Abstract
van Dalen T, Kirkham JF, Chari A, D’Arco F, Moeller F, Eltze C, Cross JH, Tisdall MM, Thornton RC. Ann Neurol. 2024;95(6):1138–1148. DOI: 10.1002/ana.26922 Objective: The objective was to analyze seizure semiology in pediatric frontal lobe epilepsy patients, considering age, to localize the seizure onset zone for surgical resection in focal epilepsy. Methods: Fifty patients were identified retrospectively, who achieved seizure freedom after frontal lobe resective surgery at Great Ormond Street Hospital. Video-electroencephalography recordings of preoperative ictal seizure semiology were analyzed, stratifying the data based on resection region (mesial or lateral frontal lobe) and age at surgery (≤4 vs. >4). Results: Pediatric frontal lobe epilepsy is characterized by frequent, short, complex seizures, similar to adult cohorts. Children with mesial onset had higher occurrence of head deviation (either direction: 55.6% vs. 17.4%; p = 0.02) and contralateral head deviation (22.2% vs. 0.0%; p = 0.03), ictal body-turning (55.6% vs. 13.0%; p = 0.006; ipsilateral: 55.6% vs. 4.3%; p = 0.0003), and complex motor signs (88.9% vs. 56.5%; p = 0.037). Both age groups (≤4 and >4 years) showed hyperkinetic features (21.1% vs. 32.1%), contrary to previous reports. The very young group showed more myoclonic (36.8% vs. 3.6%; p = 0.005) and hypomotor features (31.6% vs. 0.0%; p = 0.003), and fewer behavioral features (36.8% vs. 71.4%; p = 0.03) and reduced responsiveness (31.6% vs. 78.6%; p = 0.002). Interpretation: This study presents the most extensive semiological analysis of children with confirmed frontal lobe epilepsy. It identifies semiological features that aid in differentiating between mesial and lateral onset. Despite age-dependent differences, typical frontal lobe features, including hyperkinetic seizures, are observed even in very young children. A better understanding of pediatric seizure semiology may enhance the accuracy of onset identification, and enable earlier presurgical evaluation, improving postsurgical outcomes.
Commentary
It is a commonly accepted fact that patients with medically intractable epilepsy; irrespective of their age; must be urgently assessed at a specialized epilepsy center to investigate if they are candidates for epilepsy surgery. This urgency is more significant in the pediatric drug-resistant epilepsy (pDRE) population where developmental outcomes are at stake. In the last several years, there has been a notable increase in the annual number of patients referred for epilepsy surgery; however pDRE patients that present to tertiary/level IV centers have gotten more complex; more patients have non-lessional, extratemporal epilepsy. 1
Knowledge of Seizure Semiology is Critical
Attention to seizure semiology is critical in the initial evaluation for epilepsy surgery. The ability to generate a hypothesis for focal seizure localization extrapolated from semiology is a core curriculum objective of the International League Against Epilepsy (ILAE). 2 Elwan et al 3 have shown that the lateralizing and localizing value of ictal semiology is equivalent to that of electroencephalogram (EEG) and magnetic resonance imaging (MRI) in adult epilepsy. In this study; although interrater agreement based on seizure semiology was moderate to substantial (kappa: 0.55–0.8) for seizure lateralization of most ictal semiologies, the interrater agreement for lobar localization especially for frontal lobe epilepsy (FLE) was moderate (kappa: 0.4). 3 Further sublobar localization wasn’t even possible due to the small numbers in the study. These findings are not surprising because frontal lobe seizures are typically nocturnal, short-lasting, and spread quickly, making an accurate assessment of the electroclinical evolution and hence localization; difficult. Since most centers are now exploring patients with Stereo EEG (SEEG), a deeper knowledge of semiology that points to sublobar localizations is essential to plan an optimal phase II (invasive) EEG exploration.
How is Semiology Best Studied?
Ictal video EEG has been critical in expanding upon the expected clinical spectrum of seizures in pDRE. 4 Studies that included patients under six years of age identified elementary motor seizures such as epileptic spasms, myoclonic seizures, tonic seizures, and hypomotor events to be the common presentations—irrespective of focal or generalized seizure onset and irrespective of further lobar localization. 4 Some authors feel that semiology confirmed by SEEG allows the best assessment of a dynamic electrical discharge in terms of its spatiotemporal and clinical evolution. 5 This is especially true of complex semiologies in FLE which in turn reflect activation of anatomically distant interconnected networks.
How is Semiology Validated?
Some researchers correlate seizure semiologies with anatomical areas of surgical resection, preoperative MRI lesion locations, and post-operative seizure freedom rates. They infer that the semiology must reflect the correct seizure onset zone (SOZ) if the area covered by anatomical resection leads to seizure freedom postoperatively. However, semiology alone without additional supportive data might not be sufficient to localize SOZ. In their study of adult FLE, Khoo et al 6 found that semiology alone; without added information from preoperative MRI or invasive EEG predicted sublobar localization correctly in only 50% of patients.
Bonini and McGonigal 7 performed a systematic analysis of adult FLE using detailed semiologic classification, correlation with SEEG using the epileptogenicity index, principal component analysis, and cluster analysis. They correlated sublobar semiologies that point to rostrocaudal, ventromedial, and dorso lateral regions of the frontal lobe. This was largely possible due to the deliberate and methodical characterization of rich semiological manifestations of epilepsy of a mature brain that can express negative or positive emotions, integrated or nonintegrated stereotypies for example. In pDRE over the age of 10 years, one could expect a similarly rich semiological expression of seizures—correlated with detailed SEEG exploration. Taussig et al 8 studied 26 pDRE under the age of three years with subdural electrodes (n = 20) or SEEG (n = 6) and highlighted the limitations of SEEG implantation in children younger than 24 months due to the limitation in anchoring SEEG bolts in a thinner skull.
Is sublobar localization possible in pDRE of frontal lobe origin? Bonini et al 5 introduced new terms for description of seizure semiology (gestural motor behaviors; integrated vs. nonintegrated motor stereotypies) while describing and thereafter classifying sublobar localization of FLE. This was before the ILAE published new terminology for seizure and epilepsy classification in 2017.
Detailed sublobar semiological data in pDRE didn’t exist till 2024. In the article that is the subject of this commentary; Thijs van Dalen et al 9 retrospectively identified children with intractable FLE that had undergone surgery and remained seizure-free for at least one year thereafter. Videos of habitual seizures were categorized by 2 independent observers based on the ILAE semiology classification. 10 Additional semiology characteristics of hyperkinetic behavior; integrated and nonintegrated behavioral features were identified and scored per the Bonini paper. Observers were blinded to the precise localization of resected cortical areas on post-operative MRI. Semiological features that occurred during the bilateral convulsive phase of the seizure were not included as these were unlikely to indicate sublobar localization at seizure onset. The mean age at the first video EEG of this cohort of 50 children was about 7 years (84.6 months) (range in months 2.0–195 ± 53.2). Authors carefully itemized and defined reduced responsiveness, postictal confusion, elementary motor signs, complex motor semiology, facial change, emotional expression, presence or absence of aura, and autonomic features. Results were categorized by age (≤4 years vs. >4 years of age) and by MRI localization of resection into the main groups of mesial FLE, lateral FLE, extensive resection (mesial + lateral plus frontal lobe), and lesionectomy.
Expected Findings
Seizures were short in all patients; more frequent and of a shorter duration in the younger group. Elementary motor signs such as myoclonic seizures, were more common at presentation in children <4 years old. Hypomotor behavior was more common in younger patients and was more likely localized to the lateral frontal region. Behavioral changes with integrated or nonintegrated motor components were enriched in patients older than 4 years of age.
New Findings
Hyperkinetic movements were noted in both age groups but also documented in a 10-month-old. Ipsilateral body-turning and contralateral head-turning were more commonly seen in mesial FLE. Additionally, ictal emotional features were commonly seen in mesial compared to lateral frontal lobe seizures.
Future Direction
One can hope to have more SEEG correlation of semiologies in the very young with advances in surgical techniques. Correlation and comparison of semiologies in noninvasively monitored pDRE that are/ are not seizure-free after FLE resection will allow identification of semiologies that could be false localizers. This and future studies will allow earlier and perhaps better-tailored surgery in pDRE.
