Have We Solved the Chicken-and-Egg Conundrum? Hippocampal Sclerosis and Temporal Lobe Epilepsy Following Febrile Status Epilepticus: Results of the 10-Year Follow-up FEBSTAT Study

Abstract

Hippocampal Sclerosis and Temporal Lobe Epilepsy Following Febrile Status Epilepticus: The FEBSTAT Study

Lewis DV, Voyvodic J, Shinnar S, Chan S, Bello JA, MoshéSL, Nordli DR Jr, Frank LM, Pellock JM, Hesdorffer DC, Xu Y, Shinnar RC, Seinfeld S, Epstein LG, Masur D, Gallentine W, Weiss E, Deng X, Sun S, FEBSTAT Study Team. Epilepsia. 2024;65(6):1568–1580. doi: 10.1111/epi.17979.

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 2 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; 6 developed mesial temporal lobe epilepsy and, of the 6, 2 had definite, 2 had equivocal, and 2 had no hippocampal sclerosis. Only 1 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.

Commentary

Febrile seizures (FS) are estimated to occur in 2% to 5% of children under 5 years of age, with a peak incidence between 12 and 18 months. ¹ Most FS are considered simple (simple FS [SFS]), although those with focal onset, prolonged duration, or that occur more than once within the same febrile illness are considered complex (complex FS [CFS]). ¹ Febrile status epileptics, defined as seizures lasting 30 min or longer, represent an extreme form of CFS. It is estimated that there are 25 000 to 35 000 cases of febrile status epilepticus (FSE) annually in the US. ¹ While SFS are considered benign, FSE can carry a higher risk for the later development of epilepsy, especially temporal lobe epilepsy (TLE). ²

A high incidence of antecedent FS, particularly prolonged FS, has been observed in surgical series of patients with TLE. ³ The incidence is most significant in a pure mesial TLE (mTLE) population with hippocampal sclerosis (HS).^2,3 This led to the hypothesis that FSE injures the hippocampus, leading to HS and mTLE. However, data on the causative role of FSE in the later development of HS and TLE are conflicting.^2,4 To address this question, the FEBSTAT (Consequences of Prolonged FS in Childhood) study, which began in 2003 and ran through 2017, was conducted.

The FEBSTAT study prospectively recruited 222 children, aged 1 month through 5 years, with FSE as they presented in the emergency department, and brain magnetic resonance imagings (MRIs) were performed within days of FSE, and follow-up MRIs, electroencephalogram (EEG), and clinical visits at 1, 5, and 10 years after that. ⁵ Controls included 109 normal MRIs of 72 children <5 years old with SFS and no epilepsy, and MRI of normal children (n = 344) from 4.5 to 18 years of age was obtained from the National Institutes of Health MRI Study of Normal Brain Development for 416 controls. ⁵ When epilepsy developed, defined as an unprovoked seizure at least 24 h apart, repeat MRI and EEG were obtained, and seizure type and epilepsy syndrome were determined. The first-year results described in nearly 20 publications have generated significant findings, including hippocampal T2 hyperintensity (10% incidence) within days of FSE, representing acute injury often evolved to a radiological appearance of HS (70%) after 1 year. ⁵

Lewis et al ⁶ present the eagerly awaited 5- and 10-year follow-up results of the FEBSTAT study in the highlighted manuscript. One key finding of the study was the potential of FSE to cause acute hippocampal injury followed by HS. Twenty-two children (10%) had acute unilateral hippocampal T2 signal hyperintensity (T2-Hyper group) associated with an increased volume of MRIs. During the 10-year follow-up, 10 out of 14 (70%) subjects developed definite HS; 2 developed equivocal HS in the affected hippocampi. In contrast, none of the children in the T2-Normal group on the initial scan developed HS or clear-cut hippocampal abnormality during the 10-year follow-up.

Another key finding of the present study is that hippocampal T2 hyperintensity after FSE can be a biomarker of epilepsy, often mTLE. Forty-four subjects (<20%) developed epilepsy, 11 with TLE. The 10-year cumulative incidence of epilepsy of the study subjects, regardless of MRI findings, was 30%. While the 10-year cumulative incidence of epilepsy in the T2-Hyper group was over 70%, the incidence for the T2-Normal group was 23%. Regardless of MRI findings, the 10-year cumulative incidence of mTLE was 4%. Importantly, while the incidence of mTLE was close to 40% for the T2-Hyper group, mTLE was not seen in the T2-Normal group. Six subjects had mTLE, 5 were in the T2-Hyper group, and 1 developed mTLE without initial hyperintensity, and that subject had hippocampal malrotation.

The third key finding is that asymmetric hippocampal growth after FSE depended on the diagnostic group but not sex. ⁶ While the T2-Hyper group had a high asymmetric index acutely, which increased over the 10-year follow-up, there was no progressive asymmetry in the T2-Normal group. Besides, volumetry showed no evidence of increasing asymmetry during the follow-up of normal hippocampi. However, it did indicate preexisting and persistent mild hippocampal volume (HV) reduction in males versus normal HV growth in females.

What did we learn? First, the good news. The vast majority of children with FSE did not have MRI evidence of acute hippocampal damage, nor did they develop any clear-cut HS and TLE later on.

Second, although FSE has been previously considered relatively benign, the highlighted study demonstrates a potential causal relationship between FSE-induced HS and subsequent TLE development. Given the known risk of delay in treatment and the lack of a standard treatment protocol for FSE, ⁷ these findings suggest that more rapid and standardized management could have prevented FSE and its sequelae.

Third, the study highlights the prognostic value of MRI in FSE, underscoring the need to reconsider obtaining routine MRIs in children with FSE. ⁶ Visual assessment of hippocampal T2 signal changes on postictal MRI with days of FSE could be used to guide early monitoring and intervention. However, given the cost of care and logistical challenges, including the need for sedation required for brain MRI in young children, the decision should be individualized.

Finally, the study's documentation of the natural history of FSE suggests the potential for MRI hippocampal T2 signal as a suitable biomarker to identify high-risk groups. Guided by post-FSE MRI, it is possible to intervene to prevent the severe but rare instances in which FS lead to refractory epilepsy. Also, post-FSE MRI can followed as a biomarker in future interventional clinical trials that aim to identify antiepileptogenic drugs that could be administered for a short period in high-risk children to prevent subsequent epilepsy.

The FEBSTAT study investigators are to be commended for their rigorous methodology and for working their way toward determining the acute and long-term consequences of FSE. However, the study has yet to settle the chicken-and-egg problem. Not all children with FSE in whom epilepsy develops have TLE (11 out of 44). Also, most children with FSE did not develop HS or TLE later, suggesting additional contributing factors. Indeed, genetic predispositions ⁸ and specific viral triggers, including human herpesvirus-6, ⁹ could explain susceptibility to FSE and seizure-induced hippocampal injury. FSE might be a marker of individuals destined to develop TLE in these scenarios.

Besides, follow-up MRIs were unavailable for most study subjects, with only 14 out of 22 subjects of the T2-Hyper group returning for MRIs at both 5- and 10-year follow-ups. This may have introduced potential bias. The latency between the occurrence of FSE and HS and TLE onset can be longer than 10 years (up to 40%), ¹⁰ which could have led to underestimating the later development of HS and mTLE. Conversely, the study's inclusion of children with previous MRI abnormalities may be biased toward overestimation. Lastly, the study employed a 1.5 Tesla MRI scanner, which may have missed subtle preexisting abnormalities. Future studies using ultrahigh field MRI are needed to determine whether preexisting MRI abnormalities are an independent risk factor for hippocampal injury or if they predispose to FSE, which then causes HS and TLE.

Despite its limitations, the article reviewed in this commentary provides compelling evidence linking FSE, HS, and TLE, especially mTLE. Early identification and treatment (when they become available) of at-risk children through post-FSE MRI could potentially prevent the development of epilepsy and its associated comorbidities. However, clinical and preclinical studies are required to elucidate the underlying mechanism(s) through which FSE leads to hippocampal injury and subsequent epileptogenesis. We also need additional biomarkers that distinguish children destined to develop TLE. These efforts could facilitate the development of targeted therapies to prevent or mitigate the long-term consequences of FSE beyond solving the chicken-and-egg conundrum.