MRI and pathology correlations in the medulla in sudden unexpected death in epilepsy (SUDEP): a postmortem study.

S Patodia,I Scheffer,M Thom,X Golay,A Somani,S M Sisodiya,T Yousry,M Tachrount

doi:10.1111/nan.12638

Abstract

Sudden unexpected death in epilepsy (SUDEP) likely arises as a result of autonomic dysfunction around the time of a seizure. In vivo MRI studies report volume reduction in the medulla and other brainstem autonomic regions. Our aim, in a pathology series, is to correlate regional quantitative features on 9.4T MRI with pathology measures in medullary regions. Forty-seven medullae from 18 SUDEP, 18 nonepilepsy controls and 11 epilepsy controls were studied. In 16 cases, representing all three groups, ex vivo 9.4T MRI of the brainstem was carried out. Five regions of interest (ROI) were delineated, including the reticular formation zone (RtZ), and actual and relative volumes (RV), as well as T1, T2, T2* and magnetization transfer ratio (MTR) measurements were evaluated on MRI. On serial sections, actual and RV estimates using Cavalieri stereological method and immunolabelling indices for myelin basic protein, synaptophysin and Microtubule associated protein 2 (MAP2) were carried out in similar ROI. Lower relative RtZ volumes in the rostral medulla but higher actual volumes in the caudal medulla were observed in SUDEP (P<0.05). No differences between groups for T1, T2, T2* and MTR values in any region was seen but a positive correlation between T1 values and MAP2 labelling index in RtZ (P<0.05). Significantly lower MAP2 LI were noted in the rostral medulla RtZ in epilepsy cases (P<0.05). Rostro-caudal alterations of medullary volume in SUDEP localize with regions containing respiratory regulatory nuclei. They may represent seizure-related alterations, relevant to the pathophysiology of SUDEP.

Highlights

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in young adults with intractable epilepsy and may have many causes [1]
Microtubule associated protein 2 (MAP2) labelling index (LI) remained significantly lower in the rostral medulla reticular formation zone (RtZ) in all epilepsy cases compared to nonepilepsy controls (NEC) (P < 0.05). In this postmortem study, incorporating high resolution MRI of the brain stem, we provide further evidence for volume alterations in autonomic regulatory regions in SUDEP compared to controls, when aligning for the obex level
We observed differences in the level of medullary myelination and neuronal marker MAP2 in epilepsy cases compared to controls which could indicate brainstem neurodegeneration

Summary

Introduction

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in young adults with intractable epilepsy and may have many causes [1]. Recent clinical, neuroimaging and experimental research provides converging evidence for a central failure of autonomic regulation of cardiovascular and. Respiratory function in SUDEP [1,2]. SUDEP often occurs nocturnally or during sleep [9] and convergence of impaired brainstem arousal systems interacting with inadequate respiratory drive during seizures may be relevant. In experimental models of SUDEP, spreading depolarizations to the dorsal medulla following seizures have been shown to mediate cardio-respiratory arrest [10]. In structural MRI studies, volume loss in the medulla in SUDEP has been shown in some but not all studies [11,12,13]

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Results

Conclusion