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]. Syndrome-specific 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 6 (HHV6), the ubiquitous virus causing the common childhood illness roseola infantum, has been implicated in cases of limbic encephalitis and subsequent mesial temporal sclerosis and partial complex seizures [15]. Mesial temporal sclerosis has developed following methotrexate-induced leukoencephalopathy in the treatment of childhood leukemia [16].

Patients with medically refractory epilepsy due to mesial temporal sclerosis have one reliable method for cure and that is surgical resection of the hippocampus and anterior temporal lobe. Thus, accurate and timely imaging diagnosis of MTS reduces morbidity by accelerating focused treatment [17].

MRI is the imaging examination of choice for the early accurate diagnosis of MTS [7, 8, 18]. Although a wide range of MRI techniques is available for diagnosing MTS such as hippocampal MR volumetrics, MR T2 relaxometry and MR spectroscopy, simple visual inspection is the cornerstone of making this diagnosis in active clinical settings [19, 20]. When attention is given to obtaining coronal inversion recovery or fast spin-echo (FSE) T2 or FLAIR imaging perpendicular to the long axis of the hippocampal body, there is optimal opportunity to inspect the hippocampus [21]. The MR imaging hallmark of MTS is the atrophic hippocampus. The presence of T2 hyperintensity is less predictable and not necessary for the diagnosis. Another primary finding of MTS is obscuration of internal hippocampal architecture. Awareness of secondary features of MTS improves the sensitivity and positive predictive value of MRI. These secondary features include temporal lobe volume loss including loss of collateral white matter, ipsilateral mamillary body and fornix atrophy, and widening of the choroidal fissure and temporal horn. Loss of the amygdala pes digitations and increased signal within the anterior temporal white matter may be additional findings [22].

Nuclear medicine techniques valuable in the investigation of MTS include single photon emission tomography (SPECT), ictal SPECT and positron emission tomography (PET) [23].

More recently, many centers active in epilepsy diagnosis and treatment have integrated magnetoencephalography (MEG) and functional MRI (fMRI) into the preoperative evaluation of patients with refractory temporal lobe epilepsy [24–26] (Fig. 1).

Fig. 1
figure 1

Left mesial temporal sclerosis. Coronal inversion recovery T2-weighted image at 3.0 tesla through the body of the hippocampi shows a smaller left hippocampus with preserved architecture. Note the symmetrical hippocampal T2 signal. Histopathological evaluation after anterior left temporal lobectomy showed hippocampal sclerosis (5 mm, gap 1 mm, TE 42 msec, TR 5,300 msec, TI 140 msec, ET 8, BW 31.25, 512 × 416 matrix + parallel imaging)

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