Distinct Patterns of Brain Metabolism in Patients at Risk of Sudden Unexpected Death in Epilepsy

Abstract

Objective: To characterize regional brain metabolic differences in patients at high risk of sudden unexpected death in epilepsy (SUDEP), using fluorine-18-fluorodeoxyglucose positron emission tomography (18FDG-PET).Methods: We studied patients with refractory focal epilepsy at high (n = 56) and low (n = 69) risk of SUDEP who underwent interictal 18FDG-PET as part of their pre-surgical evaluation. Binary SUDEP risk was ascertained by thresholding frequency of focal to bilateral tonic-clonic seizures (FBTCS). A whole brain analysis was employed to explore regional differences in interictal metabolic patterns. We contrasted these findings with regional brain metabolism more directly related to frequency of FBTCS.Results: Regions associated with cardiorespiratory and somatomotor regulation differed in interictal metabolism. In patients at relatively high risk of SUDEP, fluorodeoxyglucose (FDG) uptake was increased in the basal ganglia, ventral diencephalon, midbrain, pons, and deep cerebellar nuclei; uptake was decreased in the left planum temporale. These patterns were distinct from the effect of FBTCS frequency, where increasing frequency was associated with decreased uptake in bilateral medial superior frontal gyri, extending into the left dorsal anterior cingulate cortex.Significance: Regions critical to cardiorespiratory and somatomotor regulation and to recovery from vital challenges show altered interictal metabolic activity in patients with frequent FBTCS considered to be at relatively high-risk of SUDEP, and shed light on the processes that may predispose patients to SUDEP.

A unified hypothesis of SUDEP: Seizure‐induced respiratory depression induced by adenosine may lead to SUDEP but can be prevented by autoresuscitation and other restorative respiratory response mechanisms mediated by the action of serotonin on the periaqueductal gray

“…These studies observed MRI evidence of atrophy of the PAG and raphe nuclei among other sites in PWE who died from SUDEP. [236][237][238][239][240][241] A recent positron emission tomography scan study in PWE who exhibited a high frequency of focal to bilateral tonic-clonic seizures and are proposed to be at high risk for SUDEP observed that several structures, including the PAG, exhibited significant metabolism increases interictally, as compared to a low-risk patient 242 The authors suggest that these findings may actually be indicative of loss of neuronal function, gliosis, and/or active inflammatory responses.…”

“…251 Another recent criterion for SUDEP susceptibility was based on the relatively high frequency of focal to bilateral tonic-clonic seizure occurrence in PWE. 242 An automated approach to SUDEP prevention, involving medical intervention to be administered via an implanted device automatically delivering electrical stimulation or medication, has recently been proposed, 252 and a peripheral approach using diaphragmatic pacing in a SUDEP model has recently been published. 253 Once criteria for SUDEP susceptibility are validated, preventative approaches should be employed.…”

Sudden unexpected death in epilepsy in children

“…Brainstem dysfunction has been implicated in SUDEP pathophysiology and altered patterns of brain metabolism have been demonstrated in patients at high risk of SUDEP. 32 Both alterations in serotonin and adenosine neurotransmission may be involved in SUDEP pathophysiology. 8,30 Serotonergic neurons influence the hyperexcitability of the brainstem respiratory center; dysfunction in serotonin has been implicated in sudden infant death syndrome and possibly SUDEP.…”

“…Brainstem dysfunction has been implicated in SUDEP pathophysiology and altered patterns of brain metabolism have been demonstrated in patients at high risk of SUDEP 32 . Both alterations in serotonin and adenosine neurotransmission may be involved in SUDEP pathophysiology 8,30 .…”