Regional cortical thickness changes accompanying generalized tonic-clonic seizures

Abstract

ObjectiveGeneralized tonic-clonic seizures are accompanied by cardiovascular and respiratory sequelae that threaten survival. The frequency of these seizures is a major risk factor for sudden unexpected death in epilepsy (SUDEP), a leading cause of untimely death in epilepsy. The circumstances accompanying such fatal events suggest a cardiovascular or respiratory failure induced by unknown neural processes rather than an inherent cardiac or lung deficiency. Certain cortical regions, especially the insular, cingulate, and orbitofrontal cortices, are key structures that integrate sensory input and influence diencephalic and brainstem regions regulating blood pressure, cardiac rhythm, and respiration; output from those cortical regions compromised by epilepsy-associated injury may lead to cardiorespiratory dysregulation. The aim here was to assess changes in cortical integrity, reflected as cortical thickness, relative to healthy controls. Cortical alterations in areas that influence cardiorespiratory action could contribute to SUDEP mechanisms.MethodsHigh-resolution T1-weighted images were collected with a 3.0-Tesla MRI scanner from 53 patients with generalized tonic-clonic seizures (Mean age ± SD: 37.1 ± 12.6 years, 22 male) at Case Western Reserve University, University College London, and the University of California at Los Angeles. Control data included 530 healthy individuals (37.1 ± 12.6 years; 220 male) from UCLA and two open access databases (OASIS and IXI). Cortical thickness group differences were assessed at all non-cerebellar brain surface locations (P < 0.05 corrected).ResultsIncreased cortical thickness appeared in post-central gyri, insula, and subgenual, anterior, posterior, and isthmus cingulate cortices. Post-central gyri increases were greater in females, while males showed more extensive cingulate increases. Frontal and temporal cortex, lateral orbitofrontal, frontal pole, and lateral parietal and occipital cortices showed thinning. The extents of thickness changes were sex- and hemisphere-dependent, with only males exhibiting right–sided and posterior cingulate thickening, while females showed only left lateral orbitofrontal thinning. Regional cortical thickness showed modest correlations with seizure frequency, but not epilepsy duration.SignificanceCortical thickening and thinning occur in patients with generalized tonic-clonic seizures, in cardiovascular and somatosensory areas, with extent of changes sex- and hemisphere-dependent. The data show injury in key autonomic and respiratory cortical areas, which may contribute to dysfunctional cardiorespiratory patterns during seizures, as well as to longer-term SUDEP risk.

Postconvulsive central apnea as a biomarker for sudden unexpected death in epilepsy (SUDEP)

“…Imaging studies in our cohort with intractable epilepsy and GCS indicate sex-specific cortical changes in autonomic and breathing control sites such as preferential, lateralized orbitofrontal cortex thinning in women. 24 Bradypnea occurred more often in seizures arising from sleep, when most SUDEP occurs. Postconvulsive bradypnea or PCCA accompanied by asystole appears to be particularly rare, occurring in only 1 seizure each in the 2 near-SUDEP cases (<1% of all GCS), and thus may represent an especially important biomarker.…”

Cerebellar, limbic, and midbrain volume alterations in sudden unexpected death in epilepsy

“…Significant positive correlations between GTCS frequency and volume were also observed for the bilateral anterior cingulate, when combining both SUDEP and high‐risk subjects in one group. Cortical thickening of the cingulate has recently been demonstrated in GTCS patients . Volume elevations associated with gliosis resulting from hyperexcitability due to repeated seizures may be operating, and may be indicative of limbic network dysfunction linked to GTCSs …”

“…Cortical thickening of the cingulate has recently been demonstrated in GTCS patients. 5 Volume elevations associated with gliosis resulting from hyperexcitability due to repeated seizures may be operating, 41 and may be indicative of limbic network dysfunction linked to GTCSs. 42 When the high-risk and SUDEP groups were considered separately, correlations between the right posterior cingulate volume and GTCS frequency became nonsignificant in both groups, and the finding of increased anterior cingulate volume with increased GTCS frequency remained the same in high-risk patients but became nonsignificant in SUDEP.…”

“…Brain structural imaging studies of SUDEP have revealed volume changes among key structures involved in autonomic and respiratory regulation in people who succumbed to SUDEP and those at high risk . Individuals with frequent GTCSs, who are at highest risk of SUDEP, exhibit cortical thickness changes in key areas that are autonomic, somatosensory, and breathing coordination sites . Less attention has been directed to structures essential for recovery from compromised breathing or cardiovascular circumstances.…”

“…3 Individuals with frequent GTCSs, who are at highest risk of SUDEP, 4 exhibit cortical thickness changes in key areas that are autonomic, somatosensory, and breathing coordination sites. 5 Less attention has been directed to structures essential for recovery from compromised breathing or cardiovascular circumstances. Regional brain volume assessments in patients who succumb may allow determination of processes that contribute to the fatal event or fail to provide adequate compensatory recovery.…”