We studied 26 intractable TLE patients with normal MRI. Investigations included stereotaxically implanted depth electrode EEG (SEEG) with quantitative and qualitative MRI. All of these 26 patients demonstrated their epileptic foci in the temporal lobe by SEEG and normal hippocampal volumes by quantitative measurement. All of these patients showed their habitual seizures during SEEG recording. We included the seizures only when the first electrographic ictal onset preceded the initial behavioral changes. We excluded if 1) electrographic seizures occurred along without clinical manifestation, 2) simultaneous temporal and extratemporal onset (multilobal onset) or definite extratemporal lobe onset occurred, 3) previous surgical treatment was performed, 4) significant FDG-PET hypometabolism or SPECT hyper- or hypoperfusion in the extratemporal area or other evidence of extratemporal onset was present, 5) either HA or structural lesions were noted on MRI. Of the 142 patients who had SEEG since 1995 when high resolution MRI became available in our institute, 116 patients were excluded by these criteria. The reasons for exclusions were as follows: 68 had extratemporal lobe or multilobal onset, 17 had HA on hippocampal volumetry, 10 had structural lesions on MRI, 5 had undergone a previous operation, 1 had electrographic seizures along, and 15 did not have available medical records.

Scalp EEG telemetry was recorded in all patients using the international 10-20 systems. Interictal epileptiform discharges were divided into anterior or diffuse temporal groups based on the topography of discharges. The anterior temporal group was defined as having interictal epileptiform discharges confined to the Fp1/2, F7/8, and T3/4, T1/2 electrodes. The diffuse temporal group was defined as having interictal epileptiform discharges also involving the T5/6 with a wider area than that of the anterior temporal group. The ictal scalp EEG was divided into localized, hemispheric or non-lateralized groups by ictal scalp EEG onset patterns. The localized onset group was defined as the ictal onset being exclusively confined to one temporal lobe. The hemispheric onset group was defined as a diffuse onset between multiple lobes but clearly lateralized to one hemisphere. The non-lateralized onset group was defined as the onset being either bilaterally simultaneous or not clearly lateralized to one hemisphere. When non-invasive studies (i.e., clinical history and seizure semiology, scalp interictal or ictal EEG, MRI, FDG-PET, MRSI, SPECT, and neuropsychological results) were inconclusive for localizing the epileptic focus, SEEG was performed with orthogonally implanted depth electrodes. The number and location of the depth electrodes were individualized by the information from the non-invasive studies. The method of insertion and strategy of SEEG was previously described in detail.18 Briefly, three depth electrode strands were introduced horizontally through the second temporal gyrus. The two deepest contacts of the anterior, middle, and posterior depth electrode strands were located in the amygdalae, anterior hippocampus, and posterior portions of the hippocampus and parahippocampal gyrus, respectively. We divided SEEG into focal and regional groups. The focal onset group was defined as the ictal onset being exclusively confined to mesial or lateral temporal structures. The seizures of the focal onset group sometimes showed delayed spread to either contralateral or other temporal structures. The regional onset group was defined as having ictal onset that occurred simultaneously in mesial and lateral temporal structures, or where ictal onset was either in mesial or lateral temporal structures but with very early spread to other temporal structures. Early spread was defined as spreading to the other ipsilateral or contralateral mesial or lateral temporal structures within a quarter of the seizure. The seizures of bilaterally independent temporal onset were counted as either focal or regional onset groups regardless of the lateralization. In the case of multiple electrographic and spreading patterns in one patient, we counted the seizures that were socially disabling and habitual.

One of the authors (S.E.K.) retrospectively reviewed the medical records of the patients in the study. We were able to successfully document all of the clinical data from the medical records. The clinical data included age of onset, duration, initial precipitating insult (IPI), family history of epilepsy, history of status epilepticus, estimated seizure frequency, generalization fraction, surgical outcome, and surgical pathology. The following definitions were used. Duration was defined as the time from onset to SEEG; IPI as any significant events preceding onset of epilepsy, including neurological or medical illness; and generalization fraction as the fraction of secondarily generalized tonic-clonic seizures (SGTC) to total estimated seizure frequency. Surgical outcome was classified using Engel's classification.19

MRI scans were acquired on a 1.5-T Gyroscan (Philips Medical Systems, Eindhoven, The Netherlands). Visual analysis was performed using spin-echo sequences [field of view (FOV) 250 mm, 256×256 matrix] with sagittal T1-weighted [repetition time (TR) 550 ms, echo time (TE) 19 ms], transverse proton density (TR 2,000 ms, TE 20 ms), T2-weighted (TR 2,100 ms, TE 20, 78 ms), as well as coronal T1-weighted images. The MRI acquisitions for volumetric assessment of the hippocampus consisted of 1- or 3-mm contiguous slices perpendicular to the plane of the Sylvian fissure, obtained with either a three-dimensional gradient fast-field echo sequence or with inversion recovery using spin-echo sequences (FOV 250 mm, 256×256 matrix, TR 18 ms, TE 10 ms, 30° angle, 160 contiguous slices, 1 mm thick). The images were transferred to a computer workstation. Volumetric measurements were performed using an interactive software program. The regions of interest were outlined using manual contouring. Anatomic guidelines for outlining the amygdala and the hippocampus followed a previously reported method.20

We randomly selected 25 patients who had TLE with unilateral HA on MRI and confirmed hippocampal neuronal loss and gliosis on surgical pathology as controls. All of these 25 patients had seizures originating from the temporal lobe ipsilateral to the atrophied hippocampus on MRI. Four patients with unilateral HA underwent SEEG because of either independent bitemporal onset on scalp EEG or contralateral temporal onset to HA on scalp EEG. These four patients showed habitual seizures during SEEG recording.

We analyzed the clinical differences between the two groups (TLE with normal MRI or TLE with HA) using Fisher's exact test or χ² test (categorical variables) and Student's t-test or Mann-Whitney test (numerical data) using MedCalc®. For all calculations, the significance level was taken as 0.05.

The clinical characteristics of TLE with normal MRI compared with TLE with unilateral HA are summarized in Table 1. There were no differences between the two groups with regard to age at evaluation, sex ratio, side of operation, and median postoperative follow up.

The duration of active epilepsy in TLE with normal MRI was significantly shorter than that of TLE with unilateral HA (16±10 yrs vs 25.9±7.8 yrs, p<0.001) but there was a tendency toward being older at onset in TLE with normal MRI. Although the frequency of IPI as part of the etiology of epilepsy did not differ between the two groups, febrile convulsions were significantly less frequent in TLE with normal MRI than in TLE with unilateral HA (4% vs 40%, p<0.01). Of the 11 patients with TLE with normal MRI who had an IPI, 64% (7/11) had seizures related to encephalitis, hypoglycemia or accidental drug intoxication as the IPI. Two patients had a history of hypoxia at birth, one had a head trauma, and only one had a febrile convulsion. The frequencies of SGTC (225±235, median 160 vs 68±48, median 50, p<0.05) and generalization fraction (14.9±13.5, median 11.4 vs 3.9×2.4, median 3.3, p<0.001) were significantly higher in TLE with normal MRI than in TLE with unilateral HA, but the frequency of complex partial seizure (CPS) did not differ between the two groups.

The family history of epilepsy and the history of status epilepticus did not differ between the two groups.

Seventeen patients with TLE with normal MRI underwent surgery. Postoperative histopathology data of the temporal cortex were available for 13 of these 17 patients: 8 patients had neuronal loss and gliosis, 1 had focal cortical dysplasia, and only 4 patients had normal histopathology. HS was pathologically diagnosed in 2 of 4 patients available for histopathology. The postoperative outcome was available for 14 of 17 patients (range 8 months to 60 months, median 17 months). The operated side did not different between the two groups, but cortico-amygdalo-hippocampectomy was more frequently performed in TLE with normal MRI than in TLE with HA group (76% vs 44%, p<0.05). Also, a good surgical outcome (Engel's classification I) was significantly less common in TLE with normal MRI than in TLE with HA group (50% vs 88%, p<0.01)

Table 2 compares the electrophysiological characteristics between TLE with normal MRI and TLE with unilateral HA. Compared with TLE with unilateral HA, the patient with normal MRI frequently showed diffuse temporal (50% vs 20%, p<0.05) or independent bitemporal (62% vs 16%, p<0.001) discharges on interictal EEG. On ictal scalp EEG, 61% (16/26) of patients with TLE with normal MRI showed independent bitemporal onset. A total of 155 seizures in the TLE with normal MRI group and 120 seizures in the TLE with unilateral HA group were counted and analyzed. The ictal seizure patterns on scalp EEG of patients with TLE with normal MRI were less localized to one temporal lobe than those in patients with TLE with unilateral HA (28% vs 65%, p<0.001). On SEEG, 61% (16/26) of patients with TLE with normal MRI showed ictal onset either in mesial or lateral temporal structures, but with very early spread to other temporal structures (12/16) or simultaneously in both mesial and lateral temporal structures (4/16). Of the other 10 patients, 2 patients had ictal onset confined to the lateral temporal neocortex, and 4 patients had ictal onset confined to either the amygdala or the hippocampus with occasional delayed spread to the contralateral or other temporal structures. The other four patients had independent bitemporal onset. A total of 266 seizures in patients with TLE with normal MRI and 25 seizures in patients with TLE with unilateral HA were counted and analyzed: 181 and 2 seizures were regional onset, respectively (68% vs 8%, p<0.001).