Clinical Investigative Study Temporal Lobe Epilepsy with Unilateral Amygdala Enlargement: Morphometric MR Analysis with Clinical and Pathological Study Yukio Kimura, MD, Noriko Sato, MD, PhD, Yuko Saito, MD, PhD, Kimiteru Ito, MD, PhD, Kouhei Kamiya, MD, Yasuhiro Nakata, MD, PhD, Masako Watanabe, MD, PhD, Norihide Maikusa, Hiroshi Matsuda, MD, PhD, Hideharu Sugimoto, MD, PhD From the Departments of Radiology, National Center Hospital of Neurology and Psychiatry, Tokyo, Japan (YK, NS, YS, KI, KK, YN); Pathology and Laboratory Medicine, National Center Hospital of Neurology and Psychiatry, Tokyo, Japan (YS); Department of Mental Disorders, National Center Hospital of Neurology and Psychiatry, Tokyo, Japan (MW); Imaging Neuroinformatics Analysis Section, Department of Imaging Neuroinformatics, Integrative Brain Imaging Center, National Center of Neurology and Psychiatry, Tokyo, Japan (NM, HM); and Department of Radiology, Jichi Medical University, Tochigi, Japan (YK, HS)
ABSTRACT BACKGROUND AND PURPOSE
Amygdala enlargement (AE) has been reported as an epileptogenic focus in subtypes of temporal lobe epilepsy (TLE). The purpose of this study was to investigate the clinical, morphological, and pathological characteristics of AE. METHODS
We retrospectively reviewed the clinical data and imaging findings of 23 TLE patients with ipsilateral AE. We performed morphological MR analyses using FreeSurfer and voxelbased morphometry (VBM) in 14 of the 23 patients and in 20 controls whose images were obtained by a 3.0-Tesla MRI. A pathological study was also performed in 2 patients who underwent operations. RESULTS
Keywords: Amygdala enlargement, focal cortical dysplasia, temporal pole, FreeSurfer, voxel-based morphometry. Acceptance: Received June 18, 2013, and in revised form October 31, 2013. Accepted for publication November 19, 2013. Correspondence: Address correspondence to E-mail: [email protected] J Neuroimaging 2014;00:1-9. DOI: 10.1111/jon.12106
All patients became seizure free or shSowed dramatic improvement by medical therapy except for two. They received operations and their pathology revealed that both patients had cortical dysplasia in from the amygdala to the ipsilateral temporal pole. The FreeSurfer analysis showed a significant difference in the amygdala volumes between the affected and nonaffected sides. VBM revealed significant increases of gray matter volumes of the temporal pole on the side of AE in seven of the 14 patients with AE (50%). CONCLUSIONS
Cortical dysplasia may be one of the pathological diagnoses in AE, and in some patients it may extend to the temporal pole.
Introduction Hippocampal sclerosis (HS) is the most common cause of epilepsy requiring surgical treatment.1 Amygdala, which is a part of the limbic system, is also an important source of epileptic seizures, but it has received less attention than the hippocampus. Invasive electrophysiological studies indicated that 5-10% of patients with temporal lobe epilepsy (TLE) had seizure onset in the amygdalae.2,3 Neuropathological studies have demonstrated isolated amygdala abnormalities in patients with intractable TLE, and their etiologies varied: gangliogliomas, astrocytomas, vascular lesions, amygdala sclerosis, cortical dysplasia, and others.4 Nontumoral unilateral amygdala enlargement (AE) has been reported in patients with TLE.1,2,5,6 The authors of these reports noted that AE could be an epileptogenic focus; the clinical and pathological features of nontumoral unilateral AE have not been well documented because many cases were well controlled
without surgical resection and the number of reports is low. We have encountered patients whose amygdalae were enlarged on MR images and whose pathological findings showed cortical dysplasia in the amygdala extending into the ipsilateral temporal pole. We retrospectively reviewed the clinical and imaging findings of cases of TLE in patients with AE, and we analyzed their amygdalae, hippocampi, and temporal poles to evaluate their gray matter volume compared to that of normal controls.
Materials and Methods Participants We retrospectively reviewed an electronic database of radiology reports of 16,951 patients who underwent brain MR imaging examinations at our institution between March 2003 and August 2012, and we searched for reports that indicated TLE. The radiological reports identified 732 patients as having TLE,
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◦ 2014 by the American Society of Neuroimaging C
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head trauma, infarction, hemorrhage or surgical history; (4) vascular abnormalities such as cavernous malformation and arteriovenous malformation. As a consequence, 23 patients with unilateral AE with ipsilateral TLE were enrolled (Tables 1 and 2). Nine were males and 14 were females, from 12 to 77 years of age, with a mean age of 36.8 ± 19.5 years. Their average age at the onset of seizure was 29.8 ± 22.4 years. All patients received MR examination. 18 Ffluorodeoxyglucose-positron emission tomography (18 F- FDGPET) and 99mTc ethyl cysteinate dimer single photon emission CT (99m Tc-ECD SPECT) were also performed under interictal status in 10 and 9 patients, respectively, to support the clinical diagnosis, because temporal hypometabolism and hypoperfusion were characteristic findings of TLE in interictal 18 F-FDG PET and 99m Tc-ECD SPECT,8–10 relatively. We also reviewed clinical data including the length of time from the first seizure onset, the type of seizures, response to drug therapy, and interictal epileptiform discharge on electroencephalogram (EEG) as well as MRI, 18 F-FDG PET, and 99m Tc-ECD SPECT findings. Twenty age-matched healthy subjects (12 females and 8 males) without neurological nor psychiatric disorders were the control group. The mean age of the controls was 42.7 years (SD 15.5 years; range 22-65 years). Institutional review board approval was obtained. The written informed consents were obtained from the control subjects, but patients’ informed consent was not required for the retrospective review.
MR Imaging Acquisition
Fig 1. A 37-year-old patient with a 3-year history of right TLE (patient 12). (A) A FLAIR coronal image and (B) a T2-weighted axial image show right amydgala enlargement (arrows).
and from this population we selected the patients whose unilateral amygdala was enlarged and who showed focal epileptiform discharge predominantly in the temporal area ipsilateral to the AE, according to the patient’ medical records (Fig 1). The AE was definite on visual inspection. The diagnosis of TLE was based on the presence of complex partial seizures (CPS) consistent with TLE.7 Six patients (patients 1, 5, 6, 9, 10, and 13) had generalized tonic–clonic (GTC) seizures, but EEG seizure patterns arising from the temporal area ipsilateral to the AE were observed. Patients with the following criteria were excluded: (1) highly suspected tumoral lesions in MR imaging such as calcification, cystic changes, or contrast enhancement; (2) hippocampal abnormalities in MR imaging on visual inspection; (3) significant past medical history of encephalitis/meningitis, severe
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Brain MR examinations were performed during an interictal period on 1.5-Tesla scanner (Magnetom Symphony, Siemens, Erlangen, Germany) (Table 1, patients 1-9) and 3.0-Tesla scanner (Achieva, Philips, Best, the Netherlands) (Table 2, patients 10-23), according to protocols specifically designed for epilepsy studies: (a) high-resolution 3-dimensional (3D) sagittal T1-weighted magnetization prepared rapid acquisition with gradient echo sequence (MPRAGE) with and without contrast medium (gadolinium-DTPA, .1 mmol/kg of body weight), with a repetition time (TR)/echo time (TE)/flip angle (FA)/ number of excitations (NEX) of 1600 milliseconds/2.64 milliseconds/15°/1 or 7.12 milliseconds/3.4 milliseconds/10°/1, 1.2mm or .60-mm thickness with no gap, 144 or 300 slices, 256 × 256 or 260 × 320 matrix, 26 cm field of view (FOV); (b) transverse turbo spin echo T2-weighted images: TR/TE/FA/NEX; 3,800 milliseconds/95 milliseconds/150°/1 or 4,507 milliseconds/80 milliseconds/90°/2, 5.0 mm or 3.0 mm thickness with 1.8 mm or 1.5 mm gap, 20 slices or 34 slices, matrix; 291 × 512 or 365 × 368, 25 cm FOV; (c) coronal fluid-attenuated inversion recovery (FLAIR) images: TR/TE/FA/NEX; 9,000 milliseconds/101 milliseconds/170°/1 or 10,000 milliseconds/120 milliseconds/90°/2, 5.0 mm or 3.0 mm thickness with 1.8 mm or 1.5 mm gap, 20 slices or 35-42 slices, matrix; 179 × 256 or 202 × 320, 25 cm FOV; (d) coronal turbo short-tau inversion recovery (STIR) images with TR/TE/inversion time (TI)/FA/NEX of 4,200 milliseconds/81 milliseconds/180 milliseconds/180°/1 or 4724 milliseconds/80 milliseconds/220 milliseconds/90°/2, 5.0 mm thickness with 1.0 mm gap or 3.0 mm thickness with 1.5 mm gap, 20 or 34 slices, 224 × 512 or 204 × 312
Table 1. Clinical Profile of the 9 Temporal Lobe Epilepsy Patients with Ipsilateral Amygdala Enlargement (AE) Scanned by 1.5-T MRI Clinical Findings Patient No.
1* 2* 3 4 5 6 7 8 9
Current Status
Age/Sex (Years)
Age of Seizure Onset (Years)
Seizure Type
Abnormal EEG Side
AE** Side
Seizure Frequency after Therapy
Current Medication
23/F 25/F 40/F 47/M 23/F 30/F 19/F 15/F 77/M
3 20 4 47 17 24 19 5 75
GTC CPS CPS CPS GTC GTC CPS CPS GTC
L R R L L L L L R
L R R L L L L L R
Free Free Free 1-2/Mo Free Free Free 1/year Free
None (received operation) None (received operation) CBZ CBZ CBZ CBZ, ZNS PB CBZ, CZP CBZ
Bil, bilateral; R, right; L, left; CPS, complex partial seizure; GTC, generalized tonic–clonic seizure; CZP, clonazepam; CBZ, carbamazepine; PB, phenobarbital; ZNS, zonisamide. * Pathology was obtained. ** Visually assessed by MRI.
Table 2. Clinical Profile and MR Analysis of the 14 Temporal Lobe Epilepsy Patients with Ipsilateral Amygdale Enlargement (AE) Examined by 3.0-T MRI
Patient No.
10 11 12 13 14 15 16 17 18 19 20 21 22 23
Amygdala Volume (mm3 )
L
Increased Gray** Matter Volume of Temporal Pole
Seizure Frequency after Therapy
Current Medication
5154 4453 4709 3990 5560 4903 3280 4640 4260 5450 4409 4308 4938 3898
NS + + NS NS + + + NS + NS NS NS +
1/Mo free 1/3Mo free 1/Mo free free free free free 1/Mo free free free
CBZ ZNS CBZ CZP CBZ CBZ CBZ CBZ CBZ CBZ, CZP CBZ LEV LEV CBZ
Hippocampus Volume (mm3 )
Age/Sex (Years)
Age of Seizure Onset (Years)
Seizure Type
Abnormal EEG Side
AE* Side
R
L
R
38/M 55/M 37/M 19/F 54/M 66/F 65/M 51/F 34/F 18/F 12/M 22/F 13/M 63/F
18 40 34 9 52 66 62 49 34 15 11 8 12 61
GTC CPS CPS GTC CPS CPS CPS CPS CPS CPS CPS CPS CPS CPS
R R Bil R R L L R R L R L L R
R R R R R L L R R L R L L R
2349 1874 2918 2315 2027 1639 1439 2165 2681 2117 2116 1458 2121 2192
1926 1550 2035 2140 1908 2491 1917 1546 2168 2470 1756 1570 2336 1628
6194 4901 5663 4949 5288 4380 3716 5040 4633 5535 5058 4011 4864 4475
Bil, bilateral; R, right; L, left; CPS, complex partial seizure; GTC, generalized tonic–clonic seizure; CZP, clonazepam; CBZ, carbamazepine; LEV, levetiracetam; ZNS, zonisamide. * Visually assessed by MRI. ** z-scores >2 was considered significant comparing to normal data base in a VBM study. +:significant, NS: not significant.
matrix, 25 cm FOV. All 20 healthy controls underwent a 3.0Tesla MR imaging study with the epilepsy protocols described above.
tained on a 3.0-Tesla MR scanner. The patients group consisted of 7 males and 7 females, from 12 to 66 years of age, with a mean age of 39.1 ± 19.9 years.
PET and SPECT
Amygdala and Hippocampal Volumetry
99m
FDG-PET and Tc-ECD SPECT were performed during the interictal period (ie, no seizure had occurred more than 24 hours). 18 F-FDG PET and 99m Tc-ECD SPECT scans were performed using a PET scanner (Siemens TruePoint Biograph 16) and a SPECT scanner (Siemens E-CAM), respectively.
MR Imaging Data Analysis and Statistics The following MR analyses were performed in 14 patients (Table 2, patients 10-23) and 20 controls whose images were ob-
We used the software FreeSurfer (version 5.1, https://surfer.nmr.mgh.harvard.edu) for the assessment of the amygdala and hippocampal volumes of the 14 patients and 20 control subjects who underwent 3.0-Tesla MRI.8-12 Image processing included the removal of nonbrain tissue with a hybrid watershed/surface deformation procedure, automated Talairach transformation, and segmentation of the subcortical white and gray matter. An example of a volume of interest (VOI) in the amygdala is given in Figure 2. The amygdala and
Kimura et al.: Temporal Lobe Epilepsy with Unilateral Amygdala Enlargement
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Fig 2. Example of the labeling of the brain structure by FreeSurfer, including VOIs in the amygdala. VOIs are indicated in blue.
hippocampal volumes were obtained and then analyzed by paired t-tests to determine the laterality between the affected and nonaffected sides in AE patients and also evaluated the differences of amygdalar volume between the affected side in AE patients and those of the larger side in normal controls and between the nonaffected side of AE patients and the smaller side of the normal controls. All statistical analyses were performed using SPSS version 19.0 for Windows (IBM, Armonk, NY, USA). A P-value of < .05 was considered significant.
VBM in the Temporal Lobe To evaluate the temporal pole gray matter volumes of the 14 patients who underwent 3.0-Tesla MRI, we performed a VBM analysis as follows. Using the latest version of SPM8 (Wellcome Department of Imaging Neuroscience, London, UK), we segmented the MRIs into gray matter, white matter, and CSF images by a unified tissue-segmentation procedure after imageintensity nonuniformity correction. These segmented gray matter images were then spatially normalized to a customized template in the standardized anatomic space by using the DARTEL toolbox.13 To preserve the gray matter volume within each voxel, we modulated the images by the Jacobean determinants derived from the spatial normalization by DARTEL and then smoothed them by using an 8-mm full-width at half-maximum (FWHM) Gaussian kernel. For the statistical analysis of the comparison with the image database for the 21 controls, we calculated the z-score: ([control mean] – [individual value])/(control SD) for each brain region, using the average image and SD contained in the image database. These z-score maps were displayed by over-
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lay on tomographic sections and surface rendering of each individual brain using a previously reported software program.14 A z-score > 2 was defined as significant.
Pathological Methods Two patients underwent epileptic surgery at our institution (patients 1 and 2). For both patients, 4% paraform-aldehyde-fixed paraffin-embedded tissues of the amygdala, temporal lobe resection specimens, and hippocampus were available. All examined resected tissues were identically treated, grossly inspected, and measured. After representative small sections were fixed in glutaraldehyde or frozen, the remaining sections were fixed in 4% paraform-aldehyde. Temporal lobe resection specimens were cut so as to obtain representative tissue slices perpendicular to the cortical surface. The amygdala was cut into evaluable sections. Although the evaluable region of the hippocampal specimens was restricted in both cases, the hippocampal specimens were fully processed and serially sectioned perpendicular to the long axis; 6-µm-thick serial sections were stained with hematoxylin and eosin and by the Kluver-Barrera ¨ method. Immunohistochemistry was performed on selected sections with a Ventana Discovery autoimmunostainer (Ventana, Tucson, AZ). The following antibodies were employed: antiphosphorylated neurofilament (SMI 31, monoclonal; Sternberger Monoclonals, Lutherville, MD), antiglial fibrillary acidic protein (GFAP, monoclonal; DAKO, Glostrup, Denmark), antivimentin (monoclonal; DAKO), antineuronal nuclei (NeuN, monoclonal; Millipore, Bedford, MA). Evaluation was performed under light microscopy.
The classification system of focal cortical dysplasia (FCD) reported by Blümcke et al. was used to evaluate the temporal lobe resection specimens.15
Results Clinical Findings
amygdalar volume of the affected side in AE patients and those of the larger side in normal controls (P < .05). On the other side, there was no significant difference between the amygdalar volume of the nonaffected side in AE patients and those of the smaller side in normal controls (P = .15). VBM in Temporal Lobe
The clinical characteristics of the 9 patients scanned by 1.5TMRI are shown in Table 1 (patients 1-9), and those of the 14 patients scanned by 3.0T-MRI are shown in Table 2 (patients 10-23). Seventeen of the 23 patients had CPS, and six had GTC seizures. Eleven patients had an EEG focus in a left temporal area, 11 patients had an EEG focus in a right temporal area, and 1 patient had bilateral foci. The EEG in 22 patients indicated focal epileptiform discharges predominantly in the temporal area ipsilateral to the AE. The EEG in 1 patient (patient 12 in Table 2) indicated bilateral temporal areas. Twenty-one patients became seizure free or showed dramatic improvement by medical therapy. Because 2 patients (patients 1 and 2) had intractable seizures (Table 1), they received selective amygdalohippocampectomy and partial resection of the adjacent temporal lobe cortex including the temporal pole. They became free from seizures after surgery (Engel’s class I). The durations of postsurgical follow-up were 10 and 8 years, respectively.
Imaging Findings AE was detected on the left side in 11 patients and the right side in 12 patients (Tables 1 and 2). Interictal 18 F-FDG PET, which was performed in 10 patients, showed regional hypometabolism in the temporal area ipsilateral to the AE in all 10 patients. Interictal 99m Tc-ECD SPECT, which was performed in 9 patients, detected regional hypoperfusion in the temporal area ipsilateral to the AE in 7 patients and normal uptake in 2 patients (patients 4 and 12).
MR Imaging Data Analysis Amygdala and Hippocampal Volumetry
Table 2 showed the amygdalae and hippocampal volumes in each patient. On the side of the AE with seizure focus, the amygdalar volume ranged from 1570.0 mm3 to 2918.0 mm3 , with a mean volume of 2244.4 ± 345.6 mm3 . On the contralateral side, the amygdalar volume was smaller and ranged from 1439.0 mm3 to 2168.0 mm3 , with a mean volume of 1816.5 ± 272.5 mm3 . There was a significant difference between the two sides (P < .05). On the ipsilateral side of the AE, the hippocampal volume ranged from 3280.0 mm3 to 6194.0 mm3 , with a mean volume of 4934.3 ± 677.6 mm3 . On the contralateral side, the hippocampal volume was smaller and ranged from 3898.0 mm3 to 5560.0 mm3 , with a mean volume of 4541.5 ± 578.7 mm3 . There was no significant difference between the two sides (P = .18). In normal controls, the larger amygdalar volume was ranged from 1313.0 mm3 to 2214.0 mm3 , with a mean volume of 1768.4 ± 226.1 mm3 , and the smaller amygdalar volume ranged from 1225.0 mm3 to 2140.0 mm3 , with a mean volume of 1683.5 ± 229.5 mm3 . There was no significant difference between the two sides (P = .25). There was a significant difference between the
Of the 14 patients with AE, 7 (50.0%) showed significant increases of gray matter volumes of temporal pole on the side of the AE compared to the normal controls by VBM (see Fig 3 and Table 2). There were no cases with a significant decrease of gray matter volume of the ipsilateral temporal pole. Neuropathological Findings
Patient 1: In the temporal lobe, a disorganized cortical layer with abundant microcolumnar organization and a small amount of dysmorphic neurons were observed. In the amygdala, increased neuronal density with frequent clustering of neurons was noted, but no evidence of tumor was present (Fig 4). No apparent abnormality was observed in the small piece of hippocampus. Patient 2: In the temporal lobe, although cortical layering was relatively spared compared to patient 1, abnormal myelination and a cluster of hypertrophic neurons in the cortex, plus ectopic neurons in the white matter, were observed. In the amygdala, clustering of hypertrophic neurons, but no evidence of tumor, was seen (Fig 5). No apparent abnormality was seen in the hippocampus. In summary, we observed cortical dysplastic abnormality in the amygdala from both patients. In addition, according to the Blümcke classification,15,16 the temporal lobe from both patients revealed abnormalities consistent with FCD type IIa and type Ic, respectively. There were no features of neoplasm nor HS. The pathological degree of dysplasia of patient 2 was milder than that of patient 1, although the MR findings of the 2 patients were not notably different.
Discussion We reviewed a series of clinical and MR imaging findings of 23 TLE patients with ipsilateral AE, which is the largest number of patients among the published studies of TLE with AE, to the best of our knowledge. Their age of onset was relatively older compared with those of HS,1 and the TLE of most of the patients was well controlled by medical therapy. Our MRI analysis showed significant increases of gray matter volumes of the temporal pole on the side of the AE by VBM in 50% of the patients. The pathology obtained from 2 patients who had intractable epilepsy revealed cortical dysplasia not only in the amygdala but also in the ipsilateral temporal pole. This is the first report that FCD extended to the ipsilateral temporal pole in some AE patients. AE in patients with TLE without neoplasm was first described in detail by Bower et al. in 2003.1 They identified 11 “image-negative” TLE patients from among 174 TLE patients. “Image-negative” was defined by the absence of neocortical lesion, normal hippocampal volumetry, and absence of any
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Fig 3. A 66-year-old patient with a 6-month history of left TLE (patient 15). (A) A FLAIR coronal image and (B) a T2-weighted axial image show left amygdala enlargement (arrow). (C) SPM8 plus DARTEL analysis with global normalization revealed a significant increase of gray matter volume in the left amygdala (arrow) and in the medial and inferior temporal pole cortex (arrowhead). Colored areas with z -scores > 2 are overlaid as significantly enlarged regions. (D) T1-weighted axial images without colored areas of (C).
increased signal in the mesial temporal lobe. Seven of the 11 “image-negative” patients had both significant amygdala asymmetry and amygdala enlargement, concordant with seizure lateralization. Bower et al. suggested that AE was a subgroup of “image-negative” TLE. They also reported that the age of onset was older in their patients with AE compared with those with HS.1 Since then, only three reports of TLE patients with AE have been published, to our knowledge,2,56 and the reports noted that the patients had a trend of relatively late-onset
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seizures and were well controlled with antiepileptic drugs. Kim et al. recently reported that eight of 12 AE patients who underwent surgical treatment revealed FCD, and the others had neoplasms such as ganglioglioma or astrocytoma.6 It is suggested that FCD is the most common pathology in patients with AE.6 Although the other two studies2,5 performed image analyses including PET findings of AE, there appears to be no study describing ipsilateral temporal pole abnormalities in TLE patients with AE.
Fig 4. A 23-year-old patient with a 20 year-history left TLE (patient 1). (A) FLAIR coronal image shows left amydgala enlargement (arrow). (B) Microcolumnar organization (arrows) seen in the disorganized cortical layer form the temporal lobe. (C) Scattered dysmorphic neurons (arrows) in the cortex adjacent to that seen in panel (A). (D) High magnification of typical dysmorphic neuron (arrow) seen in panel (B). (E) Clustering of small neurons in the amygdala. (B), (C), and (E): Klüver-Barrera stain. (D) Hematoxylin-eosin stain. (B) Bar = 20 µm, (C) Bar = 100 µm, (D) Bar = 50 µm.
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Fig 5. A 25-year-old patient with a 5-year history of right TLE (patient 2). (A) A FLAIR coronal image shows right amydgala enlargement (arrow). (B) Clustering of relatively hypertrophic neurons in the amygdala. (B) Klüver-Barrera stain, bar = 50 µm.
FCD is a localized cerebral cortical malformation that causes epilepsy in children and adults. The etiology of FCD is not clear, and the contribution of congenital factors and acquired changes is currently being discussed. The histopathologic features of FCD range from mild cortical dyslamination to severer forms. According to the Palmini classification system,17 FCD
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can be histopathologically distinguished as types I and II. In 2011, the International League Against Epilepsy (ILAE) Task Force introduced a new classification system,15 as follows. In FCD type I, there is isolated neocortical dyslamination that may be radial (type Ia), tangential (type Ib), or a combination of both (type Ic). FCD type II also has isolated neocortical dyslamination. Type IIa also has dysmorphic neurons, and type IIb has balloon cells with or without dysmorphic neurons. Type III includes other epileptogenic lesions in association with FCD type I. For example, type IIIa show HS, type IIIb epileptogenic tumors, type IIIc vascular malformations, and type IIId lesions acquired during early life (eg, as a result of trauma, ischemic injury, or encephalitis). We performed a histopathological analysis of 2 young patients who underwent surgical resection, and we observed cortical dysplasia in the enlarged amygdala and in the adjacent ipsilateral temporal pole in each patient. In the MRI analysis, 7 (50%) patients showed a significant increase of gray matter volume of the temporal pole on the ipsilateral side of the AE by VBM. It was postulated that cortical dysplasia of the amygdala may extend to the ipsilateral temporal pole. In general, cerebral FCD was detected as increased gray matter volume by VBM analysis.18,19 In the present study, most of the AE patients were free from seizures after taking antiepileptic drugs. Only 2 patients had intractable seizures and thus underwent surgery. Patient 1 was a 23-year-old female who had suffered from epilepsy for 20 years, and patient 2 was a 25-year-old female with a 5-year history. The histopathological analysis of both patients revealed that cortical dysplasia extended from the amygdala to the ipsilateral temporal pole. In the amygdalae of both patients, there were no dysmorphic neurons or balloon cells, and no disorganized cortical architecture or clusters of neurons, and we thus thought that their amygdalar pathologies were cortical dysplasia. However, in the temporal pole, patient 1 had FCD type IIa and patient 2 had FCD type Ic. Our histopathological analysis revealed that the severity of dysplasia in the amygdala and temporal pole of patient 1 greater than that of patient 2. This may indicate that the age of onset is affected by the severity of dysplasia. FCD type II patients have an earlier age of seizure onset and histopathologically severer than FCD type I.20 Tassi et al.21 reported the surgical outcomes of 215 patients with FCD type I.24 Of these 215 patients, 133 (62%) had FCD localized in the temporal lobe. Unlike FCD type II, FCD type I is not clearly defined by MRI.22 FCD type I is most commonly found in the temporal lobe, where it is associated with ipsilateral hippocampal sclerosis in more than 70% of cases.23 This type of dual pathology is equivalent to type IIIa in the new ILAE classification.15 Pail et al. reported that VBM made a superior contribution to the detection of temporopolar structural malformations compared to visual inspection.18 Many studies have discussed the accuracy of techniques that evaluate the volume of specific brain structures, such as the hippocampus or amygdala by comparing the volumes with those that are manually obtained. Three reports describe amygdalar volume measurements in AE patients; two of the studies used hand-tracing1,2 and the third used VBM.5 We evaluated amygdala and hippocampaus volumes by using FreeSurfer in
the present study, because the measurement of amygdala and hippocampaus volumes with FreeSurfer was reported to be highly correlated to hand tracing24 and it measures not only the amygdala but also the hippocampus simultaneously. Our results showed that there was no significant difference in the hippocampal volume between the ipsilateral and contralateral sides, and that concomitant HS was unlikely. There are several limitations of our study. The first one was that because this was a retrospective study, not all patients were examined by 3.0-Tesla MRI. Nine of the 23 patients were examined by 1.5-Tesla MRI. There are differences in scan protocols (such as slice thickness) between 1.5 and 3.0-Tesla MRI in the detection and in accuracy of characterization of structural brain abnormalities in the patients with epilepsy.25 All 20 healthy controls underwent a 3.0-Tesla MRI. The VBM was thus applicable only to the 3.0-Tesla MRI data since the control data were acquired only by 3.0-Tesla MRI. The second limitation was that the diagnosis in the patients who underwent 3.0-Tesla MRI had not been proved by pathological studies. We studied a limited number of patients with histopathological proof, and additional investigation are needed to understand further explore the radiological and pathological correlations in AE cases on 3.0-Tesla MRI.
Conclusions We retrospectively reviewed the clinical and MR imaging findings of TLE patients with AE. AE can be defined as a subtype of TLE. In some of the AE patients, FCD extended to the temporal pole, and this information would be useful to advise the excision site. Further studies of AE should be conducted to clarify the etiology of TLE.
Acknowledgments We are grateful to Dr. Kinuko Suzuki, Neuropathologist at the Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology for her help.
Conflict of Interest We declare that we have no Conflict of interest.
References 1. Bower SPC, Vogrin SJ, Morris K, et al. Amygdala volumetry in “imaging-negative” temporal lobe epilepsy. J Neurol Neurosurg Psychiatr 2003;74:1245-1249. 2. Mitsueda-Ono T, Ikeda A, Inouchi M, et al. Amygdalar enlargement in patients with temporal lobe epilepsy. J Neurol Neurosurg Psychiatr 2011;82:652-657. 3. Paesschen WV, Connelly A, Johnson CL, et al. The amygdala and intractable temporal lobe epilepsy: a quantitative magnetic resonance imaging study. Neurology 1996;47:1021-1031. 4. Gyimesi C, Pannek H, Woermann FG, et al. Absolute spike frequency and etiology predict the surgical outcome in epilepsy due to amygdale lesions. Epilepsy Res 2010;92:177-182. 5. Takaya S, Ikeda A, Mistueda-Ono T, et al. Temporal lobe epilepsy with amygdala enlargement: a morphologic and functional study. J Neuroimaging 2014;24:54-62.
6. Kim DW, Lee SK, Chung CK, et al. Clinical features and pathological characteristics of amygdala enlargement in mesial temporal lobe epilepsy. J Clin Neurosci 2012;19:509-512. 7. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndrome. Epilepsia 1989;30:389399. 8. Fischl B, Sereno MI, Tootell RB, et al. High-resolution intersubject averaging and a coordinate system for the cortical surface. Hum Brain Mapp 1999;8:272-284. 9. Fischl B, Sereno MI, Dale AM. Cortical surface-based analysis. II: inflation, flattening, and a surface-based coordinate system. Neuroimage 1999;9:195-207. 10. Fischl B, Dale AM. Measuring the thickness of the human cerebral cortex from magnetic resonance images. Proc Natl Acad Sci USA 2000;97:11050-11055. 11. Fischl B, Liu A, Dale AM. Automated manifold surgery: constructing geometrically accurate and topologically correct models of the human cerebral cortex. IEEE Trans Med Imaging 2001;20: 70-80. 12. Fischl B, Salat DH, Busa E, et al. Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain. Neuron 2002;33:341-355. 13. Ashburner J. A fast diffeomorphic image registration algorithm. Neuroimage 2007;38:95-113. 14. Matsuda H, Mizumura S, Nemoto K, et al. Automatic voxelbased morphometry of structural MRI by SPM8 plus diffeomorphic anatomic registration through exponentiated lie algebra improves the diagnosis of probable Alzheimer disease. AJNR Am J Neuoradiol 2012;33:1109-1114. 15. Blümcke I, Thom M, Aronica E, et al. The clinicopathologic spectrum of focal cortical dysplasias: a consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission. Epilepsia 2011;52:158-174. 16. Coras R, Boer OJ, Armstrong D, et al. Good interobserver and intraobserver agreement in the evaluation of the new ILAE classification of focal cortical dysplasias. Epilepsia 2012;53:13411348. 17. Palmini A, Najm I, Avanzini G, et al. Terminology and classification of the cortical dysplasias. Neurology 2004;62:S2-S8. 18. Pail M, Marecek R, Hermanova M, et al. The role of voxelbased morphometry in the detection of cortical dysplasia within the temporal pole in patients with intractable mesial temporal lobe epilepsy. Epilepsia 2012;54:1004-1012. 19. Bonilha L, Montenegro MA, Rorden C, et al. Voxel-based morphometry reveals excess gray matter concentration in patients with focal cortical dysplasia. Epilepsia 2006;47:908-915. 20. Krsek P, Pieper T, Karlmeier A, et al. Different presurgical characteristics and seizure outcomes in children with focal cortical dysplasia type I or II. Epilepsia 2009;50:125-137. 21. Tassi L, Gabelli R, Colombo N, et al. Type I focal cortical dysplasia: surgical outcome is related to histopathology. Epileptic Disord 2010;12:181-191. 22. Colombo N, Salamon N, Raybaud C, et al. Imaging of malformations of cortical development. Epileptic Disord 2009;11:194-205. 23. Diehl B, Najm I, La Presto E, et al. Temporal lobe volumes in patients with hippocampal sclerosis with or without cortical dysplasia. Neurology 2004;62:1729-1735. 24. Morey RA, Petty CM, Xu Y, et al. A comparison of automated segmentation and manual tracing for quantifying hippocampal and amygdale volumes. Neuroimage 2009;45:855-866. 25. Phal PM, Usmanov A, Nesbit GM, et al. Qualitative comparison of 3-T and 1.5-T MRI in the evaluation of epilepsy. Am J Roentgenol 2008;191:890-895.
Kimura et al.: Temporal Lobe Epilepsy with Unilateral Amygdala Enlargement
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ABSTRACT BACKGROUND AND PURPOSE
Amygdala enlargement (AE) has been reported as an epileptogenic focus in subtypes of temporal lobe epilepsy (TLE). The purpose of this study was to investigate the clinical, morphological, and pathological characteristics of AE. METHODS
We retrospectively reviewed the clinical data and imaging findings of 23 TLE patients with ipsilateral AE. We performed morphological MR analyses using FreeSurfer and voxelbased morphometry (VBM) in 14 of the 23 patients and in 20 controls whose images were obtained by a 3.0-Tesla MRI. A pathological study was also performed in 2 patients who underwent operations. RESULTS
Keywords: Amygdala enlargement, focal cortical dysplasia, temporal pole, FreeSurfer, voxel-based morphometry. Acceptance: Received June 18, 2013, and in revised form October 31, 2013. Accepted for publication November 19, 2013. Correspondence: Address correspondence to E-mail: [email protected] J Neuroimaging 2014;00:1-9. DOI: 10.1111/jon.12106
All patients became seizure free or shSowed dramatic improvement by medical therapy except for two. They received operations and their pathology revealed that both patients had cortical dysplasia in from the amygdala to the ipsilateral temporal pole. The FreeSurfer analysis showed a significant difference in the amygdala volumes between the affected and nonaffected sides. VBM revealed significant increases of gray matter volumes of the temporal pole on the side of AE in seven of the 14 patients with AE (50%). CONCLUSIONS
Cortical dysplasia may be one of the pathological diagnoses in AE, and in some patients it may extend to the temporal pole.
Introduction Hippocampal sclerosis (HS) is the most common cause of epilepsy requiring surgical treatment.1 Amygdala, which is a part of the limbic system, is also an important source of epileptic seizures, but it has received less attention than the hippocampus. Invasive electrophysiological studies indicated that 5-10% of patients with temporal lobe epilepsy (TLE) had seizure onset in the amygdalae.2,3 Neuropathological studies have demonstrated isolated amygdala abnormalities in patients with intractable TLE, and their etiologies varied: gangliogliomas, astrocytomas, vascular lesions, amygdala sclerosis, cortical dysplasia, and others.4 Nontumoral unilateral amygdala enlargement (AE) has been reported in patients with TLE.1,2,5,6 The authors of these reports noted that AE could be an epileptogenic focus; the clinical and pathological features of nontumoral unilateral AE have not been well documented because many cases were well controlled
without surgical resection and the number of reports is low. We have encountered patients whose amygdalae were enlarged on MR images and whose pathological findings showed cortical dysplasia in the amygdala extending into the ipsilateral temporal pole. We retrospectively reviewed the clinical and imaging findings of cases of TLE in patients with AE, and we analyzed their amygdalae, hippocampi, and temporal poles to evaluate their gray matter volume compared to that of normal controls.
Materials and Methods Participants We retrospectively reviewed an electronic database of radiology reports of 16,951 patients who underwent brain MR imaging examinations at our institution between March 2003 and August 2012, and we searched for reports that indicated TLE. The radiological reports identified 732 patients as having TLE,
Copyright
◦ 2014 by the American Society of Neuroimaging C
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head trauma, infarction, hemorrhage or surgical history; (4) vascular abnormalities such as cavernous malformation and arteriovenous malformation. As a consequence, 23 patients with unilateral AE with ipsilateral TLE were enrolled (Tables 1 and 2). Nine were males and 14 were females, from 12 to 77 years of age, with a mean age of 36.8 ± 19.5 years. Their average age at the onset of seizure was 29.8 ± 22.4 years. All patients received MR examination. 18 Ffluorodeoxyglucose-positron emission tomography (18 F- FDGPET) and 99mTc ethyl cysteinate dimer single photon emission CT (99m Tc-ECD SPECT) were also performed under interictal status in 10 and 9 patients, respectively, to support the clinical diagnosis, because temporal hypometabolism and hypoperfusion were characteristic findings of TLE in interictal 18 F-FDG PET and 99m Tc-ECD SPECT,8–10 relatively. We also reviewed clinical data including the length of time from the first seizure onset, the type of seizures, response to drug therapy, and interictal epileptiform discharge on electroencephalogram (EEG) as well as MRI, 18 F-FDG PET, and 99m Tc-ECD SPECT findings. Twenty age-matched healthy subjects (12 females and 8 males) without neurological nor psychiatric disorders were the control group. The mean age of the controls was 42.7 years (SD 15.5 years; range 22-65 years). Institutional review board approval was obtained. The written informed consents were obtained from the control subjects, but patients’ informed consent was not required for the retrospective review.
MR Imaging Acquisition
Fig 1. A 37-year-old patient with a 3-year history of right TLE (patient 12). (A) A FLAIR coronal image and (B) a T2-weighted axial image show right amydgala enlargement (arrows).
and from this population we selected the patients whose unilateral amygdala was enlarged and who showed focal epileptiform discharge predominantly in the temporal area ipsilateral to the AE, according to the patient’ medical records (Fig 1). The AE was definite on visual inspection. The diagnosis of TLE was based on the presence of complex partial seizures (CPS) consistent with TLE.7 Six patients (patients 1, 5, 6, 9, 10, and 13) had generalized tonic–clonic (GTC) seizures, but EEG seizure patterns arising from the temporal area ipsilateral to the AE were observed. Patients with the following criteria were excluded: (1) highly suspected tumoral lesions in MR imaging such as calcification, cystic changes, or contrast enhancement; (2) hippocampal abnormalities in MR imaging on visual inspection; (3) significant past medical history of encephalitis/meningitis, severe
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Brain MR examinations were performed during an interictal period on 1.5-Tesla scanner (Magnetom Symphony, Siemens, Erlangen, Germany) (Table 1, patients 1-9) and 3.0-Tesla scanner (Achieva, Philips, Best, the Netherlands) (Table 2, patients 10-23), according to protocols specifically designed for epilepsy studies: (a) high-resolution 3-dimensional (3D) sagittal T1-weighted magnetization prepared rapid acquisition with gradient echo sequence (MPRAGE) with and without contrast medium (gadolinium-DTPA, .1 mmol/kg of body weight), with a repetition time (TR)/echo time (TE)/flip angle (FA)/ number of excitations (NEX) of 1600 milliseconds/2.64 milliseconds/15°/1 or 7.12 milliseconds/3.4 milliseconds/10°/1, 1.2mm or .60-mm thickness with no gap, 144 or 300 slices, 256 × 256 or 260 × 320 matrix, 26 cm field of view (FOV); (b) transverse turbo spin echo T2-weighted images: TR/TE/FA/NEX; 3,800 milliseconds/95 milliseconds/150°/1 or 4,507 milliseconds/80 milliseconds/90°/2, 5.0 mm or 3.0 mm thickness with 1.8 mm or 1.5 mm gap, 20 slices or 34 slices, matrix; 291 × 512 or 365 × 368, 25 cm FOV; (c) coronal fluid-attenuated inversion recovery (FLAIR) images: TR/TE/FA/NEX; 9,000 milliseconds/101 milliseconds/170°/1 or 10,000 milliseconds/120 milliseconds/90°/2, 5.0 mm or 3.0 mm thickness with 1.8 mm or 1.5 mm gap, 20 slices or 35-42 slices, matrix; 179 × 256 or 202 × 320, 25 cm FOV; (d) coronal turbo short-tau inversion recovery (STIR) images with TR/TE/inversion time (TI)/FA/NEX of 4,200 milliseconds/81 milliseconds/180 milliseconds/180°/1 or 4724 milliseconds/80 milliseconds/220 milliseconds/90°/2, 5.0 mm thickness with 1.0 mm gap or 3.0 mm thickness with 1.5 mm gap, 20 or 34 slices, 224 × 512 or 204 × 312
Table 1. Clinical Profile of the 9 Temporal Lobe Epilepsy Patients with Ipsilateral Amygdala Enlargement (AE) Scanned by 1.5-T MRI Clinical Findings Patient No.
1* 2* 3 4 5 6 7 8 9
Current Status
Age/Sex (Years)
Age of Seizure Onset (Years)
Seizure Type
Abnormal EEG Side
AE** Side
Seizure Frequency after Therapy
Current Medication
23/F 25/F 40/F 47/M 23/F 30/F 19/F 15/F 77/M
3 20 4 47 17 24 19 5 75
GTC CPS CPS CPS GTC GTC CPS CPS GTC
L R R L L L L L R
L R R L L L L L R
Free Free Free 1-2/Mo Free Free Free 1/year Free
None (received operation) None (received operation) CBZ CBZ CBZ CBZ, ZNS PB CBZ, CZP CBZ
Bil, bilateral; R, right; L, left; CPS, complex partial seizure; GTC, generalized tonic–clonic seizure; CZP, clonazepam; CBZ, carbamazepine; PB, phenobarbital; ZNS, zonisamide. * Pathology was obtained. ** Visually assessed by MRI.
Table 2. Clinical Profile and MR Analysis of the 14 Temporal Lobe Epilepsy Patients with Ipsilateral Amygdale Enlargement (AE) Examined by 3.0-T MRI
Patient No.
10 11 12 13 14 15 16 17 18 19 20 21 22 23
Amygdala Volume (mm3 )
L
Increased Gray** Matter Volume of Temporal Pole
Seizure Frequency after Therapy
Current Medication
5154 4453 4709 3990 5560 4903 3280 4640 4260 5450 4409 4308 4938 3898
NS + + NS NS + + + NS + NS NS NS +
1/Mo free 1/3Mo free 1/Mo free free free free free 1/Mo free free free
CBZ ZNS CBZ CZP CBZ CBZ CBZ CBZ CBZ CBZ, CZP CBZ LEV LEV CBZ
Hippocampus Volume (mm3 )
Age/Sex (Years)
Age of Seizure Onset (Years)
Seizure Type
Abnormal EEG Side
AE* Side
R
L
R
38/M 55/M 37/M 19/F 54/M 66/F 65/M 51/F 34/F 18/F 12/M 22/F 13/M 63/F
18 40 34 9 52 66 62 49 34 15 11 8 12 61
GTC CPS CPS GTC CPS CPS CPS CPS CPS CPS CPS CPS CPS CPS
R R Bil R R L L R R L R L L R
R R R R R L L R R L R L L R
2349 1874 2918 2315 2027 1639 1439 2165 2681 2117 2116 1458 2121 2192
1926 1550 2035 2140 1908 2491 1917 1546 2168 2470 1756 1570 2336 1628
6194 4901 5663 4949 5288 4380 3716 5040 4633 5535 5058 4011 4864 4475
Bil, bilateral; R, right; L, left; CPS, complex partial seizure; GTC, generalized tonic–clonic seizure; CZP, clonazepam; CBZ, carbamazepine; LEV, levetiracetam; ZNS, zonisamide. * Visually assessed by MRI. ** z-scores >2 was considered significant comparing to normal data base in a VBM study. +:significant, NS: not significant.
matrix, 25 cm FOV. All 20 healthy controls underwent a 3.0Tesla MR imaging study with the epilepsy protocols described above.
tained on a 3.0-Tesla MR scanner. The patients group consisted of 7 males and 7 females, from 12 to 66 years of age, with a mean age of 39.1 ± 19.9 years.
PET and SPECT
Amygdala and Hippocampal Volumetry
99m
FDG-PET and Tc-ECD SPECT were performed during the interictal period (ie, no seizure had occurred more than 24 hours). 18 F-FDG PET and 99m Tc-ECD SPECT scans were performed using a PET scanner (Siemens TruePoint Biograph 16) and a SPECT scanner (Siemens E-CAM), respectively.
MR Imaging Data Analysis and Statistics The following MR analyses were performed in 14 patients (Table 2, patients 10-23) and 20 controls whose images were ob-
We used the software FreeSurfer (version 5.1, https://surfer.nmr.mgh.harvard.edu) for the assessment of the amygdala and hippocampal volumes of the 14 patients and 20 control subjects who underwent 3.0-Tesla MRI.8-12 Image processing included the removal of nonbrain tissue with a hybrid watershed/surface deformation procedure, automated Talairach transformation, and segmentation of the subcortical white and gray matter. An example of a volume of interest (VOI) in the amygdala is given in Figure 2. The amygdala and
Kimura et al.: Temporal Lobe Epilepsy with Unilateral Amygdala Enlargement
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Fig 2. Example of the labeling of the brain structure by FreeSurfer, including VOIs in the amygdala. VOIs are indicated in blue.
hippocampal volumes were obtained and then analyzed by paired t-tests to determine the laterality between the affected and nonaffected sides in AE patients and also evaluated the differences of amygdalar volume between the affected side in AE patients and those of the larger side in normal controls and between the nonaffected side of AE patients and the smaller side of the normal controls. All statistical analyses were performed using SPSS version 19.0 for Windows (IBM, Armonk, NY, USA). A P-value of < .05 was considered significant.
VBM in the Temporal Lobe To evaluate the temporal pole gray matter volumes of the 14 patients who underwent 3.0-Tesla MRI, we performed a VBM analysis as follows. Using the latest version of SPM8 (Wellcome Department of Imaging Neuroscience, London, UK), we segmented the MRIs into gray matter, white matter, and CSF images by a unified tissue-segmentation procedure after imageintensity nonuniformity correction. These segmented gray matter images were then spatially normalized to a customized template in the standardized anatomic space by using the DARTEL toolbox.13 To preserve the gray matter volume within each voxel, we modulated the images by the Jacobean determinants derived from the spatial normalization by DARTEL and then smoothed them by using an 8-mm full-width at half-maximum (FWHM) Gaussian kernel. For the statistical analysis of the comparison with the image database for the 21 controls, we calculated the z-score: ([control mean] – [individual value])/(control SD) for each brain region, using the average image and SD contained in the image database. These z-score maps were displayed by over-
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lay on tomographic sections and surface rendering of each individual brain using a previously reported software program.14 A z-score > 2 was defined as significant.
Pathological Methods Two patients underwent epileptic surgery at our institution (patients 1 and 2). For both patients, 4% paraform-aldehyde-fixed paraffin-embedded tissues of the amygdala, temporal lobe resection specimens, and hippocampus were available. All examined resected tissues were identically treated, grossly inspected, and measured. After representative small sections were fixed in glutaraldehyde or frozen, the remaining sections were fixed in 4% paraform-aldehyde. Temporal lobe resection specimens were cut so as to obtain representative tissue slices perpendicular to the cortical surface. The amygdala was cut into evaluable sections. Although the evaluable region of the hippocampal specimens was restricted in both cases, the hippocampal specimens were fully processed and serially sectioned perpendicular to the long axis; 6-µm-thick serial sections were stained with hematoxylin and eosin and by the Kluver-Barrera ¨ method. Immunohistochemistry was performed on selected sections with a Ventana Discovery autoimmunostainer (Ventana, Tucson, AZ). The following antibodies were employed: antiphosphorylated neurofilament (SMI 31, monoclonal; Sternberger Monoclonals, Lutherville, MD), antiglial fibrillary acidic protein (GFAP, monoclonal; DAKO, Glostrup, Denmark), antivimentin (monoclonal; DAKO), antineuronal nuclei (NeuN, monoclonal; Millipore, Bedford, MA). Evaluation was performed under light microscopy.
The classification system of focal cortical dysplasia (FCD) reported by Blümcke et al. was used to evaluate the temporal lobe resection specimens.15
Results Clinical Findings
amygdalar volume of the affected side in AE patients and those of the larger side in normal controls (P < .05). On the other side, there was no significant difference between the amygdalar volume of the nonaffected side in AE patients and those of the smaller side in normal controls (P = .15). VBM in Temporal Lobe
The clinical characteristics of the 9 patients scanned by 1.5TMRI are shown in Table 1 (patients 1-9), and those of the 14 patients scanned by 3.0T-MRI are shown in Table 2 (patients 10-23). Seventeen of the 23 patients had CPS, and six had GTC seizures. Eleven patients had an EEG focus in a left temporal area, 11 patients had an EEG focus in a right temporal area, and 1 patient had bilateral foci. The EEG in 22 patients indicated focal epileptiform discharges predominantly in the temporal area ipsilateral to the AE. The EEG in 1 patient (patient 12 in Table 2) indicated bilateral temporal areas. Twenty-one patients became seizure free or showed dramatic improvement by medical therapy. Because 2 patients (patients 1 and 2) had intractable seizures (Table 1), they received selective amygdalohippocampectomy and partial resection of the adjacent temporal lobe cortex including the temporal pole. They became free from seizures after surgery (Engel’s class I). The durations of postsurgical follow-up were 10 and 8 years, respectively.
Imaging Findings AE was detected on the left side in 11 patients and the right side in 12 patients (Tables 1 and 2). Interictal 18 F-FDG PET, which was performed in 10 patients, showed regional hypometabolism in the temporal area ipsilateral to the AE in all 10 patients. Interictal 99m Tc-ECD SPECT, which was performed in 9 patients, detected regional hypoperfusion in the temporal area ipsilateral to the AE in 7 patients and normal uptake in 2 patients (patients 4 and 12).
MR Imaging Data Analysis Amygdala and Hippocampal Volumetry
Table 2 showed the amygdalae and hippocampal volumes in each patient. On the side of the AE with seizure focus, the amygdalar volume ranged from 1570.0 mm3 to 2918.0 mm3 , with a mean volume of 2244.4 ± 345.6 mm3 . On the contralateral side, the amygdalar volume was smaller and ranged from 1439.0 mm3 to 2168.0 mm3 , with a mean volume of 1816.5 ± 272.5 mm3 . There was a significant difference between the two sides (P < .05). On the ipsilateral side of the AE, the hippocampal volume ranged from 3280.0 mm3 to 6194.0 mm3 , with a mean volume of 4934.3 ± 677.6 mm3 . On the contralateral side, the hippocampal volume was smaller and ranged from 3898.0 mm3 to 5560.0 mm3 , with a mean volume of 4541.5 ± 578.7 mm3 . There was no significant difference between the two sides (P = .18). In normal controls, the larger amygdalar volume was ranged from 1313.0 mm3 to 2214.0 mm3 , with a mean volume of 1768.4 ± 226.1 mm3 , and the smaller amygdalar volume ranged from 1225.0 mm3 to 2140.0 mm3 , with a mean volume of 1683.5 ± 229.5 mm3 . There was no significant difference between the two sides (P = .25). There was a significant difference between the
Of the 14 patients with AE, 7 (50.0%) showed significant increases of gray matter volumes of temporal pole on the side of the AE compared to the normal controls by VBM (see Fig 3 and Table 2). There were no cases with a significant decrease of gray matter volume of the ipsilateral temporal pole. Neuropathological Findings
Patient 1: In the temporal lobe, a disorganized cortical layer with abundant microcolumnar organization and a small amount of dysmorphic neurons were observed. In the amygdala, increased neuronal density with frequent clustering of neurons was noted, but no evidence of tumor was present (Fig 4). No apparent abnormality was observed in the small piece of hippocampus. Patient 2: In the temporal lobe, although cortical layering was relatively spared compared to patient 1, abnormal myelination and a cluster of hypertrophic neurons in the cortex, plus ectopic neurons in the white matter, were observed. In the amygdala, clustering of hypertrophic neurons, but no evidence of tumor, was seen (Fig 5). No apparent abnormality was seen in the hippocampus. In summary, we observed cortical dysplastic abnormality in the amygdala from both patients. In addition, according to the Blümcke classification,15,16 the temporal lobe from both patients revealed abnormalities consistent with FCD type IIa and type Ic, respectively. There were no features of neoplasm nor HS. The pathological degree of dysplasia of patient 2 was milder than that of patient 1, although the MR findings of the 2 patients were not notably different.
Discussion We reviewed a series of clinical and MR imaging findings of 23 TLE patients with ipsilateral AE, which is the largest number of patients among the published studies of TLE with AE, to the best of our knowledge. Their age of onset was relatively older compared with those of HS,1 and the TLE of most of the patients was well controlled by medical therapy. Our MRI analysis showed significant increases of gray matter volumes of the temporal pole on the side of the AE by VBM in 50% of the patients. The pathology obtained from 2 patients who had intractable epilepsy revealed cortical dysplasia not only in the amygdala but also in the ipsilateral temporal pole. This is the first report that FCD extended to the ipsilateral temporal pole in some AE patients. AE in patients with TLE without neoplasm was first described in detail by Bower et al. in 2003.1 They identified 11 “image-negative” TLE patients from among 174 TLE patients. “Image-negative” was defined by the absence of neocortical lesion, normal hippocampal volumetry, and absence of any
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Fig 3. A 66-year-old patient with a 6-month history of left TLE (patient 15). (A) A FLAIR coronal image and (B) a T2-weighted axial image show left amygdala enlargement (arrow). (C) SPM8 plus DARTEL analysis with global normalization revealed a significant increase of gray matter volume in the left amygdala (arrow) and in the medial and inferior temporal pole cortex (arrowhead). Colored areas with z -scores > 2 are overlaid as significantly enlarged regions. (D) T1-weighted axial images without colored areas of (C).
increased signal in the mesial temporal lobe. Seven of the 11 “image-negative” patients had both significant amygdala asymmetry and amygdala enlargement, concordant with seizure lateralization. Bower et al. suggested that AE was a subgroup of “image-negative” TLE. They also reported that the age of onset was older in their patients with AE compared with those with HS.1 Since then, only three reports of TLE patients with AE have been published, to our knowledge,2,56 and the reports noted that the patients had a trend of relatively late-onset
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seizures and were well controlled with antiepileptic drugs. Kim et al. recently reported that eight of 12 AE patients who underwent surgical treatment revealed FCD, and the others had neoplasms such as ganglioglioma or astrocytoma.6 It is suggested that FCD is the most common pathology in patients with AE.6 Although the other two studies2,5 performed image analyses including PET findings of AE, there appears to be no study describing ipsilateral temporal pole abnormalities in TLE patients with AE.
Fig 4. A 23-year-old patient with a 20 year-history left TLE (patient 1). (A) FLAIR coronal image shows left amydgala enlargement (arrow). (B) Microcolumnar organization (arrows) seen in the disorganized cortical layer form the temporal lobe. (C) Scattered dysmorphic neurons (arrows) in the cortex adjacent to that seen in panel (A). (D) High magnification of typical dysmorphic neuron (arrow) seen in panel (B). (E) Clustering of small neurons in the amygdala. (B), (C), and (E): Klüver-Barrera stain. (D) Hematoxylin-eosin stain. (B) Bar = 20 µm, (C) Bar = 100 µm, (D) Bar = 50 µm.
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Fig 5. A 25-year-old patient with a 5-year history of right TLE (patient 2). (A) A FLAIR coronal image shows right amydgala enlargement (arrow). (B) Clustering of relatively hypertrophic neurons in the amygdala. (B) Klüver-Barrera stain, bar = 50 µm.
FCD is a localized cerebral cortical malformation that causes epilepsy in children and adults. The etiology of FCD is not clear, and the contribution of congenital factors and acquired changes is currently being discussed. The histopathologic features of FCD range from mild cortical dyslamination to severer forms. According to the Palmini classification system,17 FCD
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can be histopathologically distinguished as types I and II. In 2011, the International League Against Epilepsy (ILAE) Task Force introduced a new classification system,15 as follows. In FCD type I, there is isolated neocortical dyslamination that may be radial (type Ia), tangential (type Ib), or a combination of both (type Ic). FCD type II also has isolated neocortical dyslamination. Type IIa also has dysmorphic neurons, and type IIb has balloon cells with or without dysmorphic neurons. Type III includes other epileptogenic lesions in association with FCD type I. For example, type IIIa show HS, type IIIb epileptogenic tumors, type IIIc vascular malformations, and type IIId lesions acquired during early life (eg, as a result of trauma, ischemic injury, or encephalitis). We performed a histopathological analysis of 2 young patients who underwent surgical resection, and we observed cortical dysplasia in the enlarged amygdala and in the adjacent ipsilateral temporal pole in each patient. In the MRI analysis, 7 (50%) patients showed a significant increase of gray matter volume of the temporal pole on the ipsilateral side of the AE by VBM. It was postulated that cortical dysplasia of the amygdala may extend to the ipsilateral temporal pole. In general, cerebral FCD was detected as increased gray matter volume by VBM analysis.18,19 In the present study, most of the AE patients were free from seizures after taking antiepileptic drugs. Only 2 patients had intractable seizures and thus underwent surgery. Patient 1 was a 23-year-old female who had suffered from epilepsy for 20 years, and patient 2 was a 25-year-old female with a 5-year history. The histopathological analysis of both patients revealed that cortical dysplasia extended from the amygdala to the ipsilateral temporal pole. In the amygdalae of both patients, there were no dysmorphic neurons or balloon cells, and no disorganized cortical architecture or clusters of neurons, and we thus thought that their amygdalar pathologies were cortical dysplasia. However, in the temporal pole, patient 1 had FCD type IIa and patient 2 had FCD type Ic. Our histopathological analysis revealed that the severity of dysplasia in the amygdala and temporal pole of patient 1 greater than that of patient 2. This may indicate that the age of onset is affected by the severity of dysplasia. FCD type II patients have an earlier age of seizure onset and histopathologically severer than FCD type I.20 Tassi et al.21 reported the surgical outcomes of 215 patients with FCD type I.24 Of these 215 patients, 133 (62%) had FCD localized in the temporal lobe. Unlike FCD type II, FCD type I is not clearly defined by MRI.22 FCD type I is most commonly found in the temporal lobe, where it is associated with ipsilateral hippocampal sclerosis in more than 70% of cases.23 This type of dual pathology is equivalent to type IIIa in the new ILAE classification.15 Pail et al. reported that VBM made a superior contribution to the detection of temporopolar structural malformations compared to visual inspection.18 Many studies have discussed the accuracy of techniques that evaluate the volume of specific brain structures, such as the hippocampus or amygdala by comparing the volumes with those that are manually obtained. Three reports describe amygdalar volume measurements in AE patients; two of the studies used hand-tracing1,2 and the third used VBM.5 We evaluated amygdala and hippocampaus volumes by using FreeSurfer in
the present study, because the measurement of amygdala and hippocampaus volumes with FreeSurfer was reported to be highly correlated to hand tracing24 and it measures not only the amygdala but also the hippocampus simultaneously. Our results showed that there was no significant difference in the hippocampal volume between the ipsilateral and contralateral sides, and that concomitant HS was unlikely. There are several limitations of our study. The first one was that because this was a retrospective study, not all patients were examined by 3.0-Tesla MRI. Nine of the 23 patients were examined by 1.5-Tesla MRI. There are differences in scan protocols (such as slice thickness) between 1.5 and 3.0-Tesla MRI in the detection and in accuracy of characterization of structural brain abnormalities in the patients with epilepsy.25 All 20 healthy controls underwent a 3.0-Tesla MRI. The VBM was thus applicable only to the 3.0-Tesla MRI data since the control data were acquired only by 3.0-Tesla MRI. The second limitation was that the diagnosis in the patients who underwent 3.0-Tesla MRI had not been proved by pathological studies. We studied a limited number of patients with histopathological proof, and additional investigation are needed to understand further explore the radiological and pathological correlations in AE cases on 3.0-Tesla MRI.
Conclusions We retrospectively reviewed the clinical and MR imaging findings of TLE patients with AE. AE can be defined as a subtype of TLE. In some of the AE patients, FCD extended to the temporal pole, and this information would be useful to advise the excision site. Further studies of AE should be conducted to clarify the etiology of TLE.
Acknowledgments We are grateful to Dr. Kinuko Suzuki, Neuropathologist at the Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology for her help.
Conflict of Interest We declare that we have no Conflict of interest.
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Kimura et al.: Temporal Lobe Epilepsy with Unilateral Amygdala Enlargement
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