Comments on hippocampal sclerosis in children younger than 2 years

I read with interest the original article by Kadom and colleagues [1] titled “Hippocampal Sclerosis in Children Younger than 2 years.” I congratulate the authors for highlighting these cases of hippocampal sclerosis (HS), or mesial temporal sclerosis (MTS), in an unexpectedly young patient group. While one cannot argue with the importance of MTS as a cause of refractory temporal lobe epilepsy in children and adults, I challenge the author’s statement that “an infectious trigger was present in all five patients.” In Table 1, the authors indicate that patient 1 had infection as the etiology of MTS and that patients 3–5 had complex febrile seizures. Unfortunately, there is no serological or CSF laboratory evidence or histopathological evidence to support the assertion that infection was the trigger leading to MTS. While the authors have increased our awareness of MTS in a younger-than-expected age group, their study raises several broader questions. An ongoing contention in epileptology is the proposed relationship between febrile seizures and the development of MTS. The prevalence of febrile seizures among developed countries is about 4% and it is thought to be even higher in poorer countries [2]. Some authors suggest that prolonged febrile seizures lead to direct injury of the hippocampus and adjacent structures, and ultimately to MTS [3]. There is strong retrospective evidence supporting this belief [4, 5]. There is increasing evidence from animal and human data that prolonged febrile seizures are associated with physiological and anatomical changes within the hippocampus that may lead to hippocampal injury, subsequent mesial temporal sclerosis and temporal lobe epilepsy in some cases [6]. More recent MR imaging studies suggest that up to 30–40% of children with prolonged febrile seizures will have acute changes within the hippocampus demonstrated on MRI [7, 8]. Additionally, the presence and the severity of temporal lobe MRI signal changes are predictive of mesial temporal sclerosis preceding the development of clinical seizures. Provenzale et al. [9] in their MRI study of 11 children (mean age of 25 months) who suffered from febrile status epilepticus reported a strong positive correlation between the conspicuity of hippocampal T2 hyperintensity and subsequent development of MTS. On the other side of the argument of MTS genesis are population-based prospective studies that have failed to find an association between febrile seizures and MTS [10–12]. In addition to the role that prolonged or complex febrile seizures may play in the genesis of hippocampal injury, clinical pathological studies have demonstrated other potential causes of mesial temporal sclerosis [7]. Dual pathology (gray matter heterotopia or focal cortical dysplasia + MTS) or “double hit” abnormality may be found in 15% of pediatric patients with mesial temporal sclerosis [7]. Genetics may play a role in hippocampal malformation and function, and ultimately in the development of clinical seizures of hippocampal origin. Familial cases of mesial temporal sclerosis have been reported [13]. Syndromespecific genes for febrile seizures (channelopathies) have been identified, as have mutations in the SOX2 gene that have been linked to mesial temporal malformation and clinical temporal lobe seizures [13, 14]. Human herpes virus G. L. Hedlund (*) Department of Radiology, Neuroradiology Division, Primary Children’s Medical Center, 100 N. Mario Capecchi Drive, Salt Lake City, UT 84113, USA e-mail: Gary.Hedlund@imail.org