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October 01, 1996; 47 (4) ARTICLES

The amygdala and intractable temporal lobe epilepsy

A quantitative magnetic resonance imaging study

Wim Van Paesschen, Alan Connelly, Cheryl L. Johnson, John S. Duncan
First published October 1, 1996, DOI: https://doi.org/10.1212/WNL.47.4.1021
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Abstract

Objective: To establish a quantitative MRI technique using T2 relaxation time mapping to study systematically the amygdala in patients with intractable temporal lobe epilepsy (TLE). Background: Identification of a focal abnormality on MRI in patients with intractable TLE is important, because outcome from surgery depends largely on the removal of the underlying pathology. Hippocampal sclerosis (HS) is the most common cause of intractable TLE, but epileptogenic lesions can be confined to the amygdala. Methods: Twenty control subjects and 82 patients with intractable TLE were studied. Patients who had foreign tissue lesions visible on routine MRI were excluded. All subjects had a hippocampal T2 map and volumetry and an amygdala T2 (AT2) map. Results: Forty-four of the 82 patients (54%) had an abnormal AT2, which was bilateral in 18. Forty-four patients (54%) had unilateral HS on MRI, 25 (57%) of whom had an abnormal AT2. Seven patients (8%) had bilateral HS, four of whom had an abnormal AT2. Thirty-one patients (38%) had normal quantitative hippocampal measures, 15 of whom had an abnormal AT2, which was bilateral in seven. Fluid attenuated inversion recovery (FLAIR) imaging, where appropriate, confirmed that the increased AT2 signal was due to parenchymal changes. Neuropathologic correlates of an increased AT2 included microdysgenesis in one and gliosis in three patients. Patients with an isolated AT2 abnormality were significantly older at the onset of habitual epilepsy and rarely had a history of febrile convulsions, in comparison with patients who had HS. An isolated AT2 abnormality correlated well with interictal EEG findings. Conclusions: The combination of AT2 mapping and FLAIR is a sensitive method to detect lesions that are not seen on routine MRI in the amygdalae of patients with intractable TLE. Further correlational studies will be required to define the role of this technique in the presurgical evaluation of patients with intractable TLE.

NEUROLOGY 1996;47: 1021-1031

Lesions of mesial temporal structures can cause amygdalohippocampal seizures, which may have characteristic electroclinical features. [1] The nature of these lesions [2-5] and the extent of resection [6,7] determines seizure outcome after surgery for intractable temporal lobe epilepsy (TLE). MRI allows identification of these lesions preoperatively. [8,9]

Hippocampal sclerosis (HS) is the most frequently encountered cause of intractable TLE, accounting for 50 to 70% of cases. [3-5,10-12] HS can be diagnosed using MRI. [13-16] Quantitative MRI, including hippocampal T2 (HCT2) mapping [17-19] and hippocampal volumetry, [20-28] has increased the sensitivity of the MRI diagnosis of HS. Surgery renders 60 to 70% of these patients with HS seizure-free. [2-5,29-31]

The amygdala is an important source of epileptic seizures but has received less attention than the hippocampus. [32,33] Depth EEG studies have documented focal ictal onset in the amygdala in about 10% and regional ictal onset in the amygdala and hippocampus at the same time in about 50% of seizures in patients with intractable TLE. [34-36]

Neuropathologic studies have demonstrated isolated lesions confined to the amygdala in patients with intractable TLE. These lesions include small tumors, which have a predilection for the amygdala, [37] vascular lesions, [4,37] amygdala sclerosis (AS), [38,39] cortical dysplasia, [4] microdysgenesis, [40] and abnormal glial cells. [4] Further, gliosis affects the ipsilateral amygdala in 50 to 75% of patients with classical HS. [4,10,11,41] These lesions of the amygdala may be detected on MRI, [40,42] but systematic studies using visual assessment found that the detection rate of these lesions was low. [38,39,42,43]

To increase the detection rate of lesions in the amygdala, we established a quantitative MRI technique using T2 relaxometry to study the amygdalae systematically and in a standardized way in patients with intractable TLE. In this study, we report the results of amygdala T2 (AT2) mapping in control subjects and patients with intractable TLE.

Methods.

Subjects.

Twenty control subjects (9 men, 11 women) with median age of 27 years (range: 21 to 37) and 82 patients with median age of 31 years (range: 14 to 64) were included in the study. All patients had clinical evidence of intractable TLE, [1] with concordant interictal EEG findings, and were in various stages of presurgical evaluation. Fifty-six patients (68%) had ictal video-EEG recordings confirming the diagnosis of TLE. All patients had routine MRI of the brain that did not reveal a foreign-tissue lesion on visual inspection of the hard copies. The routine images were obtained on a GE Signa 1.5-T scanner, and included a 3-D spoiled gradient echo (SPGR) sequence (35/8/0.75 [TR/TE/NEX], flip angle 30 degrees, matrix size 256 times 192, 200 mm field of view [FOV], 124 1.5-mm contiguous coronal sections), and proton density and T2-weighted images in the coronal plane perpendicular to the long axis of the hippocampus (5-mm thick sections with intersection gap of 1.5 mm, 3100/30-90/0.75 [TR/TE/NEX], 220 mm FOV, matrix size 256 times 256).

Clinical evaluation.

All patients and reliable witnesses were seen before they had the quantitative MRI and were asked systematically, by the same person, for age of onset of habitual epilepsy, duration of epilepsy, history of febrile convulsions or meningoencephalitis, age at the time of these events, family history of febrile convulsions and epilepsy, seizure types and description, average frequency of each seizure type during the year preceding the imaging, and total number of secondary generalized seizures (SGS) in their lifetime. The results of this questionnaire were compared with the medical records and were adjusted only when the medical records contained information that was well documented, and could not have been provided by the patient.

MR imaging.

For both control subjects and patients, all imaging to enable AT2 mapping, HCT2 mapping and hippocampal volume (HCV) measurements was obtained on a 1.5-T Siemens SP63 Magnetom Scanner. Total scanning time was 30 minutes. The magnetization prepared rapid gradient echo (MPRAGE) was obtained first, followed by the HCT2 map, and finally the AT2 map. During the acquisition of the HCT2 map, the coordinates for the AT2 map were determined on the reformatted MPRAGE dataset.

Hippocampal volume

(HCV) was measured as described before. [44] Images for hippocampal volumetric studies were obtained using a 3-D MPRAGE sequence 10/4/200/1 (TR/TE/TI/NEX), flip angle 12 degrees, matrix size 256 times 256, and 128 sagittal partitions in the third dimension with partition thickness of 1.25 mm. The MPRAGE dataset was reformatted into 1-mm thick contiguous sections in a tilted coronal plane that was perpendicular to the long axis of the hippocampus. The reformatted images were transferred to a SUN workstation and analyzed using Xdispim, a member of the Dispimage family of medical image display and measurement tools. [45] After enlargement and appropriate windowing of the images, the hippocampi were outlined with a cursor using a 1-in-3 random and systematic sampling strategy. Hippocampal boundaries were as described by Watson et al. [46] The HCV was calculated by summing the hippocampal cross-sectional areas and multiplying this figure by the distance between two sections, i.e., 3 mm (Cavalieri's principle). [22] Intracranial volume (ICV) was measured on the sagittal 1.25-mm unreformatted MPRAGE dataset with a 1-in-10 random and systematic sampling strategy. HCV was corrected for ICV. The mean control HCV (+/- SD) was 5,180 +/- 416 mm3. The lower limit of the control HCV reference range was defined by 2 SD below the mean control value and was 4,348 mm3. Mean (+/- SD) hippocampal volume ratio (HCVR) was 0.96 +/- 0.03. The lower limit of the reference range for the control group was taken as 3 SD below the mean control HCVR. This yielded a lower limit of 0.87.

A HCT2 map

was obtained using a 16 echo sequence, as previously described. [17-19] HCT2 section thickness was 8 mm. The HCT2 map was oriented in a tilted coronal plane along the anterior border of the brainstem perpendicular to and at the level of the body of the hippocampus. HCT2 was measured by placing the largest possible circle as a region of interest (ROI) within the hippocampus while avoiding boundaries where partial volume effects with CSF might occur. Mean control HCT2 (+/- SD) was 102.4 +/- 2.8 msec. The upper limit of the reference range for the control group was taken as 2 SD above mean control HCT2. This yielded an upper normal limit of 108 msec.

The AT2 map

2000/22-262/1 (TR/TE/NEX), 16 echoes, matrix 135 times 256, FOV 220 times 165 mm, thickness 5 mm was oriented in a tilted axial plane parallel to and above the long axis of the hippocampus Figure 1. This plane has been suggested by Kuzniecky and Jackson [47] for the study of the amygdalae. The coordinates of the AT2 map were determined on the reformatted MPRAGE dataset during the scanning session. A section through the amygdala at right angles to the long axis of the hippocampus was selected on the unreformatted sagittal MPRAGE image of the right amygdala and hippocampus. On this tilted coronal section a set of 1-mm horizontal sections symmetrically through the amygdala was chosen. Five sections that covered the amygdalae optimally were selected and the coordinates of the middle section were taken for the AT2 map. The phase encode direction was chosen to be in the anteroposterior direction to avoid ghosting artefacts from vessels affecting signal intensities of the amygdalae. AT2 was measured by placing a ROI in the largest possible circular area within the amygdala while avoiding boundaries with CSF, and was expressed in milliseconds (msec).

Figure

Figure 1. (A) Sagittal 1.25-mm section of the unreformatted MPRAGE 3-D volume acquisition showing the right hippocampus and amygdala (indicated with text and arrows). The orientation of the AT2 map is shown by the white line. The AT2 map lies parallel and superior to the long axis of the hippocampus. The coordinates for the AT2 map were determined on the MPRAGE 3-D volume dataset after reformatting in the coronal and axial plane, while the patient was still on Table 1. (B) Sixteen images through the amygdalae, all with the same coordinates and section thickness of 5 mm, but with different echo times (TE), ranging from TE of 22 msec to TE of 262 msec, were obtained. Three such images with TE of 22, 150, and 262 msec, respectively, are shown. (C) From these 16 images with different TE, T2 values were calculated for each pixel and displayed as an AT2 map. The AT2 signal (expressed in milliseconds [msec]), as defined in this study, was measured by placing the largest possible circle within the amygdala as a ROI, while avoiding the boundaries with CSF, as demonstrated for the left (L) amygdala.

A fluid attenuated inversion recovery (FLAIR) image

4200/90/2010/1 (TR/TE/TI/NEX) was obtained in patients who had a focal increased AT2 signal, to rule out the possibility that this was the result of CSF. The FLAIR scan was obtained in the same scanning session, with the same coordinates as the AT2 map to enable comparison between the AT2 map and the FLAIR image.

An MRI diagnosis of HS was made using a combination of qualitative assessment of T1- and T2-weighted MR images together with quantitative assessment of HCT2, HCV corrected for ICV, HCVR and inspection of a HCV distribution graph compared against a control graph, as described before. [44]

Statistics.

The data were analyzed using SPSS for Windows Release 6. [48] Fisher's exact test, Kruskal-Wallis test, and one-way ANOVA were used where indicated.

Results.

Controls.

The AT2 values were normally distributed in the 20 control subjects examined. The mean control AT2 (+/- SD) was 99.3 +/- 2.5 msec, ranging from 95 to 104 msec. There were no significant gender or right-left differences. The mean difference between left and right AT2 was 0.35 +/- 1.42 msec. An AT2 value >or=to 105 msec (i.e., more than 2 SD above the mean control value) or a side-to-side difference of >or=to5 msec (i.e., 3 SD above mean control values or higher) were considered as abnormal. An abnormal AT2 signal was considered lateralized if there was a unilateral increased AT2 >or=to105 msec, or if the side-to-side difference was >or=to5 msec. Test-retest intrarater repeatability was -0.01 +/- 0.66 msec and test-retest interrater repeatability was 0.02 +/- 0.73 msec.

Patients.

A total of 44 of 82 patients (52%) had an abnormal AT2 map. Thirty-five of these 44 patients (80%) had an AT2 >or=to 105 msec, which was bilateral in 18. The median value of the higher AT2 of these 35 patients was 108 msec (range: 105 to 113 msec). Eight of these 44 patients (18%) had an AT2 within normal limits, but which was >or=to5 msec above that of the other side. One of these 44 patients (2%) had a hypodense lesion in the amygdala.

Patients were subdivided according to quantitative hippocampal and amygdala measures Figure 2.

Figure

Figure 2. Subdivision of 82 patients with intractable TLE on the basis of quantitative hippocampal MRI and AT2 mapping.

Amygdala T sub 2 mapping in patients with unilateral hippocampal sclerosis.

Forty-four of the 82 patients (54%) with intractable TLE had unilateral HS on MRI. Nineteen of these patients (43%) had normal AT2s, i.e., isolated HS, and 25 (57%) had an abnormal AT2. Of these 25 patients with an abnormal AT2, five had AT2 values in the normal range, but a side-to-side difference >or=to5 msec, with the higher AT2 on the side of the HS in all; nine patients had a unilateral increased AT2 >or=to 105 msec on the side of the HS Figure 3; nine patients had bilateral increased AT2s, two with AT2s of equal magnitude, six with the higher value on the side of the HS, and one with the higher value on the opposite side (105 msec on the side of the HS, and 106 msec on the other side).

Figure

Figure 3. The patient was a 42-year-old man with a history of prolonged febrile convulsions at the age of 2 years, and subsequent development of intractable TLE. He had an average of one complex partial seizure (CPS) per week and had had a total of around 40 SGS. Interictal EEGs showed a left temporal epileptic focus. MRI showed left HS. On the HCT2 map (A), the left hippocampus (in the white circle) was visibly atrophic and had an increased HCT2 signal. Hippocampal quantitation confirmed left HS: HCT2 right = 99 msec, HCT2 left = 125 msec (normal [Nl]: <or=to 108 msec); HCVR (L/R) = 0.51 (Nl: >or=to 0.87); HCV right = 4,375 mm3, HCV left = 2,245 mm3 (Nl: >or=to 4,348 mm3). The AT2 map (B) showed an increased AT2 signal on the left side (white arrow). AT2 on the left was 109 msec and on the right 101 msec (Nl: <or=to 104 msec). Notice that the hippocampus is not visible in the plane of the AT2 map. Therefore, the amygdalae can be evaluated independently of the hippocampi. The FLAIR image (C) confirmed that the high AT2 signal on the left (white arrow) was not due to partial volume effects with CSF, since CSF is black in this sequence. The high T2 signal was due to tissue changes, and in the context of HS on the same side most likely represented concomitant AS, i.e., amygdalohippocampal sclerosis.

Finally, two patients had a unilateral increased AT2 on the opposite side of the HS. Both had evidence from ictal scalp-EEG recordings of bitemporal ictal onset. Hippocampal quantitative measures were unusual in one of these two patients: HCT2 right = 105 msec, HCT2 left = 114 msec (Nl: <or=to 108 msec), HCVR (L/R) = 0.97 (Nl: >or=to 0.87), HCV right = 4,510 mm3, HCV left = 4,371 mm3 (Nl: >or=to 4,348 mm3), AT2 right = 107 msec, AT2 left = 104 msec (Nl: <or=to 104 msec). This patient probably had left HS (i.e., increased HCT2 signal and HCV in the low normal range), but we could not exclude some involvement of the right hippocampus, in view of the hippocampal symmetry. This patient had depth-EEG studies with recording of three seizures. One seizure started in the left, and two in the right, mesial temporal structures, one with the first EEG changes in the right amygdala, the other with the first EEG changes in the right hippocampus.

Amygdala T sub 2 mapping in patients with bilateral hippocampal sclerosis.

Seven of the 82 patients (8%) with intractable TLE had bilateral HS on MRI. Three of these patients had normal AT2s, two had bilateral increased AT2s, one had a unilateral increased AT2, and one had AT2s within normal limits, but a side-to-side difference of 5 msec.

AT2 mapping in otherwise MRI-negative patients.

Thirty-one of the 82 patients (38%) with intractable TLE had normal routine MRI and normal quantitative hippocampal measures. AT2 mapping was normal in 16 of these 31 patients (52%). AT2 mapping showed an abnormality in 15 of these 31 apparently MRI-negative cases (48%). Twelve of these patients had an AT2 >or=to 105 msec, which was bilateral in seven. Two patients had AT2 values within normal limits but a side-to-side difference >or=to 5 msec, and one patient had a hypodense lesion in one amygdala and exhibited an abnormally low AT2 within this lesion.

A FLAIR image in the same plane as the AT2 map was useful to confirm that an increased AT2 signal was not due to CSF, and was helpful for the visual assessment of increased AT2 signals. Nine of the 15 patients with normal routine MRI and hippocampal quantitation but abnormal AT2 had a lesion that was detectable on visual assessment of the AT2 map and FLAIR. Five of these had a focal or nodular hyperintense T2 signal in the amygdala Figure 4 and Figure 5, three had a more diffuse increased T2 signal throughout the amygdala Figure 6, and one had a focal lesion that was hypodense on the AT2 map, and hyperintense on a T1-weighted image Figure 7. In the remaining six of these 15 patients, an abnormal AT2 signal was measured, which was not appreciated on visual assessment of AT2 map or FLAIR. The T2 signal of the small and focal lesions measured with a ROI confined to the lesion was higher than when measured with the larger ROI as defined for this study (see Figure 5).

Figure

Figure 4. The patient was a 25-year-old man with onset of TLE at the age of 16 years. There was no history of febrile convulsions, meningitis, or cerebral trauma. An aura was characterized by a strange cephalic sensation, dizziness, an epigastric rising sensation, a diffuse warm sensation, and deja vu. A CPS was characterized by unresponsiveness, staring, and prominent oral automatisms. He had an average of five CPS per week, and never had a SGS. Interictal EEG showed left frontotemporal epileptic activity. Ictal EEG showed left-sided onset without clear localization. Routine MRI was normal and hippocampal quantitation was normal: HCT2 right = 102 msec, HCT2 left = 108 msec (Nl: <or=to 108 msec), HCVR (L/R) = 0.92 (Nl: >or=to 0.87), HCV right = 5,925 mm sup 3, HCV left = 5,471 mm3 (Nl: >or=to 4,348 mm3). The AT2 map (A) revealed an increased AT2 of 108 msec on the left and a normal AT2 of 102 msec on the right. The FLAIR image (B)--for this patient not in the same plane as the AT2 map--showed a lesion with increased T2 signal in the posterior aspect of the left amygdala (white arrow), which was also visible on the AT2 map, but was initially mistaken for CSF. The patient underwent an anterior temporal lobectomy with amygdalectomy and minimal hippocampal resection. A sagittal section of the unreformatted MPRAGE shows the left hippocampus and amygdala (C; T = tail of hippocampus; B = body of hippocampus). The white box corresponds to the location of the resected specimen shown in (D). The resected specimen shows the resected left amygdala, cut in the sagittal direction, and the anterior part of the head of the hippocampus (Magnification: times 12, before 67.1% reduction). Microscopic examination of the posterior aspect of the amygdala (indicated by the black box) revealed abnormal clusters of neurones admixed with primitive neuroblastlike cells (E) (Magnification: times 170, before 67.1% reduction). This region corresponded to the region of the abnormal AT2 signal. In the resected temporal neocortex, heterotopic neurones were seen in the white matter and the molecular layer. These findings were consistent with a diagnosis of microdysgenesis. Patient has been seizure-free for more than 1 year after surgery.

Figure

Figure 5. The patient was a 26-year-old woman who had a febrile convulsion at the age of 2 years and subsequently developed intractable TLE from the age of 5 years. Auras were characterised by panic, an epigastric rising sensation, and deja vu. Interictal EEGs showed bilateral frontotemporal epileptiform discharges. Routine MRI was normal and hippocampal quantitation was normal: HCT2 right = 108 msec, HCT2 left = 108 msec (Nl: <or=to 108 msec), HCVR = 0.98 (Nl: >or=to 0.87), HCV right = 5,530 mm3, HCV left = 5,402 mm3, (Nl: >or=to 4,348 mm3). The AT2 map (A) showed bilateral increased AT2 values of 109 msec on the right and 108 msec on the left (Nl: <or=to 104 msec). The T2 values of the brighter regions in the amygdalae (grey arrows), measured with a small circle, were 119 msec on the right and 121 msec on the left. The FLAIR image (B) showed bilateral increased signals in the amygdalae with a streak-like and elongated shape (black arrows), in the same position as those seen on the AT2 map, confirming the tissue origin of the increased signal.

Figure

Figure 6. The patient was a 54-year-old man with onset of TLE at the age of 21 years. There was no history of febrile convulsions or meningitis. He had an average of one CPS per month and had had a total of four SGS. Interictal EEG showed a clear right anterotemporal epileptic focus. Routine MRI was reported as normal. Hippocampal quantitation was normal: HCT2 right = 108 msec, HCT2 left = 104 msec (Nl: <or=to 108 msec), HCVR (R/L) = 0.99 (Nl: >or=to 0.87), HCV right = 5,018 mm3, HCV left = 5,079 mm3 (Nl: >or=to 4,348 mm3). On visual inspection of the AT2 map (A), there was an increased T2 signal throughout the right amygdala and a triangular region of increased T2 signal anterior to the right amygdala (white arrows). The AT2 on the right was 113 msec, and on the left was 100 msec (Nl: <or=to 104 msec). The FLAIR image (B) confirmed that this increased T2 signal was not due to CSF, but due to tissue changes in this region (white arrows).

Figure

Figure 7. The patient was a 42-year-old man with onset of TLE at the age of 9 years. There was no history of febrile convulsions, meningitis, or cerebral trauma. A typical aura was characterised by a deja vu, fear, an epigastric rising sensation, gustatory and olfactory hallucinations, and an experiential sensation that time went by four times as fast as usual. A CPS was characterized by unresponsiveness, oral automatisms, and automatisms of the right arm and hand. He had an average of three CPS per week and never had a SGS. Interictal EEG showed a right anterotemporal epileptogenic focus, and ictal EEG showed bilateral discharges for the first 10 seconds followed by right anterotemporal rhythmic theta waves. Routine MRI was normal and hippocampal quantitation was normal: HCT2 right = 105 msec, HCT2 left = 99 msec (Nl: <or=to 108 msec), HCVR (L/R) = 0.95 (Nl: >or=to 0.87), HCV right = 5,321 mm3, HCV left = 5,049 mm3 (Nl: >or=to 4,348 mm3). The AT2 map (A) showed a hypodense lesion (white arrow) in the right amygdala near the uncinate gyrus. The AT2 as defined for this study was normal in both amygdalae, on the right 100 msec and on the left 98 msec. However, the T2 measured with a ROI that fitted this hypodense lesion was 70 msec. This lesion was also visible as an intra-axial hyperdense lesion (black arrow) on a 1-mm thick T1-weighted section of the reformatted MPRAGE dataset (B), which was used to determine the coordinates of the AT2 map.

Interictal EEG.

Nine of the 15 patients with normal hippocampi and an abnormal AT2 had a lateralized abnormality on the AT2 map (i.e., five with a unilateral AT2 >or=to 105 msec, two with bilateral AT2s >or=to 105 msec and a side-to-side difference >or=to 5 msec, two with AT2s in the normal range and a side-to-side difference >or=to 5 msec, and one with a hypodense lesion). Eight of these nine patients had an epileptiform abnormality over the concordant temporal lobe (see Figure 4, Figure 6, and Figure 7), and one had bitemporal slowing. Six patients had a nonlateralized abnormal AT2 map (i.e., bilateral increased AT2s and side-to-side difference < 5 msec). Three of these had a unilateral epileptiform abnormality over the temporal lobe with the higher AT2 signal, and three had bilateral epileptiform abnormalities over the temporal, frontotemporal (see Figure 5) and frontal lobes respectively.

Clinical correlations.

Clinical data of patients with isolated unilateral HS, unilateral amygdalohippocampal sclerosis, an isolated AT2 abnormality, and normal routine and quantitative MRI were compared Table 1. A history of febrile convulsions was obtained predominantly in the groups with HS with or without concomitant amygdala abnormality. As a group, patients with HS were younger at the onset of their habitual epilepsy and at the age of evaluation than patients with an isolated AT2 abnormality or normal MRI. Duration of habitual epilepsy, seizure types and frequencies, and the frequency of a family history of epilepsy or febrile convulsions and history of meningoencephalitis did not differ between the groups.

View this table:

Table 1. AT2 mapping and clinical correlations

Neuropathologic correlations.

So far, two patients with an isolated abnormal AT2 signal underwent an anterior temporal lobectomy with amygdalectomy and minimal hippocampal resection. One of these patients had AS, and 1 year after the operation, there was a 75% reduction in seizure frequency. The second patient had microdysgenesis (without gliosis) of the resected amygdala and temporal neocortex and has been seizure-free for more than one year after surgery (see Figure 4).

To date, 27 patients with unilateral HS, 14 of whom had an ipsilateral increased AT2 signal, have been operated on. Amygdala specimens of two of these patients were available. The AT2 values of the resected amygdala of these two patients were increased and were 110 and 112 msec respectively. In both cases, neuropathologic examination of a glial fibrillary acidic protein (GFAP)-stained section revealed gliosis of the amygdala.

Discussion.

Methodology.

AT2 mapping, a new MRI approach to study patients with intractable TLE, is similar in principle to HCT2 mapping, [17-19] but the orientation is in a tilted axial plane through the amygdala. [47] This plane allows the evaluation of the amygdala independently of the hippocampi, which are not visualized in this plane. The standardized determination of the orientation of the amygdala images is of critical importance. The thickness is only 5 mm instead of 8 mm of the HCT2 map, which would be too large for the size of the amygdala. The range of abnormally high AT2 signals (105 to 113 msec) was considerably smaller than the HCT2 signal range in HS (109 to 142 msec). [19] The largest circle that could be fitted into the amygdala as an ROI was used to measure the AT2. In patients with small focal lesions with a high T2 signal in the amygdala, the use of a large circle, as defined in the present study, led to a lower AT2 reading than the AT2 value of the lesion itself. We used the same measurement technique for purposes of standardization and reproducibility and found it to be excellent.

Detection of an increased AT2 signal is difficult on visual assessment of the MRI. Bronen et al. [43] reported an increased AT2 signal on visual inspection of MR images of only two of 48 patients (4%) with HS, and Miller et al. [39] reported an increased AT2 signal in only two of 11 patients (18%) with neuropathologic evidence of isolated AS. The sensitivity of detecting an abnormal signal on visual inspection of a hard copy of the image with TE = 118 msec (from the set of images used to calculate the AT2 map) was 38% in our study. [49]

Amygdalohippocampal sclerosis and isolated hippocampal sclerosis.

Pathologic studies have shown AS to be present on the side of classical HS in 50 to 76% of cases. [4,10,11,41] In this current study, an abnormal AT2 signal was present on the side of classical HS in 23 of 44 patients (52%) with unilateral HS. Cendes et al., [24] using amygdala volumetry, detected atrophy on the side of the smaller hippocampus in a similar percentage of patients. We have found amygdala volumetry to have a poor repeatability, with a coefficient of repeatability [50] of more than 20%, and it was therefore not used to study these patients. Neuropathologic studies revealed the presence of gliosis of the amygdala in two patients with unilateral HS who had an increased AT2 signal on the same side, which indicates that AT2 mapping is able to detect AS. Amygdala tissue was available for neuropathologic examination for only two of the 27 patients with unilateral HS operated on so far, which highlights one of the difficulties that has hampered the study of the role of the amygdala in TLE. [32,33]

Clinical features of patients with isolated HS did not differ significantly from those with amygdalohippocampal sclerosis, which is in agreement with the observations of Falconer and Cavanagh [37] and Bruton. [4] Gambardella et al., [51] however, reported that patients with amygdala atrophy experienced significantly more SGS per year compared with patients with isolated HS. The pathologies detected by AT2 mapping and amygdala volumetry may not be identical, and clinical characteristics therefore may not be comparable. Also, differences in reporting SGS frequency might explain this discrepancy.

Two patients had the unusual combination of unilateral HS and a contralateral increased AT2. Other unusual features in these two patients were the late age of onset (26 and 30 years), with no evidence of prior cerebral insult, such as febrile convulsion or meningitis. One of these had two different types of seizure onset. Further, these were the only patients in the study with unilateral HS and independent bitemporal onset of seizures on ictal scalp-EEG studies. Ictal depth-EEG recordings in one of these patients showed ictal onset in the amygdala with the abnormal AT2.

Isolated lesions of the amygdala.

Thirty-one patients (38%) with intractable TLE had a normal routine MRI and normal quantitative hippocampal measures and were considered MRI-negative. In 15 of these 31 patients (48%), the AT2 map showed an abnormal signal, which was bilateral in 7 (47%). This is a higher rate of bilateral abnormality than was found with HCT2 values, which we found in 16 to 29% of patients with HS. A FLAIR image was useful to confirm that the high signal was of parenchymal origin and not due to partial volume effects with CSF. Bergin et al. [52] showed that FLAIR is useful to detect abnormalities in the amygdala in patients with TLE that were not apparent on routine MRI.

Compared with patients with HS, patients with an isolated abnormality of the amygdala did not have a history of febrile convulsions and had the onset of their habitual epilepsy at a significantly older age, in agreement with previous findings. [3,4,10,18,25,53,54] The results also concur with the observations of Miller et al. [39] in patients with isolated AS. Berkovic et al. [5] observed that 36% of patients with TLE and normal routine MRI had a good seizure outcome following temporal lobectomy. This group was characterized on ictal SPECT by a pattern of unilateral anteromesial temporal hyperperfusion, suggesting that the epileptogenic zone was confined to the anteromesial temporal lobe. [55] Some of these patients might have had a unilateral lesion of the amygdala that was undetected on routine qualitative MRI, but which might have been detected by AT2 mapping and FLAIR imaging.

Neuropathology of epileptogenic lesions of the amygdala.

We detected a variety of lesions on visual assessment of the AT2 map and the FLAIR image, ranging from small nodules to a diffuse increase of the AT2 signal. This probably reflects the wide range of lesions that may occur in the amygdalae of patients with intractable TLE, which have been described in the neuropathologic literature. Falconer and Cavanagh [37] and Bruton [4] documented several patients with small tumors and vascular anomalies confined to the amygdala who became seizure-free after temporal lobectomy. They noted that small tumors have a predilection for the amygdala and rarely affect the hippocampus. Bruton [4] described four patients in his group of 21 patients with indefinite pathology who had unusually large, hyperchromatic glial cells, resembling giant astrocytes scattered in an otherwise normal amygdala, which possibly represented a subtle glial abnormality. He noted that these four benefited from surgery in contrast to the other patients in this group, who did poorly. Bruton [4] also reported cortical dysplasia of the amygdala as a cause of intractable TLE.

To date, two patients in our study with an isolated increased AT2 have undergone an anterior temporal lobectomy with amygdalectomy and minimal resection of the hippocampus. One of these two patients had AS and had a 75% reduction in seizure frequency after one year. Hudson et al. [38] reported 11 patients with isolated AS, who represented 10% of the patients who were operated on for intractable TLE. Only three of these 11 patients (27%) became seizure-free after surgery, which suggested that AS was not the epileptogenic zone. They concluded that AS might be associated with a more widespread epileptogenic abnormality, which was not detected on microscopic examination of the resected temporal lobe. [38]

The second patient who underwent an anterior temporal lobectomy with amygdalectomy and minimal resection of the hippocampus had microdysgenesis of the amygdala and temporal neocortex and has been seizure-free for more than 1 year. Microdysgenesis is the microscopic variant of cortical dysplasia. [56] Feindel et al. [40] reported microdysgenesis of the amygdala as a cause of intractable TLE. Several authors reported that microdysgenesis was not detectable on MRI. [57-59] In our patient, however, there was a clearly increased T2 signal corresponding to the location of abnormal clusters of neurones admixed with primitive neuroblast-like cells in the posterior aspect of the amygdala.

This neuropathologic variety of epileptic lesion of the amygdala is in contrast to the limited range of epileptic lesions of the hippocampus, which is predominantly HS. Atrophy is probably not a feature of a majority of these epileptogenic amygdala lesions. AT2 mapping in combination with FLAIR imaging therefore might be a better technique than amygdala volumetry to detect these lesions.

Surgical techniques for TLE.

There have been descriptions of several surgical techniques for patients with TLE. [60-64] Feindel and Rasmussen [61,64] noted that seizure outcome was similar for patients who underwent temporal lobectomy with amygdalectomy and minimal hippocampal resection as for those who underwent a standard temporal lobectomy with major hippocampectomy. They concluded that resection of the amygdala might be crucial for a good seizure outcome. Goldring et al., [62] on the other hand, reported outcome results similar to those of Feindel and Rasmussen using an anterior temporal lobectomy that spared the amygdala. So far, no guidelines have been formulated for the indications of each of these surgical techniques.

Formulating these guidelines would be important since Milner [65] and Smith and Milner [66] reported that memory functions of patients who underwent an anterior temporal lobectomy with amygdalectomy and minimal hippocampal resection were significantly better than those of patients who had undergone an operation with major hippocampectomy. Trenerry et al. [67] reported that MRI hippocampal volume data provided meaningful information in evaluating the risk for memory impairment following temporal lobectomy and stressed the detrimental effect on memory functions of removing a nonatrophic left hippocampus. Miller et al. [39] reported that the memory functions of patients with isolated AS deteriorated after standard temporal lobectomy, including the intact hippocampus, compared with patients with amygdalohippocampal sclerosis, who underwent the same operation. Several other studies have demonstrated the importance of the hippocampus [23,68-71] but not the amygdala [72] for memory functions. With our quantitative MRI protocol of mesial temporal structures, it might be possible to provide better presurgical information.

MRI-negative intractable TLE.

An important subgroup of 16 patients (20%) had intractable TLE with normal routine MRI, hippocampal quantitation, and AT2 map. This is in accordance with pathologic studies before MRI was available. Corsellis [73] reported that no definite structural abnormality could be found in 20% of postoperative specimens of patients with intractable TLE, Green and Scheetz [74] found a frequency of 18%, although Jensen and Klinken [7] reported only three of 78 patients (4%) with no structural abnormality. This group should be studied with all modern imaging techniques and neuropathologic correlations after surgery to define further the epileptogenic lesions in these patients. Before contemplating surgery in such patients, one should consider that removal of a pathologically normal temporal lobe does not generally cure the epilepsy and also leads to a worse social and personal outcome. [2,4]

AT2 mapping in combination with FLAIR imaging is a powerful tool in the systematic study of the amygdalae of patients with intractable TLE, particularly when routine MRI and hippocampal quantitative measures were unremarkable. Outcome studies and correlation studies with functional tests such as EEG, [75] PET, [55] SPECT, [76] and neuropsychometry, and neuropathologic study will be necessary to gain a better understanding of the role of AT2 mapping and the amygdala in intractable TLE.

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