Is Bigger Better? Exploring the Compensatory Versus Pathological Nature of Amygdala Hypertrophy

Abstract

Original Article Citation

Zubal R, Velicky Buecheler M, Sone D, Postma T, De Tisi J, Caciagli L, Winston GP, Sidhu MK, Long L, Xiao B, Mcevoy AW, Miserocchi A, Vos SB, Baumann CR, Duncan JS, Koepp MJ, Galovic M. Brain Hypertrophy in Patients With Mesial Temporal Lobe Epilepsy With Hippocampal Sclerosis and Its Clinical Correlates. Neurology. 2025 Jan 28;104(2):e210182. doi: 10.1212/WNL.0000000000210182. Epub 2024 Dec 23. PMID: 39715478; PMCID: PMC11666274.

Background and Objectives: Mesial temporal lobe epilepsy (mTLE) is generally associated with focal brain atrophy, but little knowledge exists on possible disease-related hypertrophy of brain structures. We hypothesized that repeated seizures or adaptive plasticity may lead to focal brain hypertrophy and aimed to investigate associated clinical correlates. Methods: In this cohort study, we included patients with mTLE undergoing detailed epilepsy evaluations and matched healthy volunteers (HVs) from 2 tertiary centers (discovery and validation cohorts). We assessed areas of brain hypertrophy and their clinical correlates using whole-brain voxel-based or surface-based morphometry (VBM, SBM), subcortical volumetry, and shape analysis of T1-weighted MRI data by fitting linear models. We evaluated the functional implications of the findings on memory encoding using fMRI. Results: We included 135 patients with mTLE with neuropathology-confirmed hippocampal sclerosis (77 left, 58 right; 82 women; mean age 37 ± 11 years) and 47 HVs (29 women, mean age 36 ± 11 years) in the discovery cohort. VBM detected increased gray matter volume of the contralateral amygdala in patients with both left (t = 8.7, p < .001) and right (t = 7.9, p < .001) mTLE. We confirmed the larger volume of the contralateral amygdala using volumetry (left mTLE 1.74 ± 0.16 mL vs HVs 1.64 ± 0.11, p < .001; right mTLE 1.79 ± 0.18 mL vs HVs 1.70 ± 0.11, p = .002) and shape analysis (left mTLE p ≤ .005; right mTLE p = .006). We validated the hypertrophy of the contralateral amygdala in the validation cohort (mTLE, n = 18, 1.91 ± 0.20 mL; HVs, n = 18, 1.75 ± 0.13; p = .009). In left mTLE, contralateral amygdala hypertrophy was associated with poorer verbal memory and, in right mTLE, with more frequent focal-to-bilateral tonic-clonic seizures. A larger volume of the contralateral amygdala correlated with increased functional activation of the right parietal memory encoding network in a subgroup (44/135 patients with mTLE, 26/47 HVs) receiving fMRI. Discussion: Unilateral mTLE due to hippocampal sclerosis is associated with hypertrophy of the contra-lateral amygdala. This may represent plasticity to compensate for verbal memory deficits or may be the consequence of seizure spread to the contralateral hemisphere.

Commentary

Is Bigger Better? Exploring the Compensatory Versus Pathological Nature of Amygdala Enlargement

Temporal lobe epilepsy (TLE) has long been associated with focal or generalized brain atrophy. This atrophy has been reported not only in the hippocampus but also frequently extends to the thalamus, putamen, neocortex, and white matter networks of patients with TLE and other epilepsy syndromes. ¹ However, one structure often defies this pattern—frequently unscathed by the shrinkage of its nearest neighbor (the hippocampus) and, in many cases, even boasting expansion: the nut of the brain, the almond … the amygdala.

The first reports of amygdala enlargement (AE) in patients with epilepsy emerged in the early 1990s but gained momentum in the 2000s due to the increased availability of 3D imaging and semi-automated methods for quantifying subcortical volumes. ² Initially, these anomalies were thought to represent a clinical subtype of nonlesional TLE, occurring in up to 64% of TLE patients with visibly normal MRIs. ³ However, subsequent studies documented its presence in other nonlesional syndromes, including nonlesional extratemporal epilepsy and even genetic generalized epilepsy. ⁴ Patients with AE have been reported to exhibit a later age of seizure onset, better responses to anti-seizure medications (ASMs), and an increased likelihood of an autoimmune etiology relative to patients with TLE and hippocampal sclerosis (TLE-HS). ⁵ Recent machine learning studies have identified TLE with isolated AE as a distinct MRI biotype with a favorable ASM response. ⁶ Thus, all evidence seemed to point to TLE with AE as a unique entity with a more benign clinical profile compared to its HS counterpart.

However, a few studies have challenged whether AE is a phenomenon only observed in nonlesional epilepsy and whether it is benign.^7,8 In a recent study published in Neurology, Zubal et al ⁸ reported AE, or hypertrophy, in a large sample of patients with TLE-HS (N = 135) and examined its laterality, clinical features, and potential mechanisms. Using three measures of tissue properties—gray matter density, shape, and volume—the authors observed amygdala hypertrophy contralateral to the seizure focus across all measures in patients with both left and right TLE-HS. One marker of hypertrophy (ie, increased amygdala volume) was also replicated in an external validation cohort. Notably, contralateral amygdala hypertrophy was associated with poorer verbal memory, longer epilepsy duration, and a history of psychosis in patients with left TLE, while in patients with right TLE, hypertrophy was linked to a higher frequency of generalized convulsive seizures. There were no indicators of ipsilateral amygdala hypertrophy in either patient group. Overall, Zubal et al's study provides compelling evidence that contralateral amygdala hypertrophy is observed in TLE-HS across imaging measures and patient cohorts—and may signify a more severe TLE phenotype than previously appreciated.

But why does amygdala hypertrophy occur? Although the amygdala is known to be part of the epileptogenic network in TLE, ⁹ its response to seizures and the significance of its increased size in the contralateral hemisphere remain a mystery. Early debates centered around whether amygdala hypertrophy was a cause or a consequence of TLE, with studies favoring the latter interpretation—that hypertrophy results from enduring seizures. ⁵ However, whether this anomaly represents a compensatory mechanism gone awry or merely a harmful effect of seizures is still debated. Zubal et al considered both possibilities. In a subset of patients who had functional MRI, amygdala hypertrophy was associated with increased right parietal activation during a memory encoding task, which the authors suggested could indicate a compensatory process. However, they provided stronger support that it reflects the harmful effect of seizures, given the strong associations between amygdala hypertrophy, longer epilepsy duration, and increased frequency of secondary generalized seizures. Furthermore, longitudinal studies have shown that up to 66% of patients with amygdala hypertrophy exhibit decreases in amygdala volume in follow-up scans, ¹⁰ with this volume reduction correlating with decreased seizure frequency or complete seizure resolution. ⁵ These findings support the interpretation of amygdala hypertrophy as a dynamic, reactive process that diminishes as seizures subside.

A lingering question is whether the presence of amygdala hypertrophy can offer prognostic insights regarding surgical or other treatment outcomes. Although not addressed by Zubal et al, prior studies have not found a clear advantage in seizure outcomes following epilepsy surgery for patients with amygdala hypertrophy compared to those without, ¹¹ despite their somewhat better response to ASMs. ⁶ However, amygdala hypertrophy has been identified in patients who later experienced sudden unexplained death in epilepsy (SUDEP). Given the amygdala's proposed role in cardio-respiratory regulation and its involvement in triggering sleep apnea, AE could serve as a crucial biomarker for SUDEP risk. ¹²

Despite decades of research into the causes and consequences of amygdala hypertrophy in TLE, much remains unknown. Are certain amygdala subfields more enlarged than others? Does AE contribute to the development of psychiatric or cognitive comorbidities that do not correlate with hippocampal abnormalities? And do different mechanisms underlie ipsilateral versus contralateral AE in TLE and other epilepsy syndromes? Although some of these questions have been explored in small patient series, large and diverse datasets may be necessary to provide definitive answers. However, regarding Zubal et al's central question—whether amygdala hypertrophy represents an adaptive process in TLE—most evidence suggests that enlargement is a pathological feature with no clear compensatory benefit.

In conclusion: stay small, amygdala! Your growth is not welcomed here.