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

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

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.

SUDEP, TH, TPH, c-fos, catecholamingergic, ventrolateral medulla
1015-6305
133-143
Patodia, Smriti
a4599af7-0545-4965-a869-5f9520fa1ddb
Tan, Ian
c586aca7-7ed8-41b9-a536-a8f0deb80bfd
Ellis, Matthew
afbca752-ced4-40dd-b0af-d9ecffbd5b63
Somani, Alyma
53e0664e-50b4-47af-a8dc-48fce1211be7
Scheffer, Ingrid E
e732f930-9f68-44c0-94d5-93c14758d3fe
Sisodiya, Sanjay M
442600da-eda0-410b-97bb-cde8326d702d
Thom, Maria
a9f63dd8-ba68-4ea1-a945-e4bbd18525d2
Patodia, Smriti
a4599af7-0545-4965-a869-5f9520fa1ddb
Tan, Ian
c586aca7-7ed8-41b9-a536-a8f0deb80bfd
Ellis, Matthew
afbca752-ced4-40dd-b0af-d9ecffbd5b63
Somani, Alyma
53e0664e-50b4-47af-a8dc-48fce1211be7
Scheffer, Ingrid E
e732f930-9f68-44c0-94d5-93c14758d3fe
Sisodiya, Sanjay M
442600da-eda0-410b-97bb-cde8326d702d
Thom, Maria
a9f63dd8-ba68-4ea1-a945-e4bbd18525d2

Patodia, Smriti, Tan, Ian, Ellis, Matthew, Somani, Alyma, Scheffer, Ingrid E, Sisodiya, Sanjay M and Thom, Maria (2021) Medullary tyrosine hydroxylase catecholaminergic neuronal populations in sudden unexpected death in epilepsy. Brain Pathology, 31 (1), 133-143. (doi:10.1111/bpa.12891).

Record type: Article

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.

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More information

Accepted/In Press date: 6 August 2020
e-pub ahead of print date: 15 August 2020
Published date: January 2021
Additional Information: Funding Information: UCL is part of the Center for SUDEP Research (CSR) and supported through the National Institute of Neurological Disorders And Stroke of the National Institutes of Health (Award Numbers neuropathology of SUDEP: 5U01NS090415 and SUDEP admin core grant: U01-NS090405). Epilepsy Society supports SMS, and through the Katy Baggott Foundation, supports the UCL Epilepsy Society Brain and Tissue Bank. This work was undertaken at UCLH/UCL who received a proportion of funding from the Department of Health?s NIHR Biomedical Research Centres funding scheme. We are very grateful for provision of additional SUDEP and control material for this study from the following resources: The MRC Sudden Death Brain Bank in Edinburgh (cases detailed in additional methods file). Tissue samples were also obtained from David Hilton at Derriford Hospital as part of the UK Brain Archive Information Network (BRAIN UK) which is funded by the Medical Research Council and Brain Tumour Research. Funding Information: UCL is part of the Center for SUDEP Research (CSR) and supported through the National Institute of Neurological Disorders And Stroke of the National Institutes of Health (Award Numbers neuropathology of SUDEP: 5U01NS090415 and SUDEP admin core grant: U01‐NS090405). Epilepsy Society supports SMS, and through the Katy Baggott Foundation, supports the UCL Epilepsy Society Brain and Tissue Bank. This work was undertaken at UCLH/UCL who received a proportion of funding from the Department of Health’s NIHR Biomedical Research Centres funding scheme. We are very grateful for provision of additional SUDEP and control material for this study from the following resources: The MRC Sudden Death Brain Bank in Edinburgh (cases detailed in additional methods file). Tissue samples were also obtained from David Hilton at Derriford Hospital as part of the UK Brain Archive Information Network (BRAIN UK) which is funded by the Medical Research Council and Brain Tumour Research. Publisher Copyright: © 2020 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology
Keywords: SUDEP, TH, TPH, c-fos, catecholamingergic, ventrolateral medulla

Identifiers

Local EPrints ID: 446229
URI: http://eprints.soton.ac.uk/id/eprint/446229
ISSN: 1015-6305
PURE UUID: d6b8bd08-32c7-4366-af5c-2b100808de44

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Date deposited: 29 Jan 2021 17:32
Last modified: 16 Mar 2024 10:34

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Contributors

Author: Smriti Patodia
Author: Ian Tan
Author: Matthew Ellis
Author: Alyma Somani
Author: Ingrid E Scheffer
Author: Sanjay M Sisodiya
Author: Maria Thom

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