Medullary tyrosine hydroxylase catecholaminergic neuronal populations in sudden unexpected death in epilepsy

Abstract

Sudden unexpected death in epilepsy (SUDEP) is mechanistically complex and one probable cause is seizure‐related respiratory dysfunction. Medullary respiratory regulatory nuclei include the pre‐Bötzinger complex (pre‐BötC) in the ventrolateral medulla (VLM), the medullary raphé nuclei (MR) and nucleus of solitary tract in the dorsomedial medulla (DMM). The region of the VLM also contains intermingled tyrosine hydroxylase (TH) catecholaminergic neurones which directly project to the pre‐BötC and regulate breathing under hypoxic conditions and our aim was to evaluate these neurones in SUDEP cases. In post‐mortem cases from three groups [SUDEP (18), epilepsy controls (8) and non‐epilepsy controls (16)] serial sections of medulla (obex + 2 to + 13 mm) were immunolabeled for TH. Three regions of interest (ROI) were outlined (VLM, DMM and MR) and TH‐immunoreactive (TH‐IR) neurones were evaluated using automated detection for overall labeling index (neurones and processes) and neuronal densities and compared between groups and relative to obex level. C‐fos immunoreactivity was also semi‐quantitatively evaluated in these regions. We found no significant difference in the density of TH‐IR neurones or labeling index between the groups in all regions. Significantly more TH‐IR neurones were present in the DMM region than VLM in non‐epilepsy cases only (P < 0.01). Regional variations in TH‐IR neurones with obex level were seen in all groups except SUDEP. We also identified occasional TH neurones in the MR region in all groups. There was significantly less c‐fos labeling in the VLM and MR in SUDEP than non‐epilepsy controls but no difference with epilepsy controls. In conclusion, in this series we found no evidence for alteration of total medullary TH‐IR neuronal numbers in SUDEP but noted some differences in their relative distribution in the medulla and c‐fos neurones compared to control groups which may be relevant to the mechanism of death.

Regional microglial populations in central autonomic brain regions in SUDEP

“…One theory of the cause of sudden unexpected death in epilepsy (SUDEP) proposes that a central, irrecoverable failure of autonomic regulation of cardiovascular and respiratory function occurs around the time of a seizure. In previous postmortem (PM) studies we have identified alterations to selective neuronal and glial populations in medullary respiratory regulatory nuclei in SUDEP, 1‐3 suggesting preexisting pathology, possibly secondary to previous seizures or episodes of seizure‐related hypoxia. In a PM pathology‐MRI (magnetic resonance imaging) correlative study we also observed volume reduction in the rostral medulla in SUDEP, 4 in keeping with in vivo MRI studies 5,6 and in support of regional alterations.…”

“…This study was underpowered to detect regional differences in SUDEP cases with recent seizures compared to epilepsy controls; however, further studies of regional microglia responses and activation states in response to seizures are clearly warranted in SUDEP. In previous studies in SUDEP, we have recognized regional alteration in neuromodulators, including neuropeptidergic, adenosine, catecholaminergic, and serotonergic systems, [1][2][3]30,32 which may reflect network changes; as these neuromodulators also regulate microglial cells and their activation, 33 it is not inconceivable that these processes are inter-related. Activated microglial cells are also known to be increased in focal epilepsy pathologies, as focal cortical dysplasia, and correlate with duration of epilepsy, 34 with evidence of regional localization of the inflammation on C 11 PK11195 PET.…”

Proteomic differences in hippocampus and cortex of sudden unexplained death in childhood

“…In addition to parallels in mechanism of death in SUDC and SUDEP [ 27 , 28 , 37 , 49 ], altered serotonergic signaling in brainstem and other regions is postulated to contribute to SUDEP risk [ 43 , 51 , 55 – 58 ]. We evaluated the same brain regions in SUDEP, but did not identify differences [ 43 ].…”

Neuropathology in the North American sudden unexpected death in epilepsy registry

“…Two additional studies found no differences between PWE and SUDEP with several markers in medullary regions. 35 , 36 Whole exome sequencing in surgical brain tissue from epilepsy patients that died from SUDEP implicate several gene variants that may increase risk of SUDEP. 58 , 59 We recently identified a number of protein differences between epilepsy and non-epilepsy control cases by localized proteomics in cortex and hippocampal CA1-3 and DG, 60 however found no significant protein differences when comparing SUDEP to epilepsy and few differences in the hippocampus of high-risk SUDEP MTLE cases with a prolonged PGES by RNAseq.…”