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Calgary Comprehensive Epilepsy Program, Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, AB, CanadaDivision of Neurosurgery, Department of Clinical Neurosciences, University of Calgary, AB, Canada
Calgary Comprehensive Epilepsy Program, Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, AB, CanadaDivision of Neurosurgery, Department of Clinical Neurosciences, University of Calgary, AB, Canada
Corresponding author at: Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, 12th Floor, Foothills Medical Centre, 1403 29th Street NW, Calgary, AB, T2N 2T9, Canada.
1 The Calgary Comprehensive Epilepsy Program collaborators: Paolo Federico, Yahya Agha-Khani, Nathalie Jette, Colin Josephson, William Murphy, Yves Starreveld, Rey Avendano, Salma Hanna.
1 The Calgary Comprehensive Epilepsy Program collaborators: Paolo Federico, Yahya Agha-Khani, Nathalie Jette, Colin Josephson, William Murphy, Yves Starreveld, Rey Avendano, Salma Hanna.
Amygdala enlargement may be associated with hippocampal enlargement.
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Most common pathology is amygdala gliosis.
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Resolution of amygdala enlargement is associated with better prognosis.
Abstract
Purpose
Amygdala enlargement (AE) has been reported in drug resistant lesional and non-lesional temporal lobe epilepsy (TLE). Its contribution to development of intractability of epilepsy is at best uncertain. Our aim was to study the natural course of AE in a heterogenous group of TLE patients with follow-up imaging and clinical outcomes.
Methods
A prospective observational study in patients with TLE with imaging features of AE recruited from epilepsy clinics between 1994 and 2018. Demographic data, details of epilepsy syndrome, outcomes and follow up neuroimaging were extracted.
Results
Forty-two patients were recruited including 19 males (45 %). Mean age at onset of epilepsy was 30.6 years and mean duration of epilepsy was 19.9 years. On MRI, 33 patients had isolated unilateral AE and eleven had AE with hippocampal enlargement (HE). Twenty (48 %) underwent temporal resections with most common histopathology being amygdalar gliosis (40 %). Engel Class IA outcome at last follow up (mean, 10 years) was 60 %.
Thirty-four patients had neuroimaging follow up of at least 1 year (mean, 5 years). AE resolved in 6, persisted in 25, evolved into bilateral HS in 1, bilateral mesial temporal atrophy in 1 and ipsilateral mesial temporal atrophy in 1. Resolution of AE was associated with better seizure free outcomes (p = 0.013).
Conclusions
TLE with AE is associated with favourable prognosis yet not benign. Over 50 % were drug resistant and surgical outcomes were similar to mTLE. Resolution of AE on follow up neuroimaging was associated with better seizure free outcomes.
Mesial temporal lobe epilepsy (mTLE) is major contributor to the group of drug resistant epilepsies and is one of the leading indications for epilepsy surgery, the most common pathology being hippocampal sclerosis (HS) [
]. These patients pose a challenge for treatment in terms of difficult presurgical work-up, frequently warranting intracranial EEG recordings. There is evidence that non-lesional patients fare worse in surgical outcomes in general as compared to lesional ones [
Mesial temporal lobe epilepsy versus amygdalar epilepsy: late seizure recurrence after initially successful amygdalotomy and regained seizure control following hippocampectomy.
], and thus may contribute to the so called non-lesional temporal lobe epilepsy (TLE-NL). Imaging studies of TLE-NL patients have identified amygdala enlargement (AE) as an increase in grey matter and amygdalar volume in 12 % of patients [
While the role of the amygdala is functionally defined and evidence of epileptogenicity in the amygdala exists, the significance of AE remains undefined. It has been hypothesized that AE represents a subtype of TLE without HS [
]. However, AE has also been reported in idiopathic generalised epilepsy and healthy controls at similar rates of 5.9 % and 6.4 % respectively raising questions whether it is a non-specific finding despite its higher occurrence in TLE-NL [
]. In this single centre study, we identified a heterogenous group with TLE with AE and report on their clinical, electroencephalographic, follow-up imaging and histopathological findings in operated cases in an attempt to study the natural course of this entity.
2. Methods
The study design was a prospective observational study comprising of TLE patients attending Epilepsy Clinics at the Calgary Epilepsy Programme. Informed consent for data utilization for research purposes was obtained from all patients and the study was approved by the Research Ethics Board. Patients with features of TLE clinically and MRI findings of AE (see criteria below) were prospectively recruited and followed. Diagnosis of TLE was made based on semiology, EEG data and MRI findings. Patients underwent detailed assessment, a pre-structured clinical proforma was filled, noting demographic details, epilepsy characteristics including age at onset, duration, frequency, seizure semiology, anti-epileptic drugs (AED) history, history of antecedents along with relevant medical and surgical history and detailed physical and neurological examination. Work-up of the epilepsy syndrome was carried out according to our centre’s protocol, including routine and sleep deprived EEGs and MRI. Patients were prescribed AEDs according to the treating physician’s discretion. Long term video-electroencephalography (VEEG) monitoring as part of presurgical work-up was done for all drug resistant cases. Further evaluation with nuclear imaging studies was done if required as per the discretion of the attending physician. Surgical candidacy was ascertained at the epilepsy surgical conference and surgeries were performed as per consensus. Histopathological data was available for all resected specimens. Clinical follow up data was retrieved from patient files.
2.1 MRI assessment
As part of the routine interpretation of epilepsy MR scans, we relied on the visual inspection by our neuroradiologist (J.S) to determine whether lateralized AE was present. AE was identified as enlargement of amygdala with or without signal change on fluid attenuated inversion recovery (FLAIR) or T2-weighted sequences. In some cases, the AE was associated with subtle uniform decreased T1-weighted signal intensity, and increased T2-weighted and fluid attenuated inversion recovery (FLAIR) signal intensity that aided in its detection. Patients with suspicion of described lesions with cystic changes, calcifications or microhemorrhages, contrast enhancement, or tumour-like characteristics were excluded as per the discretion of a board-certified neuroradiologist (JS) with >15 years of experience in epilepsy imaging. Patients who had clustering of seizures or status epilepticus within the two weeks prior to MR imaging were excluded in order to eliminate the possibility of peri-ictal imaging changes.
All patients underwent imaging using a conventional high-resolution epilepsy MRI protocol, although the MR vendors and specific parameters have varied during the 24 years of this study. However, our current 1.5 T and 3 T epilepsy MR protocols include axial 3-mm thick TSE T2 and FLAIR, axial 3-mm thick T2* GRE or 1-mm thick SWI, sagittal 1-mm thick 3D FLAIR with isotropic multiplanar reformats, axial 1-mm T1 MP-RAGE or FSPGR with isotropic multiplanar reformats, axial 3-mm DWI (b = 0 and 1000 mm/s2, and oblique coronal 3-mm thick FLAIR and TSE T2-weighted images orthogonal to the long axis of the hippocampus. Magnetic resonance spectroscopy (MRS) was performed in a subset of cases using single voxel positioned over each amygdala and a short echo time (TE 30/35) was sampled.
2.2 Statistics
Statistical analyses was done using SPSS 23.0. For statistical comparisons, Fischer’s exact test was used. A p-value < 0.05 was considered significant. For univariate analysis of continuous variables, analysis of variance (ANOVA) was used.
3. Results
3.1 Baseline demographic, clinical and imaging characteristics
We identified 42 patients with TLE with evidence of AE with or without HE on MRI brain [Table 1]. They included 23 females (55 %) with mean age at onset of epilepsy being 30.6 years (SD 17.6; range 0.5–72). Mean duration of epilepsy was 19.9 years (SD 9.5, range 4–40). Twenty- three had left AE and 19 had right AE. Eleven had additional HE (6 left, 5 right) [Fig. 1]. All AE were unilateral and the associated HE was ipsilateral. Thirty-four (81 %) had MRI follow up of at least one year (average,5 years; SD 3; range 1–11) [Table 2,3 ]. MR Spectroscopy (MRS) was available for four patients (Patients 15, 19, 24, 25) and showed lateralized increase in myoinositol (mI) peak (Fig. 2).
Fig. 2Resolution of Right AE after 7 years of imaging follow up in Patient 19. The patient is seizure free on single AED at 12 years of clinical follow up. A1) Right AE on coronal T2W image A2) Right AE on axial FLAIR image. Follow up imaging after 7 years shows B1) Resolution of AE on coronal T2W and B2) Resolution of AE on axial FLAIR images. C) Lateralized increased myoinositol peak (3.6 ppm) in the enlarged right amygdala.
Twenty-five patients had focal aware seizures (FAS), 34 had focal impaired awareness seizures (FIAS) and 31 had bilateral tonic clonic seizures (BTCS). Twenty-seven patients had ictal onset with symptoms: deja vu [
]. Five (12 %) had antecedents for epilepsy; but none had febrile convulsions.
Focal temporal IEDs ipsilateral to side of AE exclusively were present in 26 patients and none had exclusive contralateral temporal IEDs. Five patients demonstrated bilateral temporal IEDs. Nine did not show IEDs and 2 showed non-specific abnormalities including diffuse and focal slowing. Twenty-seven patients (64 %) had drug refractory epilepsy and underwent presurgical evaluation. Twenty six patients had ictal recordings with 22 having ipsilateral temporal onset and 4 with bilateral independent temporal onsets. None had ictal onset from temporal lobe contralateral to AE. Three patients (Patients 26, 27, 40) had intracranial monitoring; two with depth electrodes (Patients 26, 27) with implantation involving amygdala and one with subdural grids (Patient 40). Both patients with coverage of amygdala had active IEDs and one had involvement of amygdala at ictal onset along with the hippocampus (Patient 27) [Fig. 3]. Both underwent surgical resection (Patient 26, left ATL; Patient 27, left SAH) with Engel I outcomes at last follow up. Histopathology showed amygdalar gliosis (Patient 27) and normal amygdala (Patient 26) respectively.
Fig. 3Intracranial EEG recording using depth electrodes in amygdala in Patient 27. Patient underwent left AH with histopathology showing amygdalar gliosis and Engel IA outcome at last follow up.
18 F Fluorodeoxyglucose positron emission tomography (FDG-PET) CT was performed for 7 patients with hypometabolism in the temporal lobe ipsilateral to AE. Three patients (Patients 34, 35, 37) in our series underwent ISSPECT with ipsilateral temporal hyperperfusion and additional contralateral posterior parietal hyperperfusion in one patient (Patient 37). Two patients (Patients 34, 35) underwent anterior temporal lobectomy (ATL) and are seizure free.
3.2 Outcomes
AE persisted in 25 (73 %), resolved in 6 (18 %) [Fig. 2] evolved into bilateral HS in 1, bilateral mesial temporal atrophy in 1 and ipsilateral mesial temporal atrophy in 1 [Table 2 and 3]. Patients with resolution of AE had better seizure free outcomes compared to those with stable MRI findings at last clinical follow up. Five (83 %) of 6 with resolution were seizure free compared to 6 (24 %) of 25 with persistent AE (p = 0.013)
3.3 Surgery and post-surgical follow up
Twenty-one patients were considered for epilepsy surgery of which 20 (48 %) underwent epilepsy surgery and 1 declined. Twelve underwent ATL and 8 underwent selective amygdalohippocampectomies (AH). Histopathology was available for all surgical specimens and included amygdalar gliosis in 8 (40 %) [Fig. 4], amygdalar sclerosis and HS in 4 (20 %), DNET in 1 (5 %), cortical dysplasia in 1 (5 %), non-specific changes in 4 (20 %) and normal in 2 (10 %). Average surgical follow up was 10 years (SD 5; range 1–18) with Engel Class IA outcome in 12 (60 %), Engel Class II outcome in 6 (30 %) and Engel Class III outcome in 2 (10 %). Six surgical patients were seizure free off AEDs at last follow up [Table 3].
Fig. 4(A) Histopathology specimen showing amygdala gliosis with GFAP positivity in Patient 31 who underwent left AH with Engel Class II outcome (B) Control specimen of normal amygdala stained with GFAP GFAP: Glial fibrillary acidic protein.
Clinical follow up of at least one year was available for all patients with an average of 9.8 years (SD 4.8; range, 1–18). AED treatment was continued in 33 patients at last follow up with 17 on polytherapy. None of the patients received immunotherapy.Twenty-two patients were seizure free at last follow up; 11 on monotherapy, 2 on polytherapy and nine off AEDs. Of the 9 patients (21 %) who were seizure free off AEDs; 6 were surgical patients. Of the 3 non-surgical patients; AE resolved in 1, persisted in 1 and became atrophic in the other. Eleven patients (50 %) in the non-surgical group remained seizure free at last follow up. Three patients deceased; one following septic shock and multiorgan failure (Patient 12), 1 with metastatic ovarian carcinoma (Patient 29) and in the other (Patient 4) the cause was uncertain.
3.5 Medical versus surgical group
The medical and surgical groups did not differ in terms of gender (p = 0.76), age at epilepsy onset (p = 0.42), duration of epilepsy (p = 0.16), laterality of AE (p = 0.99) and duration of clinical follow up (p = 0.64).
3.6 Associated hippocampal enlargement
Of the eleven patients who had associated HE; seven underwent epilepsy surgery with Engel class I outcome in six (86 %). Pathology showed HS [
]. It should be noted that the majority of previous studies relating to AE with TLE are cross-sectional or with short follow ups and did not look into long-term outcomes. To the best of our knowledge, this is the largest and the longest prospective study investigating natural course of AE.
AE has been reported in TLE-NL ranging between 12 % and 63 % [
] reporting ictal onset contralateral to AE. Variable rates of bilateral AE in TLE have been reported in studies using volumetric analysis between 6–35 % [
] demonstrated that patients with TLE-AE have isolated enlargement in the dorsomedial part of the amygdala with no significant volume change in the hippocampus. This morphologic pattern was considered distinct from mTLE-HS, in which hippocampal atrophy is the most prominent finding [
]. Another MRI volumetric study showed no significant difference in bilateral hippocampal volumes in TLE-AE; but surprisingly showed significant increases in gray matter volumes in the ipsilateral temporal pole in half of the patients [
]. AE associated with HE is a novel finding in this study. However, whether HE is an isolated pathology or part of AE pathology is uncertain and needs larger studies. Presence of associated HE did not influence surgical outcomes in our study.
AE has been observed to remain stable, remit or rarely progress. In our study, AE persisted in 25 (73 %), resolved in 6 (18 %), evolved into bilateral HS in 1, bilateral mesial temporal atrophy in 1 and ipsilateral mesial temporal atrophy in 1.Coan et al. [
] proposed that AE may be the result of hypertrophy secondary to hypoxic insult and could progress to atrophy and HS later as was seen with Patient 1. Our findings showing progression to bilateral HS reiterate bilaterality of mTLE [
]. The same patient had history of status epilepticus. None with bilateral changes on follow up had history of encephalitis or febrile convulsions. Previous studies have reported higher rates of remission over a shorter follow up [
] demonstrated decrease in the volume of the amygdala in 22 of 33 patients (67 %) on MRI volumetry on follow up between 6 months to 1 year. Malter et al. [
] reported on 40 patients with new onset TLE-AE who were followed up for a median duration of 25 months. AE remained stable in 40 %, partial remission occurred in 30 % and full remission in 30 % at last follow up. Higher remission rates compared to our study despite having a shorter follow up is probably due to use of volumetric methods which are more accurate in detecting AE than visual inspection. This could also suggest remitting relapsing course; however none of our patients who had multiple interval scans suggested this. However, they [
Evaluation of amygdala pathology using (11)C-methionine positron emission tomography/computed tomography in patients with temporal lobe epilepsy and amygdala enlargement.
] demonstrated experiential symptoms with amygdalar stimulation in refractory TLE. Lower amygdalar volumes were found to be associated with ictal fear [
]. Deja vu was the most common symptom at ictal onset followed by epigastric sensation, fear, vague cephalic sensation, olfactory hallucination, nausea, metallic taste and autonomic features which have been described in previous studies on “amygdalar epilepsy”(6). Twenty five (60 %) patients had focal aware seizures, 34 (80 %) had focal impaired awareness seizures and 31(74 %) had bilateral tonic clonic seizures (BTCS). The occurrence of BTCS was higher in our series compared to those reported previously [
Evaluation of amygdala pathology using (11)C-methionine positron emission tomography/computed tomography in patients with temporal lobe epilepsy and amygdala enlargement.
The role of AE in epileptogenicity has always been a matter of debate. Studies have shown spontaneous interictal like discharges contributing to seizures from lateral nucleus of amygdala in patients with epilepsy with abnormal patterns of receptor densities and synaptic function [
Mesial temporal lobe epilepsy versus amygdalar epilepsy: late seizure recurrence after initially successful amygdalotomy and regained seizure control following hippocampectomy.
]. Our study provides evidence for epileptogenicity in AE with notable concordance of IEDs and ictal onset to the side of AE. Majority of previous studies have shown high IED concordance to AE ranging between 89–100 % [
] have suggested autoimmune etiology for AE especially due to its remitting nature. In our series, one patient (Patient 22) underwent cerebrospinal fluid (NMDA, LGI1, CASPR, AMPA, GAD65) and another (Patient 36) had serum (NMDA, LGI1, CASPR) antibody testing with negative results and ongoing seizures with persistent AE. In a series of patients with new onset TLE-AE [
], all received some form of immunotherapy but none of the serum testing for antibodies for limbic encephalitis (LE) was positive. That the higher rate of remission in their series was a result of immunotherapy is difficult to correlate in the light of negative antibody results and spontaneous remission in those not treated with immunotherapy. Lv et al. [
] also reported low yield with autoantibody testing in TLE-AE with a single patient testing positive for LGI1 in both CSF and serum on testing 21 patients with 12 having both CSF and serum tested and the remaining having serum testing only. None of our patients had AE contralateral to ictal onset or bilateral AE which could suggest autoimmune etiology [
] demonstrated significant glucose hypometabolism on FDG-PET CT in affected amygdala in TLE-AE without hypometabolism in the hippocampus which is commonly involved in TLE-HS; concluding that amygdala per se is an epileptogenic focus. In addition, glucose hypometabolism on FDG-PET images in TLE-AE was relatively restricted to the affected amygdala, with greater hypometabolism ipsilateral to the AE. In contrast, significant glucose hypometabolism in the hippocampus, which is a defining feature of MTLE- HS, [
Evaluation of amygdala pathology using (11)C-methionine positron emission tomography/computed tomography in patients with temporal lobe epilepsy and amygdala enlargement.
] using 11 C- methionine PET suggested that it could help differentiate neoplastic from non-neoplastic pathology in AE and contribute to clinical decision making. Previous studies have shown concordance to AE and hypoperfusion in ipsilateral temporal lobe with interictal SPECT [
]. There are no reports of ISSPECT in TLE-AE to the best of our knowledge. All three patients in our series who underwent ISSPECT had findings concordant to AE.
Previous studies in drug refractory mTLE have shown better outcomes with inclusion of amygdala in the resection [
] proposed the concept of abnormal pathology in amygdala in TLE in the absence of HS. He described isolated amygdaloid sclerosis in patients without HS which was as severe as seen in HS. Kim et al. [
] found that the main etiology of AE was FCD followed by brain tumours. However, 5 out of the 8 patients with FCD had additional HS, even though there was no radiological evidence. None in their series of 12 patients had amygdala gliosis. In the series by Mitsueda-Ono et al. [
], 2 patients had refractory epilepsy and subsequently underwent AH, with pathology showing gliosis and cortical dysplasia in the amygdala. Minami et al. [
] reported aggregated hypertrophic neurons without gliosis which were not compatible with FCD as the pathological characteristic of AE. These findings are completely different from our study even though mild gliosis was found in 9 out of the 11 specimens.
In our study, half of the patients became drug refractory. This higher rate may be due to longer follow up and chronicity of epilepsy with associated extended networks. Majority of studies have demonstrated lower rates of drug refractoriness [
Evaluation of amygdala pathology using (11)C-methionine positron emission tomography/computed tomography in patients with temporal lobe epilepsy and amygdala enlargement.
] retrospectively studied 12 patients who had undergone surgical treatment for refractory epilepsy with radiological evidence of AE, and 11 became seizure free at follow up of more than a year. Minami et al. [
] reported seizure freedom at 1 year follow up in 10 of 11 patients who underwent surgery for AE. Amongst 22 patients who were followed up on medical management, half were seizure free at last clinical follow up and 3 were seizure free off medications.
This is the only study to the best of our knowledge that has MRS done in AE causing epilepsy. All four patients who had MRS showed mI as the dominant peak with increased myoinositol/creatinine (mI/Cr) ratio. Increased mI is thought to result from induction of Na+/mI cotransporter (SMIT) resulting in glial proliferation [
]. mI is considered to be an astrocyte marker and correlates with increased population of glial cells. Its elevations are described with low grade gliomas [
]. The increased mI levels in our patients could be consistent with the most common pathology of amygdala gliosis and could be a potential biomarker. It could represent some form of tissue reaction in AE. It is noteworthy that in one patient (Patient 24), the lateralised increased mI/Cr ratio persisted on follow up imaging despite resolution of AE suggesting that microscopic pathology could be persisting despite radiological resolution. Despite this patient became seizure free and is off AED at clinical follow up at 10 years. There was also decrease in N-acetyl aspartate/creatinine (NAA/Cr) ratio which is a marker of neuronal injury. Decrease in NAA with presence of lactate is considered to be a marker of epileptogenic zone in TLE [
]; single voxel based MRS could prove to be a tool to identify “epileptogenic” AE in the future. Larger studies with pathology are required to ascertain this.
4.1 Limitations
Volumetric analysis was not performed in our study and may be considered a limitation. Given presumed etiology of autoimmune encephalitis in AE, investigation with autoimmune markers would have been ideal especially for cases with inconclusive pathology.
4.2 Conclusions
AE is a distinct form of TLE with most common pathology being gliosis and may be associated with HE. Whether AE progresses to or is a risk factor for HS needs to be ascertained with larger studies. Serial neuroimaging may help identify patients with resolution of AE which is associated with better prognosis and to detect neoplastic change. With high proportion of drug refractoriness, surgery is a good option with reasonable outcomes. Further studies are required to assess the role of mI peak on MRS in identifying “epileptogenic” AE. Presence of coexistent HE did not influence surgical outcomes in our study.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.
Declaration of Competing Interest
None.
References
Falconer M.A.
Taylor D.C.
Surgical treatment of drug-resistant epilepsy due to mesial temporal sclerosis. Etiology and significance.
Mesial temporal lobe epilepsy versus amygdalar epilepsy: late seizure recurrence after initially successful amygdalotomy and regained seizure control following hippocampectomy.
Evaluation of amygdala pathology using (11)C-methionine positron emission tomography/computed tomography in patients with temporal lobe epilepsy and amygdala enlargement.
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