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JNNP Online First, published on September 15, 2014 as 10.1136/jnnp-2014-308383 Epilepsy
RESEARCH PAPER
Surgery for amygdala enlargement with mesial temporal lobe epilepsy: pathological findings and seizure outcome Noriaki Minami,1,2 Michiharu Morino,1 Takehiro Uda,1 Takashi Komori,3 Yasuhiro Nakata,4 Nobutaka Arai,5 Eiji Kohmura,2 Imaharu Nakano1 1
Department of Neurosurgery, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan 2 Department of Neurosurgery, Kobe University School of Medicine, Kobe, Hyogo, Japan 3 Department of Laboratory Medicine and Pathology (Neuropathology), Tokyo Metropolitan Neurological Hospital, Tokyo, Japan 4 Department of Neuroradiology, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan 5 Brain Pathology Research Center, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan Correspondence to Dr Noriaki Minami, Department of Neurosurgery, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan; [email protected] Received 22 April 2014 Revised 2 July 2014 Accepted 2 September 2014
To cite: Minami N, Morino M, Uda T, et al. J Neurol Neurosurg Psychiatry Published Online First: [please include Day Month Year] doi:10.1136/jnnp2014-308383
ABSTRACT Objective Amygdala enlargement (AE) has been suggested to be a subtype of mesial temporal lobe epilepsy (MTLE). However, most reports related to AE have referred to imaging studies, and there have been few reports regarding surgical and pathological findings. The present study was performed to clarify the surgical outcomes and pathology of AE. Methods Eighty patients with drug-resistant MTLE were treated surgically at the Tokyo Metropolitan Neurological Hospital between April 2010 and July 2013. Of these patients, 11 were diagnosed as AE based on presurgical MRI. Nine patients with AE underwent selective amygdalohippocampectomy, while the remaining two patients underwent selective amygdalotomy with hippocampal transection. Intraoperative EEG was routinely performed. The histopathology of the resected amygdala tissue was evaluated and compared with the amygdala tissue of patients with hippocampal sclerosis. Results Pathological findings indicated that 10 of 11 specimens had closely clustering hypertrophic neurons with vacuolisation of the background matrix. Slight gliosis was seen in nine specimens, while the remaining two showed no gliotic changes. Intraoperative EEG showed abnormal sharp waves that seemed to originate not from the amygdala but from the hippocampus in all cases. Ten patients became seizure-free during the postoperative follow-up period. Conclusions Histopathologically, clustering hypertrophic neurons and vacuolation with slight gliosis or without gliosis were considered to be pathological characteristics of AE. Amygdalohippocampectomy or hippocampal transection with amygdalotomy is effective for seizure control in patients with AE.
Recently, amygdala enlargement (AE) has attracted attention as a possible subtype of MRI-negative mesial temporal lobe epilepsy (MTLE). However, as the entity is not widely recognised, AE is often overlooked in many facilities and treated as MRI-negative MTLE, which is refractory to surgical treatment.1–6 Although there are increasing numbers of reports describing radiographic features of AE,7–11 there have been few reports referring to the pathological findings and surgical outcome of AE.12 This is probably because patients with AE tend to be less symptomatic and surgical indication is restricted. The present study was performed to
assess the surgical outcome and pathological findings of AE with MTLE.
METHODS Participants A total of 80 patients with drug-resistant MTLE were treated surgically by a single surgeon (MM) at the Tokyo Metropolitan Neurological Hospital between April 2010 and July 2013. Among the 80 patients, 11 were diagnosed as AE with MTLE based on specific MRI findings. For each patient, the clinical assessment included a careful review of the seizure semiology, MRI, scalp EEG, N-isopropyl(123I)-p-iodoamphetamine single-photon emission CT, neuropsychological examination and continuous long-term video EEG monitoring. Eight of the 11 patients with AE underwent [18F]fluorodeoxyglucose positron emission tomography and [11C] methionine positron emission tomography examination. All patients were followed up for a minimum of 1 year after surgery. A series of 26 patients who underwent surgical treatment for TLE with hippocampal sclerosis (HCS) at the same facility were also included as controls for comparison of the pathological findings.
Preoperative MRI evaluation MRI findings were evaluated by two experienced neuroradiologists using a 1.5 T MRI scanner (SignaEXCITE HD DV16; GE Medical Systems, Milwaukee, Wisconsin, USA) or a 3 T MRI scanner (Discovery 750; GE Medical Systems). Two neuroradiologists defined AE as a lesion with unilateral enlargement and slightly increased signal intensity of the amygdala on both axial and coronal fluid-attenuated inversion recovery (FLAIR) or T2-weighted images (figure 1). Patients with MRI-enhanced lesions, cysts, calcifications or well-circumscribed intensity lesions were not included in this study because they were strongly suspected to have lowgrade gliomas, such as ganglioglioma (figure 2).
Resective surgery After frontotemporal craniotomy, the trans-sylvian approach was applied for all cases. Trans-sylvian selective amygdalohippocampectomy (TSA)13–16 was performed in nine patients, and two patients underwent selective amygdalotomy with hippocampal transection (HT).17 18 The surgical procedure was as follows. After adequate exposure of the sylvian fissure, the inferior peri-insular sulcus was
Minami N, et al. J Neurol Neurosurg 2014;0:1–8. doi:10.1136/jnnp-2014-308383 Copyright Article author (or their employer) 2014.Psychiatry Produced by BMJ Publishing Group Ltd under licence.
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Epilepsy
Figure 1 All of the 11 amygdala enlargement cases with subtle abnormalities on fluid-attenuated inversion recovery images are shown. Slightly enlarged amygdala with mild high intensity was seen.
identified, and the inferior horn was opened with cortical incision along the sulcus. Then, intraoperative electrical recording of the hippocampus (6×1 grid electrode), amygdala (4×1 grid electrode), medial temporal (4×1 grid electrode), basal temporal (4×1 grid electrode) and lateral temporal area (4×1 grid electrode) was performed (figure 3). The affected amygdala was then resected in a piecemeal manner using microforceps, microscissors and ultrasonic aspiration. Once the resection of the amygdala was completed, the uncus could be resected according to the same method. At this time, the hippocampal recording was performed again to compare electrical changes before and after removal of the amygdala. In performing TSA, the hippocampal head was dissected subpially towards the dorsal part of the hippocampus, and the hippocampal body was cut dorsally at the innominate sulcus between the collateral eminence and the hippocampal body. The feeding artery could then be identified and cut. Finally, the hippocampal tail was dissected posteriorly and removed to permit an en bloc resection of the hippocampus and parahippocampal gyrus. The EEG of the lateral temporal area was recorded again at this point for comparison before and after removal of the hippocampus. In performing HT, vertical transection of the hippocampus at 5 mm intervals was performed using a ring-shaped blunt dissector. After transection, the hippocampal EEG was recorded to compare electrical changes before and after transection of the hippocampus. 2
Histology and immunohistochemistry Surgical specimens were fixed in 10% buffered formalin and processed for embedding in paraffin. H&E stain, Klüver-Barrera (KB) stain and Manlow’s stain were utilised for routine histological analyses. Representative sections were immunostained with antibodies directed against neuronal nuclei antigen (NeuN; A60, 1:10; Chemicon, Temecula, California, USA) and glial fibrillary acidic protein (GFAP; polyclonal, 1:400; Dako Cytomation, Glostrup, Denmark). The sections were incubated overnight with primary antibodies, and antigens were manually visualised using a detection kit (EnVision +kit/HRP; Dako Cytomation) with diaminobenzidine as the chromogen. Making a rational pathological diagnosis, the neuropathologists also examined a series of amygdala specimens from 26 HCS cases and 2 heterotopic grey matter cases, and performed comparisons with specimens of AE. The degree of gliosis was rated for each section (none: no gliotic change; mild: not seen on Manlow’s stain but seen on GFAP; moderate: seen on Manlow’s stain; severe: diffuse and advanced gliotic change). The degree of vacuolisation was also classified into three groups (none: no vacuolisation; mild: only seen on H&E; moderate: seen on both H&E and KB).
Outcome assessment Postoperative seizure outcomes were assessed according to Engel’s classification.19 All participants were followed up for a
Minami N, et al. J Neurol Neurosurg Psychiatry 2014;0:1–8. doi:10.1136/jnnp-2014-308383
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Epilepsy Figure 2 As shown in these four images, patients with MRI-enhanced lesions, cysts, calcifications or well-circumscribed intensity lesions were not included in this study because they were strongly suspected to be low-grade gliomas, including ganglioglioma.
Figure 3 (A) Intraoperative EEG of case 11 before removal of the affected amygdala. The abnormal sharp waves seemed to originate not from the amygdala but from the hippocampus. Electrodes 1–6 were set on the hippocampus (Hip), 7–10 were set on the amygdala (Amy), 11–14 were set on the medial temporal area (MTL), 15–18 were set on the basal temporal area (Base) and 19–22 were set on the lateral temporal area (LTL). (B) Hippocampal EEG before transection of the hippocampus showing almost the same frequency of the abnormal sharp waves as before removal of the affected amygdala. (C) Hippocampal EEG after transection of the hippocampus showing definitely decreased frequency of abnormal sharp waves.
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4
N D 56 22 F M 10 11
51 15
N N D 23 21 26 19 20 22 F F F 7 8 9
→: no particular findings; ↑: hypermetabolism; ↓: hypometabolism. AE, amygdala enlargement; CPS, complicated paroxysmal seizure; F, female; FDG-PET, [18F]fluorodeoxy-glucose positron emission tomography; GTC, general tonic clonic seizure; M, male; MET-PET, [11C]methionine positron emission tomography; NAD: non available data; SPECT, single-photon emission CT; SPS, simple paroxysmal seizure; D, dominant; N, non dominant.
Right temporal Left temporal No laterality Left temporal → → ↓ ↓ – – 2/day 4–5/month
– –
AE AE
Bilateral temporal Right temporal Intact Right temporal Right temporal No laterality → ↑ ↑ ↓ ↑ → – – – 1/month 4–5/year 4–5/month
– + –
AE AE AE
Right temporal Left temporal Left temporal Right temporal Left temporal Left temporal NAD ↑ → NAD NAD → NAD ↓ → NAD NAD ↓ – – – – – + – – – – – –
CPS Aura, GTC CPS CPS CPS Aura (pallor), SPS (tinnitus), CPS CPS GTC SPS (dystonic movement), GTC CPS CPS D D N N D N 28 25 21 23 59 38 21 17 14 19 56 34
Seizure semiology Dominance of the affected side
4–5/day 4–5/year 2–3/day 4–5/year 2–3/week 1/month
History of neonatal asphyxia
F M F M F M
There were no complications associated with the surgical procedure. Postoperative scalp EEG demonstrated that abnormal sharp waves disappeared in six patients and subsided in two patients (table 3). Ten of 11 patients became seizure-free during the follow-up period.
Gender
Surgical outcome
Age at surgery
Intraoperative EEG showed abnormal sharp waves that seemed to originate not from the amygdala but from the hippocampus in all cases (figure 3). Although there were no changes in hippocampal EEG before and after removal of the amygdala, significant improvement of the abnormal sharp wave was observed after removal or transection of the hippocampus in 10 of 11 cases.
Age at onset
Intraoperative EEG
Table 1 Patient demographics and preoperative examinations
Pathological findings indicated that 10 of 11 specimens had closely aggregated hypertrophic neurons with vacuolisation in the background matrix (figure 4). Similar findings were made in 7 of 28 specimens in the control group with HCS (figure 5 and table 2). In particular, it was prominent in the two specimens of patients with HCS with heterotopic grey matter (table 2; controls 17 and 18). Vacuolation, which was considered to be due to enlarged dendrites, was detected in both groups. However, the degree of vacuolation tended to be more developed in the AE group than the control group. In addition, vacuolation was found diffusely in the AE group, while the affected area was limited in the control group. Aggregated oligodendroglia-like cells (OLCs) were identified in case 11 (figure 4). Gliosis was detected more frequently in the control group than in the AE group, and the degree of gliosis was also more developed in controls. The presence of neuronal loss was unclear in both groups. None of the specimens in the present study had lymphocytic infiltration or eosinophilic granular bodies, which are commonly seen in ganglioglioma. On pathological examination of the resected hippocampus from patients with AE, six of nine specimens showed mild gliosis, and all of six specimens were classified as grade I according to Watson’s pathological grading for HCS.20
Frequency of attacks
Pathological findings
History of febrile convulsion
MRI
FDG-PET
MET-PET
The demographic and clinical features of the study participants are listed in table 1. The 11 patients included in the study consisted of 4 males and 7 females. The mean age at seizure onset was 26.3 years (range 14–56), yielding a mean duration of epilepsy of 4.8 years by the time of surgery (range 1–8 years). Eight patients had typical complex partial seizures (CPS) and the remaining three had generalised tonic clonic seizures without CPS. Two patients also presented with simple partial seizures; one presented with dystonic movement, and the other presented with tinnitus. Aura was observed in two patients, one of whom presented with pallor. One patient had a history of febrile convulsions, and another had a history of neonatal asphyxia.
1 2 3 4 5 6
RESULTS Patient demographics
AE AE AE AE AE AE
Decreased lesion of blood flow in SPECT
Seizure focus diagnosed based on interictal scalp EEG
minimum of 1 year after surgery (12–47 months; mean 26.8 months). Patient outcome and follow-up were evaluated by an outpatient chart review. Postoperative neuropsychological evaluation was obtained using the Wechsler Memory Scale-Revised (WMS-R) 6 months after surgery. Postoperative interictal scalp EEG was also performed for all surgical cases. The results of interictal scalp EEG change were categorised into three groups: complete response (almost complete disappearance of abnormal waves), partial response (decrease of abnormal waves) and no significant change.
Right temporal Left Temporal Right temporal Right temporal Left temporal Right temporal
Epilepsy
Minami N, et al. J Neurol Neurosurg Psychiatry 2014;0:1–8. doi:10.1136/jnnp-2014-308383
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Epilepsy Figure 4 Cases (amygdala enlargement; ×400). (A) Extensive vacuolation of the neuropil. (B) Swelling of neuritis and cytoplasm of the neurons. (C) Vacuolation was visible on Klüver-Barrera staining. (D) Close aggregation of hypertrophic neurons on neuronal nuclei antigen (NeuN) immunohistochemistry (A–D, table 2, case 8). (E) Some neurons were situated in a back-to-back position (arrows). (F) Clustering of the neurons was evident on NeuN immunohistochemistry. (G) Focal accumulation of oligodendroglia-like cells. (H) Only minimal gliosis was present in the background tissue (glial fibrillary acidic protein immunohistochemistry; E–H, table 2, case 11).
DISCUSSION HCS is widely recognised as the most common subtype of MTLE because of its specific findings on MRI. On the other hand, AE has attracted renewed attention as a possible subtype of MTLE.7–9 11 12 The amygdala is part of the limbic system, and has been suggested to play an important role in MTLE. Laboratory animal studies demonstrated that the amygdala tends to acquire the kindling phenomenon more easily than the hippocampus.21 22 However, little clinical information is available regarding the relationships between epilepsy and the amygdala. There are several reasons for this lack of data. First, pathological evaluation of the amygdala is difficult because the specimens are usually fragmented. Second, electrical discharge from the amygdala is usually synchronised with that from the hippocampus.23 Third, patients presenting with specific limbic symptoms related to the amygdala are very rare.24 Therefore, there have been few investigations focusing on the amygdala. However, there are increasing numbers of reports regarding AE,
particularly those based on imaging findings. Some reports discussed amygdala volumetry, confirming the existence of AE.7–11 25 To the best of our knowledge, there have been few reports regarding surgical and pathological findings in MTLE with AE, probably because patients with MTLE with AE tend to be less symptomatic and surgery is less likely to be indicated.12 25 Hence, the present study was performed to clarify the intraoperative EEG findings of the amygdala, the pathological findings and the surgical outcome of MTLE with AE. Previous reports have indicated that the frequency of a history of febrile convulsion in patients with HCS ranges from 20% to 48%.26 27 On the other hand, the incidence of a history of febrile convulsion was reported to be significantly lower in patients with AE than in those with HCS (14% vs 48%, respectively, p=0.12).7 It was also noted that the average age of onset in the AE group was significantly higher than that in the HCS group (29 years old vs 11 years old, respectively, p=0.01).7 It was reported previously that the average age of onset of MTLE
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Epilepsy Figure 5 Controls (×400). (A) Mildly hypertrophic neurons in the vacuolated neuropil. There was a certain distance between each neuron (H&E staining). (B) Fine vacuolation was not detectable on Klüver-Barrera (KB) staining. (C) Clustering of neurons was absent on neuronal nuclei antigen (NeuN) immunohistochemistry. (D) Only focal and minimal gliosis was identified in the background on glial fibrillary acidic protein (GFAP) immunohistochemistry (A–D, table 2, control 13). (E) Neuronal loss and vacuolation of the neuropil. (F) Some neurons showed pyknosis (KB staining). Neurons were atrophic rather than hypertrophic. (G) Neuronal loss was apparent on NeuN immunohistochemistry. (H) Mild gliosis in the background tissue (GFAP immunohistochemistry; E–H, table 2, control 19).
with AE was 27.4 years, consistent with our results.12 The seizure semiology of amygdalar epilepsy is characterised by ictal fear, painful gastric sensations and marked autonomic symptoms, such as changes in heart rate and respiration, facial pallor and goose flesh,24 phenomena referred to as ‘limbic seizure’. In our series, only one patient presented with pallor as an aura (table 1, case 6). Aggregated hypertrophic neurons without gliosis were considered to be a pathological characteristic of AE. OLCs, often seen in the histopathology of dysplastic tissue or glioneuronal tumours, were also found in case 11, indicating dysplastic changes not only in the neurons but also in the glial tissue.28 In a previous report, 8 of 12 surgical cases of AE were pathologically diagnosed as focal cortical dysplasia (FCD).12 Two pathological cases of AE were also reported previously; the temporal cortex was examined in these cases and disorganisation of the cortical layer and dysmorphic neurons was observed, suggesting 6
the existence of FCD.25 Cytoskeletal impairments, such as hypertrophic neurons, are sometimes observed in cortical dysplasia.29 In addition, two specimens with heterotopic grey matter revealed prominent aggregated hypertrophic neurons (controls 15 and 16). However, in our AE series, the localisation of the hypertrophic neurons without heterotopic displacement was not compatible with the pathological features of FCD. Although our pathological findings were similar to FCD, it seems inappropriate to apply this term in these cases. Ganglioglioma could be a candidate for differential diagnosis because it sometimes presents with mild high intensity on FLAIR or T2-weighted imaging; however, it usually shows calcified or cystic lesions.30 Ganglioglioma also has specific pathological findings, that is, glial proliferation, lymphocytic infiltration and eosinophilic granular bodies.31 Moreover, the association between ganglioglioma and BRAF V600E mutation has recently been a topic of interest among brain tumour
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Epilepsy Table 2 Pathological findings of the amygdala Case number Cases 1 2 3 4 5 6 7 8 9 10 11 Controls 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39
Table 3
Age
Sex
MRI
Vacuolation
Cluster/ swelling
28 25 22 21 59 38 23 21 26 56 22
F M F M F M F F F F M
AE AE AE AE AE AE AE AE AE AE AE
1 1 1 2 2 1 2 2 2 2 2
Y N Y Y Y Y Y Y Y Y Y
1 1 1 1 1 1 1 1 1 0 0
53 38 38 39 21 18 35 37 36 24 51 22 35 30 28 43 30 27 57 50 8 55 46 3 52 19 27 56
M F F M F F F F M F F F M F M F F F F F M F M F F F F F
HCS HCS HCS HCS HCS HCS HCS HCS HCS HCS HCS HCS HCS HCS HCS HCS Heterotopia Heterotopia HCS HCS HCS HCS HCS HCS HCS HCS HCS HCS
0 1 2 2 0 0 1 1 1 0 0 2 0 1 2 1 1 1 1 1 0 0 1 1 1 1 1 0
N N N N N N Y N N N N Y N N Y N Y Y Y Y N N N N N N N N
0 0 0 2 0 0 2 2 2 2 2 0 0 2 2 1 2 1 0 2 1 0 0 0 0 0 2 2
Gliosis
AE, amygdala enlargement; F, female; HCS, hippocampal sclerosis; Heterotopia, heterotopic grey matter; M, male; N, no; Y, yes; 0, none; 1, mild; 2, severe.
researchers.32 Therefore, the possibility of ganglioglioma was excluded. It is difficult to express these findings using pathological terms; ‘hamartoma’ or ‘dysplasia’ is relatively close as an appropriate expression. In one of 11 cases, aggregated hypertrophic neurons were not detected, suggesting that the underlying disease of AE may be heterogeneous. Some specimens in the HCS group showed similar findings, indicating that the phenomenon could also occur in patients with HCS. The vacuolation in the background matrix, which was considered to be due to the enlarged dendrites of hypertrophic neurons, was identified in both AE and controls. Although the possibility that vacuolation was an artefact due to surgical manipulation could not be excluded, there were differences in the frequency and severity of vacuolation between the two groups. There was one valuable previous report regarding the cellular pathology of
1 2 3 4 5 6 7 8 9 10 11
Outcome
Main seizure focus diagnosed based on intraoperative EEG findings
Seizure outcome (Engel’s classification)
Surgical complications
Postoperative scalp EEG
Hip Hip Hip Hip Hip Hip Hip Hip Hip Hip Hip
Ia Ia IIIa Ia Ia Ia Ia Ia Ia Ia Ia
– – – – – – – – – – –
CR CR CR CR NSC CR PR PR NSC NSC CR
CR, complete response; Hip, hippocampus; NSC: no significant change; PR, partial response.
amygdala neurons in human TLE,33 according to which neurons in the TLE group were significantly smaller than those in controls and had fewer dendrites, whereas the density of spines in these cells was increased in patients with TLE. Another similar report indicated that the regional distribution of neuropathological changes varied between the different subnuclei of the amygdala in patients with TLE and strengthened the suggestion that the amygdala was the main target of epilepsy-related neuronal cell damage.34 These pathological findings were completely different from our results, because they described amygdala sclerosis, confirming that AE belongs to a special entity in TLE. Although slight gliosis was found in 9 of 11 specimens in the AE group, no neuronal cell loss was detected, and thus there was no evidence of amygdala sclerosis or amygdala atrophy.35 Wieser24 reported one patient in whom stereotactic intracranial EEG monitoring confirmed amygdalar seizure. He emphasised that amygdalar discharges were restricted to the amygdala, and could be detected only by direct recording from the amygdalar nuclei by stereotactically inserted electrodes. We performed intraoperative EEG in all surgical cases and attempted to record amygdalar discharges putting the 4×1 electrode grid on each amygdala directly, but were unable to confirm such findings. The abnormal sharp wave seemed to be discharged from the hippocampus in all cases. Moreover, although there were no changes in hippocampal EEG before and after removal of the amygdala, significant improvement of EEG was observed after removal or transection of the hippocampus in 10 of 11 cases. These results suggest that, at the time of surgery, the main epileptic focus migrated to the hippocampus, affected by repetitive seizures. However, it was impossible to clarify whether the amygdala was the primary epileptic focus. Wieser24 reported a patient who presented with late seizure recurrence after amygdalotomy, and the patient underwent a second operation, that is, hippocampectomy. Therefore, simultaneous resection of the amygdala and hippocampus is recommended for intractable epilepsy with AE, even if the hippocampus is not considered to be the main epileptic focus. There have been few reports describing the surgical outcome of AE cases. According to a previous report of 12 surgical cases of AE, standard anterior temporal lobectomy (ATL) was performed when the affected lesion was located on the nondominant side, and the authors attempted to preserve the
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Epilepsy hippocampus when the affected lesion was located on the dominant side.12 They noted that 11 of 12 patients became seizurefree during follow-up after standard ATL. In our series, 10 of 11 patients became seizure-free during the follow-up period. These results indicate the efficacy of surgical treatment for AE. When performing surgery, selective amygdalohippocampectomy is the first choice with regard to preservation of memory function.18 If the affected side is located on the dominant hemisphere, HT is one of the surgical options to preserve memory function, although it is inferior to hippocampectomy with regard to seizure suppression.18 Medical treatment should be performed prior to surgical treatment, and only medically intractable cases should be considered for surgical intervention.
7 8
9
10
11 12
13
LIMITATIONS The primary limitations of this whole study were the small sample size and the lack of statistical analysis. Evaluation of resected amygdaloid tissue was not performed because an en bloc resection of the amygdala is technically difficult. Moreover, from the viewpoint of the nature of the facility, this study was limited to surgical cases with AE, and this is likely to represent only a subset of AE cases.
14
15 16 17
CONCLUSIONS Clustering hypertrophic neurons with slight gliosis or without gliosis were considered to be pathological features of AE. Vacuolisation in the background matrix is also frequently observed, but less often than aggregated hypertrophic neurons. The surgical outcome was rather favourable, and medically intractable cases should be treated surgically. When performing surgery, simultaneous resection of the amygdala and hippocampus is recommended. Contributors NM wrote the whole manuscript and gathered the patients’ data. MM performed all the surgeries of this study and revised the manuscript, especially as to surgical procedure and seizure outcome. TU collected the patient data about intraoperative EEG, preoperative and postoperative scalp EEG, and pathology. He also checked the whole manuscript and edited the EEG section. TK and NA determined the pathological diagnosis of the specimens. They also checked the article, especially as to the paragraphs about pathology. YN made the radiographic diagnosis of the patients with amygdala enlargement. He also checked the manuscript, especially the portion pertaining to the radiographic findings. EK checked the final version of the article before submission. IN checked the whole manuscript before submission.
18
19 20
21 22 23 24
25
26
Competing interests None. Ethics approval As this study was based on a retrospective chart review and did not deal with human participants, the requirement for ethics committee approval was waived. We collected and assessed data regarding radiographic findings, EEG findings, seizure outcome and pathological slides. All data were anonymised by the removal of any identifying marks. Provenance and peer review Not commissioned; externally peer reviewed.
27 28 29 30
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Bower SP, Vogrin SJ, Morris K, et al. Amygdala volumetry in “imaging-negative” temporal lobe epilepsy. J Neurol Neurosurg Psychiatry 2003;74:1245–9. Coan AC, Morita ME, Campos BM, et al. Amygdala enlargement occurs in patients with mesial temporal lobe epilepsy and hippocampal sclerosis with early epilepsy onset. Epilepsy Behav 2013;29:390–4. Coan AC, Morita ME, de Campos BM, et al. Amygdala enlargement in patients with mesial temporal lobe epilepsy without hippocampal sclerosis. Front Neurol 2013;4:166. Keller J, Shen L, Gomez RG, et al. Hippocampal and amygdalar volumes in psychotic and nonpsychotic unipolar depression. Am J Psychiatry 2008;165: 872–80. Mitsueda-Ono T, Ikeda A, Inouchi M, et al. Amygdalar enlargement in patients with temporal lobe epilepsy. J Neurol Neurosurg Psychiatry 2011;82:652–7. 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;19:509–12. Morino M, Ichinose T, Uda T, et al. Memory outcome following transsylvian selective amygdalohippocampectomy in 62 patients with hippocampal sclerosis. J Neurosurg 2009;110:1164–9. Morino M, Uda T, Naito K, et al. Comparison of neuropsychological outcomes after selective amygdalohippocampectomy versus anterior temporal lobectomy. Epilepsy Behav 2006;9:95–100. Wieser HG, Yasargil MG. Selective amygdalohippocampectomy as a surgical treatment of mesiobasal limbic epilepsy. Surg Neurol 1982;17:445–57. Yasargil MG, Teddy PJ, Roth P. Selective amygdalo-hippocampectomy. Operative anatomy and surgical technique. Adv Tech Stand Neurosurg 1985;12:93–123. Shimizu H, Kawai K, Sunaga S, et al. Hippocampal transection for treatment of left temporal lobe epilepsy with preservation of verbal memory. J Clin Neurosci 2006;13:322–8. Uda T, Morino M, Ito H, et al. Transsylvian hippocampal transection for mesial temporal lobe epilepsy: surgical indications, procedure, and postoperative seizure and memory outcomes. J Neurosurg 2013;119:1098–104. Engel J Jr, Van Ness P, Rasmussen TB, et al. Outcome with respect to epileptic seizures. In: Engel J Jr. ed. Surgical treatment of the epilepsies. Raven Press, 1993:609–21. Watson C, Nielsen S, Cobb C, et al. Pathological grading system for hippocampal sclerosis: correlation with magnetic resonance imaging-based volume measurements of the hippocampus. J Epilepsy 1996;9:56–64. Goddard GV. Development of epileptic seizures through brain stimulation at low intensity. Nature 1967;214:1020–1. McIntyre DC, Racine RJ. Kindling mechanisms: current progress on an experimental epilepsy model. Prog Neurobiol 1986;27:1–12. Bartolomei F, Wendling F, Regis J, et al. Pre-ictal synchronicity in limbic networks of mesial temporal lobe epilepsy. Epilepsy Res 2004;61:89–104. Wieser HG. Mesial temporal lobe epilepsy versus amygdalar epilepsy: late seizure recurrence after initially successful amygdalotomy and regained seizure control following hippocampectomy. Epileptic Disord 2000;2:141–52. Kimura Y, Sato N, Saito Y, et al. Temporal lobe epilepsy with unilateral amygdala enlargement: morphometric MR analysis with clinical and pathological study. J Neuroimaging 2014. Published Online First. doi: 10.1111/jon.12106 Harvey AS, Grattan-Smith JD, Desmond PM, et al. Febrile seizures and hippocampal sclerosis: frequent and related findings in intractable temporal lobe epilepsy of childhood. Pediatr Neurol 1995;12:201–6. Kuks JB, Cook MJ, Fish DR, et al. Hippocampal sclerosis in epilepsy and childhood febrile seizures. Lancet 1993;342:1391–4. Komori T, Arai N. Dysembryoplastic neuroepithelial tumor, a pure glial tumor? Immunohistochemical and morphometric studies. Neuropathology 2013;33:459–68. Duong T, De Rosa MJ, Poukens V, et al. Neuronal cytoskeletal abnormalities in human cerebral cortical dysplasia. Acta Neuropathol 1994;87:493–503. Zentner J, Wolf HK, Ostertun B, et al. Gangliogliomas: clinical, radiological, and histopathological findings in 51 patients. J Neurol Neurosurg Psychiatry 1994;57:1497–502. Hitotsumatsu T, Iwaki T, Fukui M, et al. Cytoplasmic inclusions of astrocytic elements of glial tumors: special reference to round granulated body and eosinophilic hyaline droplets. Acta Neuropathol 1994;88:501–10. Koelsche C, Wohrer A, Jeibmann A, et al. Mutant BRAF V600E protein in ganglioglioma is predominantly expressed by neuronal tumor cells. Acta Neuropathol 2013;125:891–900. Aliashkevich AF, Yilmazer-Hanke D, Van Roost D, et al. Cellular pathology of amygdala neurons in human temporal lobe epilepsy. Acta Neuropathol 2003;106:99–106. Yilmazer-Hanke DM, Wolf HK, Schramm J, et al. Subregional pathology of the amygdala complex and entorhinal region in surgical specimens from patients with pharmacoresistant temporal lobe epilepsy. J Neuropathol Exp Neurol 2000;59:907–20. Zentner J, Wolf HK, Helmstaedter C, et al. Clinical relevance of amygdala sclerosis in temporal lobe epilepsy. J Neurosurg 1999;91:59–67.
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Surgery for amygdala enlargement with mesial temporal lobe epilepsy: pathological findings and seizure outcome Noriaki Minami, Michiharu Morino, Takehiro Uda, Takashi Komori, Yasuhiro Nakata, Nobutaka Arai, Eiji Kohmura and Imaharu Nakano J Neurol Neurosurg Psychiatry published online September 15, 2014
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JNNP Online First, published on September 15, 2014 as 10.1136/jnnp-2014-308383 Epilepsy
RESEARCH PAPER
Surgery for amygdala enlargement with mesial temporal lobe epilepsy: pathological findings and seizure outcome Noriaki Minami,1,2 Michiharu Morino,1 Takehiro Uda,1 Takashi Komori,3 Yasuhiro Nakata,4 Nobutaka Arai,5 Eiji Kohmura,2 Imaharu Nakano1 1
Department of Neurosurgery, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan 2 Department of Neurosurgery, Kobe University School of Medicine, Kobe, Hyogo, Japan 3 Department of Laboratory Medicine and Pathology (Neuropathology), Tokyo Metropolitan Neurological Hospital, Tokyo, Japan 4 Department of Neuroradiology, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan 5 Brain Pathology Research Center, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan Correspondence to Dr Noriaki Minami, Department of Neurosurgery, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan; [email protected] Received 22 April 2014 Revised 2 July 2014 Accepted 2 September 2014
To cite: Minami N, Morino M, Uda T, et al. J Neurol Neurosurg Psychiatry Published Online First: [please include Day Month Year] doi:10.1136/jnnp2014-308383
ABSTRACT Objective Amygdala enlargement (AE) has been suggested to be a subtype of mesial temporal lobe epilepsy (MTLE). However, most reports related to AE have referred to imaging studies, and there have been few reports regarding surgical and pathological findings. The present study was performed to clarify the surgical outcomes and pathology of AE. Methods Eighty patients with drug-resistant MTLE were treated surgically at the Tokyo Metropolitan Neurological Hospital between April 2010 and July 2013. Of these patients, 11 were diagnosed as AE based on presurgical MRI. Nine patients with AE underwent selective amygdalohippocampectomy, while the remaining two patients underwent selective amygdalotomy with hippocampal transection. Intraoperative EEG was routinely performed. The histopathology of the resected amygdala tissue was evaluated and compared with the amygdala tissue of patients with hippocampal sclerosis. Results Pathological findings indicated that 10 of 11 specimens had closely clustering hypertrophic neurons with vacuolisation of the background matrix. Slight gliosis was seen in nine specimens, while the remaining two showed no gliotic changes. Intraoperative EEG showed abnormal sharp waves that seemed to originate not from the amygdala but from the hippocampus in all cases. Ten patients became seizure-free during the postoperative follow-up period. Conclusions Histopathologically, clustering hypertrophic neurons and vacuolation with slight gliosis or without gliosis were considered to be pathological characteristics of AE. Amygdalohippocampectomy or hippocampal transection with amygdalotomy is effective for seizure control in patients with AE.
Recently, amygdala enlargement (AE) has attracted attention as a possible subtype of MRI-negative mesial temporal lobe epilepsy (MTLE). However, as the entity is not widely recognised, AE is often overlooked in many facilities and treated as MRI-negative MTLE, which is refractory to surgical treatment.1–6 Although there are increasing numbers of reports describing radiographic features of AE,7–11 there have been few reports referring to the pathological findings and surgical outcome of AE.12 This is probably because patients with AE tend to be less symptomatic and surgical indication is restricted. The present study was performed to
assess the surgical outcome and pathological findings of AE with MTLE.
METHODS Participants A total of 80 patients with drug-resistant MTLE were treated surgically by a single surgeon (MM) at the Tokyo Metropolitan Neurological Hospital between April 2010 and July 2013. Among the 80 patients, 11 were diagnosed as AE with MTLE based on specific MRI findings. For each patient, the clinical assessment included a careful review of the seizure semiology, MRI, scalp EEG, N-isopropyl(123I)-p-iodoamphetamine single-photon emission CT, neuropsychological examination and continuous long-term video EEG monitoring. Eight of the 11 patients with AE underwent [18F]fluorodeoxyglucose positron emission tomography and [11C] methionine positron emission tomography examination. All patients were followed up for a minimum of 1 year after surgery. A series of 26 patients who underwent surgical treatment for TLE with hippocampal sclerosis (HCS) at the same facility were also included as controls for comparison of the pathological findings.
Preoperative MRI evaluation MRI findings were evaluated by two experienced neuroradiologists using a 1.5 T MRI scanner (SignaEXCITE HD DV16; GE Medical Systems, Milwaukee, Wisconsin, USA) or a 3 T MRI scanner (Discovery 750; GE Medical Systems). Two neuroradiologists defined AE as a lesion with unilateral enlargement and slightly increased signal intensity of the amygdala on both axial and coronal fluid-attenuated inversion recovery (FLAIR) or T2-weighted images (figure 1). Patients with MRI-enhanced lesions, cysts, calcifications or well-circumscribed intensity lesions were not included in this study because they were strongly suspected to have lowgrade gliomas, such as ganglioglioma (figure 2).
Resective surgery After frontotemporal craniotomy, the trans-sylvian approach was applied for all cases. Trans-sylvian selective amygdalohippocampectomy (TSA)13–16 was performed in nine patients, and two patients underwent selective amygdalotomy with hippocampal transection (HT).17 18 The surgical procedure was as follows. After adequate exposure of the sylvian fissure, the inferior peri-insular sulcus was
Minami N, et al. J Neurol Neurosurg 2014;0:1–8. doi:10.1136/jnnp-2014-308383 Copyright Article author (or their employer) 2014.Psychiatry Produced by BMJ Publishing Group Ltd under licence.
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Epilepsy
Figure 1 All of the 11 amygdala enlargement cases with subtle abnormalities on fluid-attenuated inversion recovery images are shown. Slightly enlarged amygdala with mild high intensity was seen.
identified, and the inferior horn was opened with cortical incision along the sulcus. Then, intraoperative electrical recording of the hippocampus (6×1 grid electrode), amygdala (4×1 grid electrode), medial temporal (4×1 grid electrode), basal temporal (4×1 grid electrode) and lateral temporal area (4×1 grid electrode) was performed (figure 3). The affected amygdala was then resected in a piecemeal manner using microforceps, microscissors and ultrasonic aspiration. Once the resection of the amygdala was completed, the uncus could be resected according to the same method. At this time, the hippocampal recording was performed again to compare electrical changes before and after removal of the amygdala. In performing TSA, the hippocampal head was dissected subpially towards the dorsal part of the hippocampus, and the hippocampal body was cut dorsally at the innominate sulcus between the collateral eminence and the hippocampal body. The feeding artery could then be identified and cut. Finally, the hippocampal tail was dissected posteriorly and removed to permit an en bloc resection of the hippocampus and parahippocampal gyrus. The EEG of the lateral temporal area was recorded again at this point for comparison before and after removal of the hippocampus. In performing HT, vertical transection of the hippocampus at 5 mm intervals was performed using a ring-shaped blunt dissector. After transection, the hippocampal EEG was recorded to compare electrical changes before and after transection of the hippocampus. 2
Histology and immunohistochemistry Surgical specimens were fixed in 10% buffered formalin and processed for embedding in paraffin. H&E stain, Klüver-Barrera (KB) stain and Manlow’s stain were utilised for routine histological analyses. Representative sections were immunostained with antibodies directed against neuronal nuclei antigen (NeuN; A60, 1:10; Chemicon, Temecula, California, USA) and glial fibrillary acidic protein (GFAP; polyclonal, 1:400; Dako Cytomation, Glostrup, Denmark). The sections were incubated overnight with primary antibodies, and antigens were manually visualised using a detection kit (EnVision +kit/HRP; Dako Cytomation) with diaminobenzidine as the chromogen. Making a rational pathological diagnosis, the neuropathologists also examined a series of amygdala specimens from 26 HCS cases and 2 heterotopic grey matter cases, and performed comparisons with specimens of AE. The degree of gliosis was rated for each section (none: no gliotic change; mild: not seen on Manlow’s stain but seen on GFAP; moderate: seen on Manlow’s stain; severe: diffuse and advanced gliotic change). The degree of vacuolisation was also classified into three groups (none: no vacuolisation; mild: only seen on H&E; moderate: seen on both H&E and KB).
Outcome assessment Postoperative seizure outcomes were assessed according to Engel’s classification.19 All participants were followed up for a
Minami N, et al. J Neurol Neurosurg Psychiatry 2014;0:1–8. doi:10.1136/jnnp-2014-308383
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Epilepsy Figure 2 As shown in these four images, patients with MRI-enhanced lesions, cysts, calcifications or well-circumscribed intensity lesions were not included in this study because they were strongly suspected to be low-grade gliomas, including ganglioglioma.
Figure 3 (A) Intraoperative EEG of case 11 before removal of the affected amygdala. The abnormal sharp waves seemed to originate not from the amygdala but from the hippocampus. Electrodes 1–6 were set on the hippocampus (Hip), 7–10 were set on the amygdala (Amy), 11–14 were set on the medial temporal area (MTL), 15–18 were set on the basal temporal area (Base) and 19–22 were set on the lateral temporal area (LTL). (B) Hippocampal EEG before transection of the hippocampus showing almost the same frequency of the abnormal sharp waves as before removal of the affected amygdala. (C) Hippocampal EEG after transection of the hippocampus showing definitely decreased frequency of abnormal sharp waves.
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4
N D 56 22 F M 10 11
51 15
N N D 23 21 26 19 20 22 F F F 7 8 9
→: no particular findings; ↑: hypermetabolism; ↓: hypometabolism. AE, amygdala enlargement; CPS, complicated paroxysmal seizure; F, female; FDG-PET, [18F]fluorodeoxy-glucose positron emission tomography; GTC, general tonic clonic seizure; M, male; MET-PET, [11C]methionine positron emission tomography; NAD: non available data; SPECT, single-photon emission CT; SPS, simple paroxysmal seizure; D, dominant; N, non dominant.
Right temporal Left temporal No laterality Left temporal → → ↓ ↓ – – 2/day 4–5/month
– –
AE AE
Bilateral temporal Right temporal Intact Right temporal Right temporal No laterality → ↑ ↑ ↓ ↑ → – – – 1/month 4–5/year 4–5/month
– + –
AE AE AE
Right temporal Left temporal Left temporal Right temporal Left temporal Left temporal NAD ↑ → NAD NAD → NAD ↓ → NAD NAD ↓ – – – – – + – – – – – –
CPS Aura, GTC CPS CPS CPS Aura (pallor), SPS (tinnitus), CPS CPS GTC SPS (dystonic movement), GTC CPS CPS D D N N D N 28 25 21 23 59 38 21 17 14 19 56 34
Seizure semiology Dominance of the affected side
4–5/day 4–5/year 2–3/day 4–5/year 2–3/week 1/month
History of neonatal asphyxia
F M F M F M
There were no complications associated with the surgical procedure. Postoperative scalp EEG demonstrated that abnormal sharp waves disappeared in six patients and subsided in two patients (table 3). Ten of 11 patients became seizure-free during the follow-up period.
Gender
Surgical outcome
Age at surgery
Intraoperative EEG showed abnormal sharp waves that seemed to originate not from the amygdala but from the hippocampus in all cases (figure 3). Although there were no changes in hippocampal EEG before and after removal of the amygdala, significant improvement of the abnormal sharp wave was observed after removal or transection of the hippocampus in 10 of 11 cases.
Age at onset
Intraoperative EEG
Table 1 Patient demographics and preoperative examinations
Pathological findings indicated that 10 of 11 specimens had closely aggregated hypertrophic neurons with vacuolisation in the background matrix (figure 4). Similar findings were made in 7 of 28 specimens in the control group with HCS (figure 5 and table 2). In particular, it was prominent in the two specimens of patients with HCS with heterotopic grey matter (table 2; controls 17 and 18). Vacuolation, which was considered to be due to enlarged dendrites, was detected in both groups. However, the degree of vacuolation tended to be more developed in the AE group than the control group. In addition, vacuolation was found diffusely in the AE group, while the affected area was limited in the control group. Aggregated oligodendroglia-like cells (OLCs) were identified in case 11 (figure 4). Gliosis was detected more frequently in the control group than in the AE group, and the degree of gliosis was also more developed in controls. The presence of neuronal loss was unclear in both groups. None of the specimens in the present study had lymphocytic infiltration or eosinophilic granular bodies, which are commonly seen in ganglioglioma. On pathological examination of the resected hippocampus from patients with AE, six of nine specimens showed mild gliosis, and all of six specimens were classified as grade I according to Watson’s pathological grading for HCS.20
Frequency of attacks
Pathological findings
History of febrile convulsion
MRI
FDG-PET
MET-PET
The demographic and clinical features of the study participants are listed in table 1. The 11 patients included in the study consisted of 4 males and 7 females. The mean age at seizure onset was 26.3 years (range 14–56), yielding a mean duration of epilepsy of 4.8 years by the time of surgery (range 1–8 years). Eight patients had typical complex partial seizures (CPS) and the remaining three had generalised tonic clonic seizures without CPS. Two patients also presented with simple partial seizures; one presented with dystonic movement, and the other presented with tinnitus. Aura was observed in two patients, one of whom presented with pallor. One patient had a history of febrile convulsions, and another had a history of neonatal asphyxia.
1 2 3 4 5 6
RESULTS Patient demographics
AE AE AE AE AE AE
Decreased lesion of blood flow in SPECT
Seizure focus diagnosed based on interictal scalp EEG
minimum of 1 year after surgery (12–47 months; mean 26.8 months). Patient outcome and follow-up were evaluated by an outpatient chart review. Postoperative neuropsychological evaluation was obtained using the Wechsler Memory Scale-Revised (WMS-R) 6 months after surgery. Postoperative interictal scalp EEG was also performed for all surgical cases. The results of interictal scalp EEG change were categorised into three groups: complete response (almost complete disappearance of abnormal waves), partial response (decrease of abnormal waves) and no significant change.
Right temporal Left Temporal Right temporal Right temporal Left temporal Right temporal
Epilepsy
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Epilepsy Figure 4 Cases (amygdala enlargement; ×400). (A) Extensive vacuolation of the neuropil. (B) Swelling of neuritis and cytoplasm of the neurons. (C) Vacuolation was visible on Klüver-Barrera staining. (D) Close aggregation of hypertrophic neurons on neuronal nuclei antigen (NeuN) immunohistochemistry (A–D, table 2, case 8). (E) Some neurons were situated in a back-to-back position (arrows). (F) Clustering of the neurons was evident on NeuN immunohistochemistry. (G) Focal accumulation of oligodendroglia-like cells. (H) Only minimal gliosis was present in the background tissue (glial fibrillary acidic protein immunohistochemistry; E–H, table 2, case 11).
DISCUSSION HCS is widely recognised as the most common subtype of MTLE because of its specific findings on MRI. On the other hand, AE has attracted renewed attention as a possible subtype of MTLE.7–9 11 12 The amygdala is part of the limbic system, and has been suggested to play an important role in MTLE. Laboratory animal studies demonstrated that the amygdala tends to acquire the kindling phenomenon more easily than the hippocampus.21 22 However, little clinical information is available regarding the relationships between epilepsy and the amygdala. There are several reasons for this lack of data. First, pathological evaluation of the amygdala is difficult because the specimens are usually fragmented. Second, electrical discharge from the amygdala is usually synchronised with that from the hippocampus.23 Third, patients presenting with specific limbic symptoms related to the amygdala are very rare.24 Therefore, there have been few investigations focusing on the amygdala. However, there are increasing numbers of reports regarding AE,
particularly those based on imaging findings. Some reports discussed amygdala volumetry, confirming the existence of AE.7–11 25 To the best of our knowledge, there have been few reports regarding surgical and pathological findings in MTLE with AE, probably because patients with MTLE with AE tend to be less symptomatic and surgery is less likely to be indicated.12 25 Hence, the present study was performed to clarify the intraoperative EEG findings of the amygdala, the pathological findings and the surgical outcome of MTLE with AE. Previous reports have indicated that the frequency of a history of febrile convulsion in patients with HCS ranges from 20% to 48%.26 27 On the other hand, the incidence of a history of febrile convulsion was reported to be significantly lower in patients with AE than in those with HCS (14% vs 48%, respectively, p=0.12).7 It was also noted that the average age of onset in the AE group was significantly higher than that in the HCS group (29 years old vs 11 years old, respectively, p=0.01).7 It was reported previously that the average age of onset of MTLE
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Epilepsy Figure 5 Controls (×400). (A) Mildly hypertrophic neurons in the vacuolated neuropil. There was a certain distance between each neuron (H&E staining). (B) Fine vacuolation was not detectable on Klüver-Barrera (KB) staining. (C) Clustering of neurons was absent on neuronal nuclei antigen (NeuN) immunohistochemistry. (D) Only focal and minimal gliosis was identified in the background on glial fibrillary acidic protein (GFAP) immunohistochemistry (A–D, table 2, control 13). (E) Neuronal loss and vacuolation of the neuropil. (F) Some neurons showed pyknosis (KB staining). Neurons were atrophic rather than hypertrophic. (G) Neuronal loss was apparent on NeuN immunohistochemistry. (H) Mild gliosis in the background tissue (GFAP immunohistochemistry; E–H, table 2, control 19).
with AE was 27.4 years, consistent with our results.12 The seizure semiology of amygdalar epilepsy is characterised by ictal fear, painful gastric sensations and marked autonomic symptoms, such as changes in heart rate and respiration, facial pallor and goose flesh,24 phenomena referred to as ‘limbic seizure’. In our series, only one patient presented with pallor as an aura (table 1, case 6). Aggregated hypertrophic neurons without gliosis were considered to be a pathological characteristic of AE. OLCs, often seen in the histopathology of dysplastic tissue or glioneuronal tumours, were also found in case 11, indicating dysplastic changes not only in the neurons but also in the glial tissue.28 In a previous report, 8 of 12 surgical cases of AE were pathologically diagnosed as focal cortical dysplasia (FCD).12 Two pathological cases of AE were also reported previously; the temporal cortex was examined in these cases and disorganisation of the cortical layer and dysmorphic neurons was observed, suggesting 6
the existence of FCD.25 Cytoskeletal impairments, such as hypertrophic neurons, are sometimes observed in cortical dysplasia.29 In addition, two specimens with heterotopic grey matter revealed prominent aggregated hypertrophic neurons (controls 15 and 16). However, in our AE series, the localisation of the hypertrophic neurons without heterotopic displacement was not compatible with the pathological features of FCD. Although our pathological findings were similar to FCD, it seems inappropriate to apply this term in these cases. Ganglioglioma could be a candidate for differential diagnosis because it sometimes presents with mild high intensity on FLAIR or T2-weighted imaging; however, it usually shows calcified or cystic lesions.30 Ganglioglioma also has specific pathological findings, that is, glial proliferation, lymphocytic infiltration and eosinophilic granular bodies.31 Moreover, the association between ganglioglioma and BRAF V600E mutation has recently been a topic of interest among brain tumour
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Epilepsy Table 2 Pathological findings of the amygdala Case number Cases 1 2 3 4 5 6 7 8 9 10 11 Controls 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39
Table 3
Age
Sex
MRI
Vacuolation
Cluster/ swelling
28 25 22 21 59 38 23 21 26 56 22
F M F M F M F F F F M
AE AE AE AE AE AE AE AE AE AE AE
1 1 1 2 2 1 2 2 2 2 2
Y N Y Y Y Y Y Y Y Y Y
1 1 1 1 1 1 1 1 1 0 0
53 38 38 39 21 18 35 37 36 24 51 22 35 30 28 43 30 27 57 50 8 55 46 3 52 19 27 56
M F F M F F F F M F F F M F M F F F F F M F M F F F F F
HCS HCS HCS HCS HCS HCS HCS HCS HCS HCS HCS HCS HCS HCS HCS HCS Heterotopia Heterotopia HCS HCS HCS HCS HCS HCS HCS HCS HCS HCS
0 1 2 2 0 0 1 1 1 0 0 2 0 1 2 1 1 1 1 1 0 0 1 1 1 1 1 0
N N N N N N Y N N N N Y N N Y N Y Y Y Y N N N N N N N N
0 0 0 2 0 0 2 2 2 2 2 0 0 2 2 1 2 1 0 2 1 0 0 0 0 0 2 2
Gliosis
AE, amygdala enlargement; F, female; HCS, hippocampal sclerosis; Heterotopia, heterotopic grey matter; M, male; N, no; Y, yes; 0, none; 1, mild; 2, severe.
researchers.32 Therefore, the possibility of ganglioglioma was excluded. It is difficult to express these findings using pathological terms; ‘hamartoma’ or ‘dysplasia’ is relatively close as an appropriate expression. In one of 11 cases, aggregated hypertrophic neurons were not detected, suggesting that the underlying disease of AE may be heterogeneous. Some specimens in the HCS group showed similar findings, indicating that the phenomenon could also occur in patients with HCS. The vacuolation in the background matrix, which was considered to be due to the enlarged dendrites of hypertrophic neurons, was identified in both AE and controls. Although the possibility that vacuolation was an artefact due to surgical manipulation could not be excluded, there were differences in the frequency and severity of vacuolation between the two groups. There was one valuable previous report regarding the cellular pathology of
1 2 3 4 5 6 7 8 9 10 11
Outcome
Main seizure focus diagnosed based on intraoperative EEG findings
Seizure outcome (Engel’s classification)
Surgical complications
Postoperative scalp EEG
Hip Hip Hip Hip Hip Hip Hip Hip Hip Hip Hip
Ia Ia IIIa Ia Ia Ia Ia Ia Ia Ia Ia
– – – – – – – – – – –
CR CR CR CR NSC CR PR PR NSC NSC CR
CR, complete response; Hip, hippocampus; NSC: no significant change; PR, partial response.
amygdala neurons in human TLE,33 according to which neurons in the TLE group were significantly smaller than those in controls and had fewer dendrites, whereas the density of spines in these cells was increased in patients with TLE. Another similar report indicated that the regional distribution of neuropathological changes varied between the different subnuclei of the amygdala in patients with TLE and strengthened the suggestion that the amygdala was the main target of epilepsy-related neuronal cell damage.34 These pathological findings were completely different from our results, because they described amygdala sclerosis, confirming that AE belongs to a special entity in TLE. Although slight gliosis was found in 9 of 11 specimens in the AE group, no neuronal cell loss was detected, and thus there was no evidence of amygdala sclerosis or amygdala atrophy.35 Wieser24 reported one patient in whom stereotactic intracranial EEG monitoring confirmed amygdalar seizure. He emphasised that amygdalar discharges were restricted to the amygdala, and could be detected only by direct recording from the amygdalar nuclei by stereotactically inserted electrodes. We performed intraoperative EEG in all surgical cases and attempted to record amygdalar discharges putting the 4×1 electrode grid on each amygdala directly, but were unable to confirm such findings. The abnormal sharp wave seemed to be discharged from the hippocampus in all cases. Moreover, although there were no changes in hippocampal EEG before and after removal of the amygdala, significant improvement of EEG was observed after removal or transection of the hippocampus in 10 of 11 cases. These results suggest that, at the time of surgery, the main epileptic focus migrated to the hippocampus, affected by repetitive seizures. However, it was impossible to clarify whether the amygdala was the primary epileptic focus. Wieser24 reported a patient who presented with late seizure recurrence after amygdalotomy, and the patient underwent a second operation, that is, hippocampectomy. Therefore, simultaneous resection of the amygdala and hippocampus is recommended for intractable epilepsy with AE, even if the hippocampus is not considered to be the main epileptic focus. There have been few reports describing the surgical outcome of AE cases. According to a previous report of 12 surgical cases of AE, standard anterior temporal lobectomy (ATL) was performed when the affected lesion was located on the nondominant side, and the authors attempted to preserve the
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Epilepsy hippocampus when the affected lesion was located on the dominant side.12 They noted that 11 of 12 patients became seizurefree during follow-up after standard ATL. In our series, 10 of 11 patients became seizure-free during the follow-up period. These results indicate the efficacy of surgical treatment for AE. When performing surgery, selective amygdalohippocampectomy is the first choice with regard to preservation of memory function.18 If the affected side is located on the dominant hemisphere, HT is one of the surgical options to preserve memory function, although it is inferior to hippocampectomy with regard to seizure suppression.18 Medical treatment should be performed prior to surgical treatment, and only medically intractable cases should be considered for surgical intervention.
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LIMITATIONS The primary limitations of this whole study were the small sample size and the lack of statistical analysis. Evaluation of resected amygdaloid tissue was not performed because an en bloc resection of the amygdala is technically difficult. Moreover, from the viewpoint of the nature of the facility, this study was limited to surgical cases with AE, and this is likely to represent only a subset of AE cases.
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CONCLUSIONS Clustering hypertrophic neurons with slight gliosis or without gliosis were considered to be pathological features of AE. Vacuolisation in the background matrix is also frequently observed, but less often than aggregated hypertrophic neurons. The surgical outcome was rather favourable, and medically intractable cases should be treated surgically. When performing surgery, simultaneous resection of the amygdala and hippocampus is recommended. Contributors NM wrote the whole manuscript and gathered the patients’ data. MM performed all the surgeries of this study and revised the manuscript, especially as to surgical procedure and seizure outcome. TU collected the patient data about intraoperative EEG, preoperative and postoperative scalp EEG, and pathology. He also checked the whole manuscript and edited the EEG section. TK and NA determined the pathological diagnosis of the specimens. They also checked the article, especially as to the paragraphs about pathology. YN made the radiographic diagnosis of the patients with amygdala enlargement. He also checked the manuscript, especially the portion pertaining to the radiographic findings. EK checked the final version of the article before submission. IN checked the whole manuscript before submission.
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Competing interests None. Ethics approval As this study was based on a retrospective chart review and did not deal with human participants, the requirement for ethics committee approval was waived. We collected and assessed data regarding radiographic findings, EEG findings, seizure outcome and pathological slides. All data were anonymised by the removal of any identifying marks. Provenance and peer review Not commissioned; externally peer reviewed.
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Minami N, et al. J Neurol Neurosurg Psychiatry 2014;0:1–8. doi:10.1136/jnnp-2014-308383
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Surgery for amygdala enlargement with mesial temporal lobe epilepsy: pathological findings and seizure outcome Noriaki Minami, Michiharu Morino, Takehiro Uda, Takashi Komori, Yasuhiro Nakata, Nobutaka Arai, Eiji Kohmura and Imaharu Nakano J Neurol Neurosurg Psychiatry published online September 15, 2014
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