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.

Safety and tolerability associated with chronic intermittent use of diazepam buccal film in adult, adolescent, and pediatric patients with epilepsy.

OBJECTIVE: Diazepam buccal film (DBF) is in development for treatment of patients experiencing bouts of increased seizure activity. We assessed safety, tolerability, and usability of self- or caregiver-administered DBF in the outpatient setting. METHODS: Patients aged 2-65 years needing treatment with a rescue benzodiazepine at least once monthly were eligible for the study. DBF (5-17.5 mg) was dispensed based on age and body weight. Patients/caregivers administered DBF for up to five seizure episodes per month. Adverse events (AEs) and usability assessments were recorded after the first dose, then every 3 months. RESULTS: Onehundred eighteen patients who used ≥1 DBF dose (adults, n = 82; adolescents, n = 19; children, n = 17) were enrolled. Eleven treatment-related AEs (10 being mild or moderate in severity) occurred in nine (7.6%) patients over a mean of 243 days of follow-up. No patient discontinued participation because of AEs. Mild local buccal discomfort, buccal swelling, and cheek skin sensitivity were reported by one patient each. Twenty-two serious AEs were reported; one was treatment-related. The three deaths reported, all unrelated to DBF, resulted from seizures or seizure with brain malignancy. Self-administration by adults was attempted on 23.6% (188/795) of use occasions. Administration of DBF occurred under ictal or peri-ictal conditions on 49.5% (538/1087) of use occasions, and DBF was successfully administered on a first or second attempt on 96.6% (1050/1087) of use occasions. Overall, patients received their dose of DBF on 99.2% (1078/1087) of use occasions. A second DBF dose was required within 24 hours after the first dose on 8.5% (92/1087) of use occasions. SIGNIFICANCE: In this observational study of chronic intermittent use, DBF was easy to administer, safe, and well tolerated in adult, adolescent, and pediatric patients with epilepsy experiencing seizure emergencies. DBF can be readily self-administered by adults with epilepsy, as well as successfully administered by a caregiver in seizure emergencies.

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).

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.

Benzodiazepine use in seizure emergencies: A systematic review.

PURPOSE: The aim of this review was to systematically examine safety and efficacy outcomes, as well as patient/caregiver satisfaction, from clinical studies in pediatric and adult patients treated with benzodiazepines (BZDs) through various administration routes in response to seizure emergencies. METHODS: A literature search was conducted to identify articles describing the use of various routes of administration (RoAs) of BZDs for the treatment of seizure emergencies through April 21, 2015, using Embase™ and PubMed®. Eligible studies included (a) randomized controlled trials or (b) controlled nonrandomized clinical trials, either retrospective or prospective. Outcome assessments reviewed were 1) time to administration, 2) time to seizure termination, 3) rate of treatment failure, 4) prevention of seizure recurrence, 5) patient and caregiver treatment satisfaction, 6) adverse events related to BDZ treatment or RoA, and 7) respiratory adverse events. RESULTS: Seventy-five studies evaluated safety and efficacy using individual or comparator BDZs of various RoAs for treating seizure emergencies in all-aged patients with epilepsy. Buccal, intranasal (IN), or intramuscular (IM) BZDs were often more rapidly administered compared with rectal and intravenous (IV) formulations. Time to seizure termination, seizure recurrence rates, and adverse events were generally similar among RoAs, whereas nonrectal RoAs resulted in greater patient and caregiver satisfaction compared with rectal RoA. SIGNIFICANCE: Results of this systematic literature review suggest that nonrectal and non-IV BZD formulations provide equal or improved efficacy and safety outcomes compared with rectal and IV formulations for the treatment of seizure emergencies.

Cognitive functioning one month and one year following febrile status epilepticus.

OBJECTIVE: The objective of this study was to determine early developmental and cognitive outcomes of children with febrile status epilepticus (FSE) one month and one year after FSE. METHODS: One hundred ninety four children with FSE were evaluated on measures of cognition, receptive language, and memory as part of the FEBSTAT study and compared with 100 controls with simple febrile seizures (FSs). RESULTS: Children with FSE did not differ dramatically on tasks compared with FS controls at one month after FSE but demonstrated slightly weaker motor development (p=0.035) and receptive language (p=0.034) at one year after FSE. Performances were generally within the low average to average range. Within the FSE cohort, non-White children performed weaker on many of the tasks compared with Caucasian children. At the one-year visit, acute hippocampal T2 findings on MRI were associated with weaker receptive language skills (p=0.0009), and human herpes virus 6 or 7 (HHV6/7) viremia was associated with better memory performances (p=0.047). CONCLUSION: Febrile status epilepticus does not appear to be associated with significant cognitive impairment on early developmental measures, although there is a trend for possible receptive language and motor delay one year after FSE. Further follow-up, which is in progress, is necessary to track long-term cognitive functioning.

Emergency management of febrile status epilepticus: results of the FEBSTAT study.

OBJECTIVE: Treatment of seizures varies by region, with no standard emergency treatment protocol. Febrile status epilepticus (FSE) is often a child's first seizure; therefore, families are rarely educated about emergency treatment. METHODS: From 2002 to 2010, 199 subjects, age 1 month to 6 years, were recruited as part of a prospective, multicenter study of consequences of FSE, which was defined as a febrile seizure or series of seizures lasting >30 min. The patients' charts were reviewed. No standardized treatment protocol was implemented for this observational study. RESULTS: One hundred seventy-nine children received at least one antiepileptic drug (AED) to terminate FSE, and more than one AED was required in 140 patients (70%). Median time from the seizure onset to first AED by emergency medical services (EMS) or emergency department (ED) was 30 min. Mean seizure duration was 81 min for subjects given medication prior to ED and 95 min for those who did not (p = 0.1). Median time from the first dose of AED to end of seizure was 38 min. Initial dose of lorazepam or diazepam was suboptimal in 32 (19%) of 166 patients. Ninety-five subjects (48%) received respiratory support by EMS or ED. Median seizure duration for the respiratory support group was 83 min; for the nonrespiratory support group the duration was 58 min (p-value < 0.001). Reducing the time from seizure onset to AED initiation was significantly related to shorter seizure duration. SIGNIFICANCE: FSE rarely stops spontaneously, is fairly resistant to medications, and even with treatment persists for a significant period of time. The total seizure duration is composed of two separate factors, the time from seizure onset to AED initiation and the time from first AED to seizure termination. Earlier onset of treatment results in shorter total seizure duration. A standard prehospital treatment protocol should be used nationwide and education of EMS responders is necessary.

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.

Genetic Testing to Inform Epilepsy Treatment Management From an International Study of Clinical Practice.

Importance: It is currently unknown how often and in which ways a genetic diagnosis given to a patient with epilepsy is associated with clinical management and outcomes. Objective: To evaluate how genetic diagnoses in patients with epilepsy are associated with clinical management and outcomes. Design, Setting, and Participants: This was a retrospective cross-sectional study of patients referred for multigene panel testing between March 18, 2016, and August 3, 2020, with outcomes reported between May and November 2020. The study setting included a commercial genetic testing laboratory and multicenter clinical practices. Patients with epilepsy, regardless of sociodemographic features, who received a pathogenic/likely pathogenic (P/LP) variant were included in the study. Case report forms were completed by all health care professionals. Exposures: Genetic test results. Main Outcomes and Measures: Clinical management changes after a genetic diagnosis (ie, 1 P/LP variant in autosomal dominant and X-linked diseases; 2 P/LP variants in autosomal recessive diseases) and subsequent patient outcomes as reported by health care professionals on case report forms. Results: Among 418 patients, median (IQR) age at the time of testing was 4 (1-10) years, with an age range of 0 to 52 years, and 53.8% (n = 225) were female individuals. The mean (SD) time from a genetic test order to case report form completion was 595 (368) days (range, 27-1673 days). A genetic diagnosis was associated with changes in clinical management for 208 patients (49.8%) and usually (81.7% of the time) within 3 months of receiving the result. The most common clinical management changes were the addition of a new medication (78 [21.7%]), the initiation of medication (51 [14.2%]), the referral of a patient to a specialist (48 [13.4%]), vigilance for subclinical or extraneurological disease features (46 [12.8%]), and the cessation of a medication (42 [11.7%]). Among 167 patients with follow-up clinical information available (mean [SD] time, 584 [365] days), 125 (74.9%) reported positive outcomes, 108 (64.7%) reported reduction or elimination of seizures, 37 (22.2%) had decreases in the severity of other clinical signs, and 11 (6.6%) had reduced medication adverse effects. A few patients reported worsening of outcomes, including a decline in their condition (20 [12.0%]), increased seizure frequency (6 [3.6%]), and adverse medication effects (3 [1.8%]). No clinical management changes were reported for 178 patients (42.6%). Conclusions and Relevance: Results of this cross-sectional study suggest that genetic testing of individuals with epilepsy may be materially associated with clinical decision-making and improved patient outcomes.

Preliminary radiology resident interpretations versus final attending radiologist interpretations and the impact on patient care in a community hospital.

OBJECTIVE: At academic institutions, overnight emergency radiology examinations are interpreted by the on-call radiology resident and are reviewed by an attending radiologist in the morning. The objective of our study was to determine the rate of discrepancies between the two interpretations and the possible effect, if any, on patient care. MATERIALS AND METHODS: The preliminary reports for 11,908 emergency diagnostic imaging examinations interpreted after hours by residents over a 3-year period (January 2002-January 2005) were reviewed retrospectively for any discrepancy with the attending radiologist's final interpretation. A discrepancy was noted if verbal notification of the ordering physician was required. The medical charts of the cases for which there was a major discrepancy between the two interpretations were reviewed. The discrepancies were categorized as to the effect on patient morbidity. The resident discrepancy rates were also compared with RADPEER data from our institution. RESULTS: The overall major discrepancy rate was 2.6%. This rate is comparable to RADPEER data, which found a misinterpretation rate of 2.1%. The technique most commonly involved in cases with discrepant interpretations was contrast-enhanced CT of the abdomen and pelvis, with the most common diagnosis related to acute appendicitis (total of 21 cases). The rate of discrepancy was highest for residents who were in their third year of training. The indications for these examinations varied; however, the effect on patient management was no significant effect in 92.8%, some negative effect in 6.9%, and significant negative effect in 0.3%. CONCLUSION: The results of this investigation highlight the minimal discrepancy rate that occurs with overnight resident coverage. Thus, there is no detrimental effect on the quality of patient care from relying on preliminary interpretations made by radiology residents.

Status Epilepticus.

Although the majority of seizures are brief and cause no long-term consequences, a subset is sufficiently prolonged that long-term consequences can result. These very prolonged seizures are termed "status epilepticus" (SE) and are considered a neurological emergency. The clinical presentation of SE can be diverse. SE can occur at any age but most commonly occurs in the very young and the very old. There are numerous studies on SE in animals in which the pathophysiology, medication responses, and pathology can be rigorously studied in a controlled fashion. Human data are consistent with the animal data. In particular, febrile status epilepticus (FSE), a form of SE common in young children, is associated with injury to the hippocampus and subsequent temporal lobe epilepsy (TLE) in both animals and humans.

Epilepsy After Febrile Seizures: Twins Suggest Genetic Influence.

BACKGROUND: A history of complex febrile seizures can increase the risk of epilepsy, but the role of genetic factors is unclear. This analysis evaluated the relationship between febrile seizures and epilepsy. METHODS: Information on the history of seizures was obtained by a questionnaire from twin pairs in the Mid-Atlantic, Danish, and Norwegian Twin Registries. The information was verified using medical records and detailed clinical and family interviews. The initial study evaluated the genetic epidemiology of febrile seizures in this population. Further information was analyzed and used to evaluate genetic associations of different febrile seizure subtypes. RESULTS: Histories of febrile seizures were validated in 1051 twins in 900 pairs. The febrile seizure type was classified as simple, complex, or febrile status epilepticus. There were 61% simple, 12% complex, and 7% febrile status epilepticus. There were 78 twins who developed epilepsy. The highest rate of epilepsy (22.2%) occurred in the febrile status epilepticus group. Concordance was highest in simple group. CONCLUSION: A twin with febrile status epilepticus is at the highest risk of developing epilepsy, but simple febrile seizures gave the highest risk for the unaffected twin to develop seizures or other neurological issues. These results are consistent with previous findings. There is a subgroup of febrile seizures that can be associated with long-term consequences. This subgroup can be associated with a significant financial and emotional burden. It is currently not possible to accurately identify which children will develop recurrent febrile seizures, epilepsy, or neuropsychological comorbidities.

Is there a need for further trials for the treatment of prolonged seizures?

Prolonged seizures are associated with morbidity and mortality of varying degrees. It is important to recognize seizures early, and treat them appropriately. This leads to the best clinical outcome. There has been an emphasis on prompt treatment, but there exists a variety of poorly executed protocols. This review addresses the question of whether additional clinical trials are necessary, not only to answer for what purpose, but also, clearly, to examine the impact additional studies may have. Overall, the acute treatment of epilepsy emergencies in children has markedly improved with availability of out-of-hospital therapies, but additional studies to determine the most efficacious, maximally safe, and best tolerated treatments are needed.