Alyma Somani1, Hanna El-Hachami1, Smriti Patodia1, Sanjay Sisodiya1,2, Maria Thom1,3. 1. Departments of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK. 2. Chalfont Centre for Epilepsy, Bucks, UK. 3. Neuropathology, National Hospital for Neurology and Neurosurgery Queen Square, London, UK.
Abstract
OBJECTIVE: Sudden unexpected death in epilepsy (SUDEP) may arise as a result of autonomic dysfunction during a seizure. The central autonomic networks (CANs) modulate brainstem cardiorespiratory regulation. Recent magnetic resonance imaging (MRI) studies in SUDEP have shown cortical and subcortical volume changes and altered connectivity between CAN regions, but the pathological correlate is unknown. Because neuroinflammation is both a cause and a consequence of seizures and may relate to regional brain pathology, our aim was to evaluate microglial populations in CANs in SUDEP. METHODS: In 55 postmortem cases, including SUDEP, epilepsy controls without SUDEP and nonepilepsy controls, we quantified Iba1-expressing microglia in 14 cortical and thalamic areas that included known CAN regions. RESULTS: Mean Iba1 labeling across all brain regions was significantly higher in SUDEP cases compared to epilepsy and nonepilepsy controls. There was significant regional variation in Iba1 labeling in SUDEP cases only, with highest labeling in the medial thalamus. Significantly higher labeling in SUDEP cases than epilepsy and nonepilepsy controls was consistently noted in the superior temporal gyrus. In cases with documented seizures up to 10 days prior to death, significantly higher mean Iba1 labeling was observed in SUDEP compared to epilepsy controls. SIGNIFICANCE: Our findings support microglial activation in SUDEP, including cortical and subcortical regions with known autonomic functions such as the thalamus and superior temporal gyrus. This may be relevant to cellular pathomechanisms underlying cardioregulatory failure during a seizure.
OBJECTIVE: Sudden unexpected death in epilepsy (SUDEP) may arise as a result of autonomic dysfunction during a seizure. The central autonomic networks (CANs) modulate brainstem cardiorespiratory regulation. Recent magnetic resonance imaging (MRI) studies in SUDEP have shown cortical and subcortical volume changes and altered connectivity between CAN regions, but the pathological correlate is unknown. Because neuroinflammation is both a cause and a consequence of seizures and may relate to regional brain pathology, our aim was to evaluate microglial populations in CANs in SUDEP. METHODS: In 55 postmortem cases, including SUDEP, epilepsy controls without SUDEP and nonepilepsy controls, we quantified Iba1-expressing microglia in 14 cortical and thalamic areas that included known CAN regions. RESULTS: Mean Iba1 labeling across all brain regions was significantly higher in SUDEP cases compared to epilepsy and nonepilepsy controls. There was significant regional variation in Iba1 labeling in SUDEP cases only, with highest labeling in the medial thalamus. Significantly higher labeling in SUDEP cases than epilepsy and nonepilepsy controls was consistently noted in the superior temporal gyrus. In cases with documented seizures up to 10 days prior to death, significantly higher mean Iba1 labeling was observed in SUDEP compared to epilepsy controls. SIGNIFICANCE: Our findings support microglial activation in SUDEP, including cortical and subcortical regions with known autonomic functions such as the thalamus and superior temporal gyrus. This may be relevant to cellular pathomechanisms underlying cardioregulatory failure during a seizure.
Authors: Andre Altmann; Mina Ryten; Martina Di Nunzio; Teresa Ravizza; Daniele Tolomeo; Regina H Reynolds; Alyma Somani; Marco Bacigaluppi; Valentina Iori; Edoardo Micotti; Rossella Di Sapia; Milica Cerovic; Eleonora Palma; Gabriele Ruffolo; Juan A Botía; Julie Absil; Saud Alhusaini; Marina K M Alvim; Pia Auvinen; Nuria Bargallo; Emanuele Bartolini; Benjamin Bender; Felipe P G Bergo; Tauana Bernardes; Andrea Bernasconi; Neda Bernasconi; Boris C Bernhardt; Karen Blackmon; Barbara Braga; Maria Eugenia Caligiuri; Anna Calvo; Chad Carlson; Sarah J A Carr; Gianpiero L Cavalleri; Fernando Cendes; Jian Chen; Shuai Chen; Andrea Cherubini; Luis Concha; Philippe David; Norman Delanty; Chantal Depondt; Orrin Devinsky; Colin P Doherty; Martin Domin; Niels K Focke; Sonya Foley; Wendy Franca; Antonio Gambardella; Renzo Guerrini; Khalid Hamandi; Derrek P Hibar; Dmitry Isaev; Graeme D Jackson; Neda Jahanshad; Reetta Kälviäinen; Simon S Keller; Peter Kochunov; Raviteja Kotikalapudi; Magdalena A Kowalczyk; Ruben Kuzniecky; Patrick Kwan; Angelo Labate; Soenke Langner; Matteo Lenge; Min Liu; Pascal Martin; Mario Mascalchi; Stefano Meletti; Marcia E Morita-Sherman; Terence J O'Brien; Jose C Pariente; Mark P Richardson; Raul Rodriguez-Cruces; Christian Rummel; Taavi Saavalainen; Mira K Semmelroch; Mariasavina Severino; Pasquale Striano; Thomas Thesen; Rhys H Thomas; Manuela Tondelli; Domenico Tortora; Anna Elisabetta Vaudano; Lucy Vivash; Felix von Podewils; Jan Wagner; Bernd Weber; Roland Wiest; Clarissa L Yasuda; Guohao Zhang; Junsong Zhang; Costin Leu; Andreja Avbersek; Maria Thom; Christopher D Whelan; Paul Thompson; Carrie R McDonald; Annamaria Vezzani; Sanjay M Sisodiya Journal: Neuropathol Appl Neurobiol Date: 2021-09-05 Impact factor: 8.090