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1 Neuroradiology (1999) 41: 471±479 Ó Springer-Verlag 1999 DIAGNOSTIC NEURORADIOLOGY C. Oppenheim D. Dormont D. Hasboun B. Bazin S. Samson S. LehØricy M. Baulac C. Marsault Bilateral mesial temporal sclerosis: MRI with high-resolution fast spin-echo and fluid-attenuated inversion-recovery sequences Received: 19 June 1998 Accepted: 7 December 1998 C.Oppenheim ( ) ) D. Dormont D. Hasboun S.LehØricy C.Marsault Department of Neuroradiology, Bâtiment Babinski, Groupe Hospitalier PitiØ-Salp tri re, 47 Boulevard de L'Hôpital, Paris Cedex 13, France catherine.oppenheim@psl. ap-hop-paris.fr, Tel: / , Fax: D. Hasboun B.Bazin S. Samson M. Baulac Department of Neurology, Epilepsy Unit, Groupe Hospitalier PitiØ-Salp tri re, Paris VI University, Paris, France Abstract We report a retrospective analysis of MRI in 206 patients with intractable seizures and describe the findings in bilateral mesial temporal sclerosis (MTS) on fast spin-echo (FSE) and fast fluid-attenuated inversion-recovery (fflair) sequences. Criteria for MTS were atrophy, signal change and loss of the digitations of the head of the hippocampus. In patients with bilateral MRI signs of MTS, correlation with clinical electro, volumetric MRI data and neuropsychological tests, when available, was performed. Bilateral MTS was observed in seven patients. Bilateral loss of the digitations and signal change on fflair was seen in all seven. In three, bilateral atrophy was obvious. In two patients, mild bilateral atrophy was observed and in two others, the hippocampi were: asymmetrical, with obvious atrophy on only one side. Volumetric data confirmed bilateral symmetrical atrophy in five patients, and volumes were at the lowest of the normal range in the other two. The EEG showed temporal abnormalities in all patients, unilateral in five and bilateral in two. All patients had memory impairment and neuropsychological data confirmed visual and verbal memory deficits; two patients failed the Wada test on both sides. High-resolution T2-weighted FSE and fflair sequences allow diagnosis of bilateral MTS, which has important therapeutic and prognostic implications. Key words Sclerosis, hippocampal Magnetic resonance imaging Epilepsy Introduction The most common histological substrate of intractable complex partial seizures in adults is mesial temporal sclerosis (MTS) [1±4]. The probability of seizure-free outcomes following temporal lobectomy is significantly greater in patients with unilateral MTS on MRI [2, 5±9]. Unilateral MTS has been studied extensively and its MRI features are well established. According to most recent series, hippocampal atrophy and signal abnormalities on T2-weighted images can identify unilateral MTS with an accuracy approaching 90%. Pathological studies [1, 10±12], however, have shown that some histological evidence of MTS (neuronal loss and gliosis) can be observed bilaterally in up to 70±80% of patients. Despite this, bilateral MTS is seldom reported on MRI [7, 13±16]. Indeed, MRI diagnosis of bilateral MTS is difficult, because qualitative diagnosis of hippocampal atrophy relies on the comparison of the size of the hippocampal formations and until recently, most volumetric studies used ratio or volume differences between the left and right hippocampus. These techniques may thus fail to enable detection of symmetrical bilateral disease [13, 15, 17, 18]. T2-weighted high-resolution fast spin-echo (FSE) and fast fluid-attenuated inversion-recovery (fflair) sequences can improve qualitative MRI diagnosis of unilateral MTS [19±21]. From December 1996, all patients we studied with medically in-

2 472 tractable partial epilepsy had these sequences as part of their investigation. In some patients, bilateral hippocampal abnormalities were observed, suggesting bilateral MTS. Our purpose here is to describe these abnormalities and to correlate the findings with clinical, electroencephalographic (EEG), neuropsychological and metabolic tests when available, and hippocampal volumetric data, to validate these MRI criteria as legitimate markers of bilateral MTS. Material and methods We studied 206 patients with a clinical diagnosis of medically intractable simple or complex partial or secondarily generalised seizures. Of the patients, 71 had a presumed temporal lobe focus. All were studied with the same protocol using a quadrature head coil on a 1.5-T unit. We performed five sequences: T1-weighted sagittal spin-echo 600/11/1 (repetition time / echo time ms / number of excitation); T2-weighted axial spin-echo images 2800/30/90/1 through the entire brain; three-dimensional spoiled gradient-recalled acquisition in the steady state (SPGR), 1.5-mm-thick sections, matrix, cm field of view, 23/5/1, 35 flip angle, providing 124 contiguous slices in the coronal plane, reformatted parallel and perpendicular to the long axis of the hippocampus; high-resolution T2-weighted FSE 3020/126/4 of the temporal lobe with 3- or 4-mm interleaved slices, matrix, cm field of view, echo-train length 8, 32 khz bandwidth, superoinferior frequency-encoding gradient; and fflair 10002/148/2200 acquisition with 5-mm interleaved slices, matrix, cm field of view, 32-kHz bandwidth, superoinferior frequency-encoding gradient. For both FSE and fflair sequences, imaging plane was perpendicular to the long axis of the hippocampus as determined on the first acquisition. All 206 MRI studies were retrospectively reviewed by two trained neuroradiologists, blinded to clinical and pathological data, and discrepancies were solved by consensus. Section-by-section visual assessment of the signal and morphology of the hippocampus was performed on sections perpendicular to the long axis of the hippocampus. Signal intensity in the hippocampi was assessed by comparing it to that of grey matter in the temporal lobe neocortex. The diagnosis of MTS was based on signal changes of the hippocampal formations on T2-weighted FSE and/or fflair, and on two morphological criteria sought on FSE or SPGR acquisitions: atrophy and loss of the digitations of the head of the hippocampus [20] (Fig. 1). In patients with MRI criteria of bilateral MTS, MRI hippocampal volume measurements were performed on a workstation, using a method described previously [22]. The volume (V) of each hippocampus and the volume relative to the a b Fig. 1 a±c hippocampi in a control. Images perpendicular to the long axis of the hippocampus at the level of its head. a 3D T1-weighted SPGR image showing normal hippocampi with no asymmetry of size. Small humps or digitations (arrowheads), are normally visible on the superior part of both hippocampal heads. b T2-weighted FSE image showing no hippocampal atrophy and sharply visible digitations (arrowheads) which protude into the temporal horns and are thus well outlined by the high-signal cerebrospinal fluid. c fflair image showing no hippocampal signal change c

3 473 Table 1 Summary of findings. % indicates that the values are below normal values Patient Age/ sex Age at onset of seizures (years) Type EEG Neuropsychological and clinical data 1 19/F 2 PSSG L temporal Memory complaints, mentally retarded, no school attendance 2 18/F 9 CPS L temporal Memory complaints, chronic psychosis 3 27/F 6 CPS R temporal Memory complaints, verbal and visual memory impairment, mentally retarded 4 26/M 3 CPS L temporal Memory complaints, verbal and visual memory impairment, normal IQ 5 46/M 17 CPS Bitemporal L>R Memory complaints 6 41/M 30 CPS R temporal Memory complaints, verbal and visual memory impairment, normal IQ 7 53/F 48 CPS Bitemporal Memory complaints PSSG simple partial seizures secondarily generalised, CPS complex partial seizures Amylobarbitone PET memory loss Bilateral dysfunction Bilateral dysfunction R temporal hypometabolism L temporal hypometabolism Atrophy on visual analysis Bilateral, symmetrical Bilateral, symmetrical Bilateral R>L Bilateral, L>R Moderate, bilateral and symmetrical Moderate, bilateral and symmetrical Signal intensitmetry Asym- changes index a on FSE and fflair Bilateral 0% Bilateral 3.7% R only on FSE, bilateral on fflair 0% Bilateral 16% L>R Doubtful on FSE, bilateral on fflair Bilateral only in head on FSE, bilateral in head and body on fflair 0% 11.4 % Hippocampal volume (ml) b Left V 2.1 % 0.22 % % V 2.6 % 0.21 % % Hippocampal volume (ml) b Right V 2.1 % 0.22 % % V 2.7 % 0.22 % % V 3.3 V % % V, V, normal normal V 2.6 % 0.23 % % V3% 0.23 % % V 3.1 % % % V3% 0.23 % % V 3.1 V % % V normal, normal V, % Bilateral, Bilateral V 2.3 % V 2.5 % symmetrical a Asymmetry index considered significant when > 14.29% b V Absolute hippocampal volume, absolute hippocampal 0.2% % 2.2% % volume divided by the global cerebral volume cerebral volume () were calculated and compared to the normal values (mean ± 2 standard deviations) obtained with this method. An asymmetry index was also calculated and compared with normal values [22]. Side-to-side hippocampal symmetry was determined by subtracting the volume of left hippocampus from that of the right, divided by the larger of the two volumes. The following values were considered as the minimum normal volume: V: 3.3 cc; : 0.261% for the right hippocampus, V: 3.4 cc; : 0.269% for the left in men, and V: 3.1 cc; : 0.263% for the right, V: 3.1 cc; : 0.265% for the left. Asymmetry indices were considered significant when greater than 14.29% (mean + 2 standard deviations). All patients with MRI criteria of bilateral MTS had a clinical examination and ictal and interictal EEG; two also had video-eeg studies. As part of presurgical investigation, two patients had positron emission tomography (PET) with 18 F-fluorodeoxyglucose and a bilateral Wada test exploring memory. Formal neuropsychological testing was carried out in three patients. Results The data are summarised in Table 1. We diagnosed unilateral MTS in 47 patients and bilateral MTS in seven. In patients 1, 2 and 7 bilateral atrophy and loss of the digitations of the head of the hippocampus were clearly seen on T1- and FSE T2-weighted images. No asymmetry in size was detected. The diagnosis was confirmed by the presence of signal changes on T2-weighted FSE and fflair images; the changes were better shown on the latter (Fig.2). In patients 5 and 6, no digitations were seen at the head of the hippocampus and both hippocampi appeared slightly small, but symmetrical. The diagnosis of bilateral MTS was confirmed by the presence of clear bilateral signal intensity abnormalities on fflair images (Fig. 3). In patients 3 and 4, the digitations in the head of the hippocampus were invisible in both hippocampal for-

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5 475 mations, which were unequal in size (Fig. 4a, 3 b). Bilateral abnormalities consistent with MTS were confirmed on the fflair images, showing signal changes in both hippocampi (Fig. 4 c). In patients 3 and 5, the fflair sequence clearly showed bilateral signal change while FSE showed signal change in only one hippocampus. The volumes of both hippocampi were less than the normal minimum value in five patients (ten hippocampi) and within the normal range in two patients (four hippocampi). In one of these four (patient 6, left hippocampus), only the value corrected by the global cerebral volume suggested atrophy; the absolute value was within the normal range. Asymmetry indices were abnormal only in patient 4. Overall, there was discordance between the quantitative and qualitative analysis of three hippocampi (right and left in patient 3, left in patient 6) in which quantitative analysis failed to detect atrophy. EEG showed temporal abnormalities in all seven patients, clearly unilateral in five (left temporal lobe in three and right in two), and bilateral in two. In patients 3 and 4, with bilateral but asymmetrical atrophy on visual analysis, seizures began from the more atrophic hippocampal formation, with the more pronounced signal abnormalities. In patient 3, volumetric measurements failed to lateralise the epileptogenic focus, as no asymmetry was found. In the other three patients with unilateral temporal lobe seizures, abnormalities were symmetrical on MRI images, without lateralising value. PET performed in patients 3 and 4, showed unilateral hypometabolism, thought to have good lateralising value. The two patients with bitemporal epileptogenic foci also had symmetrical abnormalities on MRI. Mental retardation was observed in two cases, chronic psychosis in one. All patients had memory impairment and formal neuropsychological tests, performed in patients 3, 4 and 6, confirmed visual and verbal memory impairment. In patients 3 and 4, who had Wada test, memory impairment was observed when amylobarbitone was injected into in either the right or left internal carotid artery. W Fig. 2 a±f Patient 7: a 53-year-old woman with complex partial seizures and memory disturbance. The EEG showed bilateral temporal epileptogenic foci. Volumetric MRI showed marked bilateral atrophy. a 3D T1-weighted SPGR image through the head of the hippocampus showing bilateral, symmetrical atrophy. b T2- weighted FSE image showing bilateral atrophy, slightly increased signal and bilateral loss of the digitations of the head of the hippocampus. c fflair image showing obvious bilaterally increased signal intensity. d 3D T1-weighted SPGR image through the body of the hippocampus showing bilateral atrophy, more marked on the right. e T2-weighted FSE image showing bilateral atrophy and slightly increased signal. f fflair showing bilaterally increased signal Discussion The most widely recognized MRI criteria for MTS are hippocampal atrophy and increased signal intensity on T2-weighted images [5, 18, 21, 23±28]. The reported sensitivity of MRI to unilateral MTS reaches 93% [29±31]. Patterns suggestive of unilateral MTS are observed in about two thirds of MRI studies of patients with temporal lobe seizures. Discrepancies exist between the MR and pathological data in the literature on bilateral MTS. While MRI studies very rarely describe images of bilateral MTS, post mortem investigations have shown that histological MTS is present bilaterally to some extent in 72% [11] to 90 % [12] of patients. Other groups have shown pathological evidence of asymmetrical bilateral hippocampal damage in 80% of subjects, symmetrical damage in 10% and strictly unilateral MTS in only 10% [1]. Bilateral involvement of the hippocampi by MTS has also been suggested by MR spectroscopy [6, 32, 33] and T2 relaxometry [34±36]. It is thus probable that some patients have undiagnosed bilateral hippocampal disease. This is not very surprising. Recognition of hippocampal atrophy relies on the comparison of the two sides and is thus difficult if both are atrophic; qualitative estimation of side-to-side asymmetry of signal intensity can be established with a high degree of accuracy but bilateral signal intensity change is more difficult to identify. It is also impossible to make the diagnosis of bilateral MTS with most volumetric techniques [8, 34, 37±40] which use asymmetry indices rather than absolute values. Recently, two other signs have been described for MRI diagnosis of MTS: high hippocampal signal on fflair [19] and loss of visibility of the digitations of the head of the hippocampus [20]. fflair has been shown to be more sensitive than spin-echo sequences to signal changes in MTS [19]. Although these signs have been described in unilateral MTS, they are useful for diagnosis of bilateral MTS since they do not rely on side-to-side comparison. Volumetric techniques which do not depend on side-to-side comparison have also been described, based on absolute volumetric and comparison of the volume of each hippocampus to a data base of healthy volunteers [39±41]. Using hippocampal signal intensity increase on fflair and loss of visibility of the digitations of the head of the hippocampus, we diagnosed bilateral MTS in 7 of 71 patients with temporal lobe epilepsy. They had loss of the digitations, signal changes on fflair and atrophy in both hippocampal formations. Pathological studies in operated patients with unilateral MTS have shown that these MRI signs correlate with gliosis and neuronal loss [5, 8, 17, 19, 20, 40]. It is therefore likely, when signal intensity abnormalities on fflair and loss of the digitations are observed bilaterally, that MTS is present, to some extent, bilaterally. Moreover, five of

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7 477 W Fig. 3 a±c Patient 5: a 46-year-old man with intractable complex partial seizures and memory deficits with bilateral temporal epileptogenic foci on EEG. Volumetric MRI showed bilateral, symmetrical atrophy. a 3D T1-weighted SPGR image showing slight atrophy with no asymmetry. b T2-weighted FSE image showing bilateral atrophy and loss of the digitations of the head of the hippocampus. c fflair image showing obviously increased signal bilaterally Fig. 4 a±c Patient 3: a 27-year-old woman, with intractable complex partial seizures, memory disturbance and a right temporal epileptogenic focus on EEG. Volumetric MRI showed both hippocampi to have volumes at the lower limit of normal. The diagnosis of bilateral mesial temporal sclerosis was supported by neuropsychological data and bilateral failure of the Wada test. a 3D T1-weighted SPGR image showing asymmetry of the hippocampi, with obvious atrophy on only the right. b T2-weighted FSE image showing bilateral loss of digitations with increased signal on only the right. c fflair image showing obvious bilaterally increased signal the seven patients had volumetric confirmation of bilateral MTS. In the other two, absolute volume measurements were found within the normal range for our institution; their hippocampal volumes were at the lower limit of normal. The fact that the normal range is quite large means that mild atrophy cannot be unambiguously distinguished from normal [38, 41, 42]. When neuronal loss is mild, the loss of hippocampal volume may be less than the combination of measurement error and normal variation, and therefore not detectable [18, 27, 43]. It is thus probable that our seven patients had bilateral MTS. However, no histopathological proof of bilateral disease can be obtained, since bilateral removal of the hippocampus would result in dramatic persistent memory impairment [44]; confirmatory data can come only from autopsy studies. Neuropsychological examination supported bilateral hippocampal damage in all three patients. That bilateral hippocampal lesions can lead to severe memory impairment is well known; severe, persistent amnesia has been described in one patient after bitemporal lobectomy [44, 45]. Memory deficit has also been described in bilateral medial temporal lobe damage due to viral encephalitis [46], ischaemia [47] and complex partial status epilepticus with bilateral mesial temporal involvement [48]. Global memory impairment has also been reported after unilateral resection, suggesting contralateral hippocampal dysfunction [49, 50]. In two patients, contralateral hippocampal damage was confirmed at autopsy [51, 52]. All our seven patients had memory impairment. Memory battery tests, when performed, showed a global deficit strongly suggesting some degree of bilateral involvement of their hippocampal structures. The selective memory deficit found in cases of unilateral MTS, was not present. Moreover, in two patients, the amylobarbitone tests, used to predict contralateral mesial temporal dysfunction, showed a bilateral memory deficit. The percentage of bilateral MTS we reported (10 %) is higher than that in the MRI literature but is comparable with the rate of severe symmetric bilateral involvement in the pathological literature. It is likely that our patients did have severe bilateral damage. Since pathological changes due to MTS are often present bilaterally but have a marked unilateral predominance, there could be patients, considered as having unilateral MTS, with bilateral and asymmetrical abnormalities not detectable with our current MRI protocol. In clinical practice, bilateral MTS can be undiagnosed on electrical and clinical data since patients can have a well-organised unilateral temporal epileptogenic focus. Of our seven patients, five had unilateral temporal lobe EEG abnormalities and only two had bilateral temporal lobe epileptogenic zones. Bilateral hippocampal damages could not be suspected on PET, since hypometabolism was unilateral. Concerning the relationship between bilateral MTS and operative outcome, some groups report poor seizure outcome in patients with temporal lobe seizures and symmetrical hippocampi [10, 25], while others observed a seizure-free outcome [7]. 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