Elsevier

Epilepsy & Behavior

Volume 60, July 2016, Pages 33-41
Epilepsy & Behavior

Review
Isolated amygdala enlargement in temporal lobe epilepsy: A systematic review

https://doi.org/10.1016/j.yebeh.2016.04.015Get rights and content

Highlights

  • Isolated amygdala enlargement has been increasingly thought to be epileptogenic.

  • Seizure characteristics and treatment outcomes between 8 studies were compared.

  • Comparisons were hindered by differing methods of assessing amygdala volume.

  • Studies agreed on a few characteristics in this group compared to controls.

  • They are the following: late seizure onset, few convulsive seizures, and good response to medication.

Abstract

Objective

The objective of this study was to compare the seizure characteristics and treatment outcomes in patient groups with temporal lobe epilepsy (TLE) identified with isolated amygdala enlargement (AE) on magnetic resonance imaging studies.

Methods

PubMed, Embase, and the Cochrane Library were searched for relevant studies using the keywords ‘amygdala enlargement’, ‘epilepsy’, and ‘seizures’ in April 2015. Human studies, written in English, that investigated cohorts of patients with TLE and AE were included.

Results

Of 204 abstracts initially identified using the search strategy, 14 studies met the inclusion criteria (11 epilepsy studies and 3 psychiatry studies). Ultimately, 8 full studies on AE and TLE involving 107 unique patients were analyzed. Gender distribution consisted of 50 males and 57 females. Right amygdala enlargement was seen in 39 patients, left enlargement in 58 patients, and bilateral enlargement in 7 patients. Surgical resection was performed in 28 patients, with the most common finding being dysplasia/hamartoma or focal cortical dysplasia. Most studies involved small samples of less than 12 patients. There was a wide discrepancy in the methods used to measure amygdala volume, in both patients and controls, hindering comparisons. Most TLE with AE studies observed a later age of seizure onset (mean: 32.2 years) compared with studies involving TLE with HS (mean of mid- to late childhood). A higher frequency of complex partial seizures compared with that of convulsive seizures is seen in patients with AE (67–100% vs. 26–47%), and they have an excellent response to antiepileptic drugs (81.8%–100% of seizure-free patients). All studies that included controls also found a significant difference in frequency of seizure types between their cases and controls.

Conclusions

Reliable assessment of amygdala volume remains a critical issue hindering better understanding of the clinical management and research of this focal epilepsy syndrome. Within these limitations, the literature suggests characteristics of an older age of epilepsy onset, a greater tendency to nonconvulsive seizures, and a good response to antiepileptic drugs in this interesting group of epilepsies.

Introduction

The most common lesions identified in focal epilepsy are hippocampal sclerosis (40%), long-term epilepsy-associated tumors (27%), and malformations of cortical development (13%) [1]. Historically, the most common form of focal epilepsy, mesial temporal lobe epilepsy (TLE) due to hippocampal sclerosis (HS), has received the widest surgical attention. Hippocampal sclerosis can be reliably detected on routine magnetic resonance imaging (MRI) studies and is well-known for its epileptogenicity [2]. Mesial TLE due to HS is often medically resistant, and surgical resection can achieve up to 70% long-term seizure freedom in patients [3].

With improved neuroimaging and correlative presurgical techniques, clinicians are becoming increasingly aware of other potentially epileptogenic temporal lobe lesions that may also have good surgical outcome [4], [5]. While seizures originating from these other causes might have been classified as ‘nonlesional’ or ‘imaging-negative’ epilepsy previously, a greater awareness of other potentially epileptogenic lesions, as well as improved imaging technology, has resulted in the identification of enlarged amygdalae in a proportion of patients (see Fig. 1).

Bower et al. retrospectively found that 64% of ‘imaging-negative’ cases had both significant amygdala asymmetry and amygdala enlargement (AE), while Coan et al. demonstrated significant AE in 12% of previously diagnosed patients with ‘nonlesional’ TLE [4], [6]. Because nonlesional TLE may be associated with an almost three times lower probability of seizure freedom after surgical resection compared with lesional TLE, this reclassification of newly identified AE lesions in TLE has important implications for patient management [7].

Using parcellation based on cytoarchitecture, Murphy et al. showed in 1987 that the amygdaloid complex is asymmetric in humans, while in 1992, Watson et al. attempted to establish standardized anatomical guidelines for outlining the hippocampus and amygdala on high-resolution MRI scans [8], [9]. Although the technology has been available to measure amygdala volumes specifically since the early 1990s, studies linking amygdala pathology and size to seizure foci until recently have been lacking [8], [9].

There are a number of clinical, electroencephalographic, radiological, and histopathological observations that have led to an increased focus on the role of the amygdala independent from HS in epilepsy in recent years. Firstly, better outcomes have been observed when the amygdala was included in surgical resection borders [10]. Secondly, studies utilizing MRI T2 relaxometry have shown that a portion of patients with ‘imaging-negative’ TLE have increased T2 signal in the amygdala ipsilateral to the focus detected by electroencephalography (EEG) [11]. Thirdly, [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) findings of glucose hypometabolism have been isolated to the amygdala and excluding the hippocampus in some patients [12]. Finally, histopathologic abnormalities have been found in amygdala specimens resected from patients with medically resistant TLE [13].

This review pools studies on TLE and AE to provide better understanding of this imperfectly described focal epilepsy syndrome. Specific focus will be on the seizure characteristics, diagnostic investigations, treatment outcomes, and histopathological results in these cohorts of patients. We aimed to identify knowledge gaps in the literature that can guide future clinical management and research.

Section snippets

Methods

Our search strategy comprised a comprehensive literature search of PubMed, Embase, and the Cochrane Library, conducted using the terms ‘amygdala enlargement’, ‘epilepsy’, and ‘seizures’, either alone or in varying combinations in April 2015. Papers were excluded for the following reasons: animal studies, irrelevant topics, non-English papers, papers not involving a population with epilepsy, case reports, and those described with coexisting brain pathology. The references of included papers were

Results

Our search strategy in April 2015 ultimately yielded 14 papers from seven countries published between 1999 and September 2014. Although three abstracts presented only at scientific meetings were unavailable for full review, for reference, they have been included in the tables of the Results section [15], [16], [17]. Three papers focusing only on psychiatric domains of TLE and AE cannot be directly compared with the other eight papers focusing on epilepsy and were not formally reviewed but were

Discussion

Methodological issues limit comparisons between studies on isolated amygdala enlargement in temporal lobe epilepsy. Population cohorts are relatively small and ascertained through mixed surgical or medical sources with varying control group comparisons. However, the key methodological issue remains the varying identification techniques for amygdala enlargement from automated software (voxel-based morphometry or FreeSurfer), to manual tracing techniques to visual inspection by blinded or

Conclusions

This review on isolated AE in epilepsy included eight key papers and, in total, 107 unique patients. Most papers provide reasonable evidence of the enlarged amygdalae as the epileptic focus and provide consistent syndrome characteristics with a later age of onset, more CPS compared with CS, and a high likelihood of being responsive to AED treatment.

Overall, however, sample sizes were small, suggesting that caution should be applied when attempting to draw conclusions with regard to patients

Disclosure of conflict of interest

Wendyl D'Souza has received travel, investigator-related, speaker honoraria and has served on a scientific advisory board from UCB Pharma; educational grants from Novartis Pharmaceuticals, Pfizer Pharmaceuticals and Sanofi–Synthelabo; educational, travel, and fellowship grants from GSK Neurology Australia; has served on scientific advisory boards and received honoraria from SciGen Pharmaceuticals. His department has received research funding from GlaxoSmithKline, SciGen, Pfizer, Novartis, and

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