreeSurfer was more accurate than FIRST, particularly in the head and tail. However, FIRST more accurately represented the amygdala shape than FreeSurfer, which inflated its anterior and posterior surfaces.

Rebuttal to Hasan and Pedraza in comments and controversies: "Improving the reliability of manual and automated methods for hippocampal and amygdala volume measurements".

Here we address the critiques offered by Hasan and Pedraza to our recently published manuscript comparing the performance of two automated segmentation programs, FSL/FIRST and FreeSurfer (Morey R, Petty C, Xu Y, Pannu Hayes J, Wagner H, Lewis D, LaBar K, Styner M, McCarthy G. (2009): A comparison of automated segmentation and manual tracing for quantifying of hippocampal and amygdala volumes. Neuroimage 45:855-866). We provide an assessment and discussion of their specific critiques. Hasan and Pedraza bring up some important points concerning our omission of sample demographic features and inclusion of left and right hemisphere volumes as independent measures in correlational analyses. We present additional data on demographic attributes of our sample and correlations analyzed separately on left and right hemispheres of the amygdala and hippocampus. While their commentary aids the reader to more critically asses our study, it falls short of substantiating that our omissions ought to lead readers to significantly revise their interpretations. Further research will help to disentangle the advantages and limitations of the various freely-available automated segmentation software packages.

Extrahippocampal involvement in human herpesvirus 6 encephalitis depicted at MR imaging.

PURPOSE: To test the hypothesis that patterns of signal intensity abnormality in human herpesvirus 6 (HHV6)-positive patients would allow distinction from patients who did not test positive for HHV6 encephalitis. MATERIALS AND METHODS: This retrospective study was performed with institutional review board committee approval by using a waiver of informed consent. Sixteen immunocompromised patients (nine males, seven females; age range, 2-39 years) underwent magnetic resonance (MR) imaging and cerebrospinal fluid polymerase chain reaction (PCR) testing for HHV6 DNA on the basis of clinical findings suspicious for encephalitis. MR images acquired during acute illness were examined without knowing PCR results. RESULTS: Nine patients were HHV6 positive. Seven showed signal intensity abnormalities, with prominent involvement of the hippocampus, and six showed additional involvement of the amygdala. Three HHV6-positive patients showed signal intensity abnormality in extrahippocampal divisions of the olfactory cortex and cortical and subcortical structures that maintain prominent connections with the hippocampal formation. Among the seven HHV6-negative patients, six had abnormalities in the hippocampus but only two showed extrahippocampal involvement, which was restricted to the amygdala. CONCLUSION: Most patients with HHV6 encephalitis have signal intensity abnormalities in the hippocampal formation and amygdala and, contrary to prior reports, some also have involvement of limbic structures outside of the medial temporal lobe. The presence of MR signal intensity abnormality in the medial temporal lobe should raise the diagnosis of HHV6 encephalitis in immunosuppressed patients, especially when hyperintense lesions are seen in the insular region and inferior frontal lobe.

Hippocampal MRI signal hyperintensity after febrile status epilepticus is predictive of subsequent mesial temporal sclerosis.

OBJECTIVE: The objective of our study was to test the hypothesis that the finding of hyperintense hippocampal signal intensity on T2-weighted MR images soon after febrile status epilepticus is associated with subsequent hippocampal volume loss and persistent abnormal signal intensity on T2-weighted images (i.e., mesial temporal sclerosis). SUBJECTS AND METHODS: Eleven children (mean age, 25 months) underwent initial MRI that included coronal temporal lobe imaging within 72 hours of febrile status epilepticus and follow-up imaging from 3 to 23 months later (mean, 9 months). A neuroradiologist blinded to clinical history graded initial and follow-up hippocampal signal intensity on a scale from 0 (normal) to 4 (markedly increased). Two blinded observers measured hippocampal volumes on initial and follow-up MR studies using commercially available software and volumes from 30 healthy children (mean age, 6.3 years). Initial signal intensity and hippocampal volume changes were compared using Kendall tau correlation coefficients. RESULTS: On initial imaging, hyperintense signal intensity ranging from 1 (minimally increased) to 4 (markedly increased) was seen in seven children. Four children had at least one hippocampus with moderate or marked signal abnormality, three children had a hippocampus with mild or minimal abnormality, and four children had normal signal intensity. The Kendall tau correlation coefficient between signal intensity increase and volume change was -0.68 (p < 0.01). Five children (two with temporal lobe epilepsy and two with complex partial seizures) had hippocampal volume loss and increased signal intensity on follow-up imaging, meeting the criteria for mesial temporal sclerosis. CONCLUSION: MRI findings of a markedly hyperintense hippocampus in children with febrile status epilepticus was highly associated with subsequent mesial temporal sclerosis.

NMDA receptor antagonists disinhibit rat posterior cingulate and retrosplenial cortices: a potential mechanism of neurotoxicity.

NMDA receptor antagonists produce region-specific neurodegeneration by an undetermined mechanism, but one proposed mechanism involves disinhibition. In certain areas of the brain, NMDA receptors mediate excitatory drive onto inhibitory interneurons. Thus, NMDA receptor/channel antagonists may reduce inhibition (i.e., produce "disinhibition"). If a sufficient level of disinhibition is produced, enhanced vulnerability to excitotoxicity may result. Furthermore, if there are region-specific differences in NMDA antagonist-induced disinhibition, this could underlie region-specific NMDA antagonist-induced neurotoxicity. In the present study, we tested this hypothesis by exposing rat brain slices to the NMDA receptor antagonist dizocilpine maleate (MK-801) and measuring MK-801-induced disinhibition in areas of higher and lower vulnerability to neurodegeneration [posterior cingulate/retrosplenial cortices (PCC/RSC) and parietal cortex, respectively]. Using whole-cell patch-clamp techniques, bicuculline-sensitive GABA(A) receptor-mediated IPSCs were measured in biocytin-labeled pyramidal neurons in the PCC/RSC and parietal cortex. In the PCC/RSC, bath-applied MK-801 (10-40 microm) produced disinhibition, shown as a concentration-dependent decrease in spontaneous IPSC frequency and amplitude; MK-801 (40 microm) also reduced evoked IPSC amplitudes. In parietal cortex, MK-801 produced significantly less disinhibition. To determine whether disinhibition is caused by presynaptic or postsynaptic mechanisms, we tested the effects of MK-801 (40 microm) against miniature IPSC (mIPSC) frequency and amplitude in tetrodotoxin (TTX; 0.5 microm)-treated slices and found that MK-801 did not alter mIPSC frequency or amplitude. Taken together, these results suggest that NMDA receptors regulate activity of inhibitory interneurons and, consequently, GABA release in certain cortical areas. This region-specific reduction in inhibitory input to pyramidal cells could underlie the region-specific neurotoxicity of NMDA antagonists.

Do prolonged febrile seizures produce medial temporal sclerosis? Hypotheses, MRI evidence and unanswered questions.

Whether or not severe febrile seizures in infancy cause hippocampal injury and subsequent medial temporal sclerosis is an often debated question in epilepsy. Recent magnetic resonance imaging (MRI) of infants suffering from febrile seizures has provided preliminary evidence that abnormally increased T2 signal intensity can be seen in the hippocampi of infants following prolonged and focal febrile seizures. Follow-up MRIs in a few of these infants have confirmed that medial temporal sclerosis can develop following these acute MRI signal changes. In this article, we review the hypotheses and MRI evidence relating to hippocampal injury during prolonged febrile seizures and the later development of medial temporal sclerosis.

Acute EEG findings in children with febrile status epilepticus: results of the FEBSTAT study.

OBJECTIVE: The FEBSTAT (Consequences of Prolonged Febrile Seizures) study is prospectively addressing the relationships among serial EEG, MRI, and clinical follow-up in a cohort of children followed from the time of presentation with febrile status epilepticus (FSE). METHODS: We recruited 199 children with FSE within 72 hours of presentation. Children underwent a detailed history, physical examination, MRI, and EEG within 72 hours. All EEGs were read by 2 teams and then conferenced. Associations with abnormal EEG were determined using logistic regression. Interrater reliability was assessed using the κ statistic. RESULTS: Of the 199 EEGs, 90 (45.2%) were abnormal with the most common abnormality being focal slowing (n = 47) or attenuation (n = 25); these were maximal over the temporal areas in almost all cases. Epileptiform abnormalities were present in 13 EEGs (6.5%). In adjusted analysis, the odds of focal slowing were significantly increased by focal FSE (odds ratio [OR] = 5.08) and hippocampal T2 signal abnormality (OR = 3.50) and significantly decreased with high peak temperature (OR = 0.18). Focal EEG attenuation was also associated with hippocampal T2 signal abnormality (OR = 3.3). CONCLUSIONS: Focal EEG slowing or attenuation are present in EEGs obtained within 72 hours of FSE in a substantial proportion of children and are highly associated with MRI evidence of acute hippocampal injury. These findings may be a sensitive and readily obtainable marker of acute injury associated with FSE.

MRI abnormalities following febrile status epilepticus in children: the FEBSTAT study.

OBJECTIVE: The FEBSTAT study is a prospective study that seeks to determine the acute and long-term consequences of febrile status epilepticus (FSE) in childhood. METHODS: From 2003 to 2010, 199 children age 1 month to 5 years presenting with FSE (>30 minutes) were enrolled in FEBSTAT within 72 hours of the FSE episode. Of these, 191 had imaging with emphasis on the hippocampus. All MRIs were reviewed by 2 neuroradiologists blinded to clinical details. A group of 96 children with first simple FS who were imaged using a similar protocol served as controls. RESULTS: A total of 22 (11.5%) children had definitely abnormal (n = 17) or equivocal (n = 5) increased T2 signal in the hippocampus following FSE compared with none in the control group (p < 0.0001). Developmental abnormalities of the hippocampus were more common in the FSE group (n = 20, 10.5%) than in controls (n = 2, 2.1%) (p = 0.0097) with hippocampal malrotation being the most common (15 cases and 2 controls). Extrahippocampal imaging abnormalities were present in 15.7% of the FSE group and 15.6% of the controls. However, extrahippocampal imaging abnormalities of the temporal lobe were more common in the FSE group (7.9%) than in controls (1.0%) (p = 0.015). CONCLUSIONS: This prospective study demonstrates that children with FSE are at risk for acute hippocampal injury and that a substantial number also have abnormalities in hippocampal development. Follow-up studies are in progress to determine the long-term outcomes in these children.

Losing neurons: selective vulnerability and mesial temporal sclerosis.

Mesial temporal sclerosis (MTS) is found in about two-thirds of patients with refractory temporal lobe epilepsy (TLE), and surgical removal of the sclerotic structures eliminates seizures in the majority of cases undergoing surgical resection. Although multiple factors have been implicated in the genesis of MTS, it is still unclear why some individuals are more likely to develop hippocampal sclerosis than others. Epileptologists have proposed that there must be at least two factors involved-an initial precipitating injury (IPI), such as a prolonged febrile seizure, CNS infection, or head trauma, and a second factor that increases vulnerability to neuronal injury. This has been termed the "two-hit hypothesis." Three of the many factors that could possibly heighten susceptibility to neuronal injury and MTS are discussed here. These are microdysgenesis, hippocampal dysgenesis, prior seizures, and genetic predisposition. We conclude that there is currently no compelling evidence to support a role for microdysgenesis in MTS. Hippocampal dysgenesis, on the other hand, may account for febrile seizures and possibly MTS in a small subpopulation of patients with TLE. Additional larger studies are needed to confirm these findings. Experimental evidence indicates that an epileptogenic hippocampus can result from prolonged febrile seizures in infant rats, even though these seizures do not cause MTS in the rat. It is not known if this pathophysiological sequence occurs in humans. Lastly, there appears to be a strong genetic component that predisposes some individuals to MTS, regardless of whether they experience an IPI.

Dietary prenatal choline supplementation alters postnatal hippocampal structure and function.

Choline, a compound present in many foods, has recently been classified as an essential nutrient for humans. Studies with animal models indicate that the availability of choline during the prenatal period influences neural and cognitive development. Specifically, prenatal choline supplementation has been shown to enhance working memory and hippocampal long-term potentiation (LTP) in adult offspring. However, the cellular mechanisms underlying these effects remain unclear. Here we report that choline supplementation, during a 6-day gestational period, results in greater excitatory responsiveness, reduced slow afterhyperpolarizations (sAHPs), enhanced afterdepolarizing potentials (ADPs), larger somata, and greater basal dendritic arborization among hippocampal CA1 pyramidal cells studied postnatally in juvenile rats (20-25 days of age). These data indicate that dietary supplementation with a single nutrient, choline, during a brief, critical period of prenatal development, alters the structure and function of hippocampal pyramidal cells.