Abstract
Sudden unexpected death in epilepsy (SUDEP) is a leading cause of premature death in patients with epilepsy. One hypothesis proposes that sudden death is mediated by post-ictal central respiratory depression, which could relate to underlying pathology in key respiratory nuclei and/or their neuromodulators. Our aim was to investigate neuronal populations in the ventrolateral medulla (which includes the putative human pre-Bötzinger complex) and the medullary raphe. Forty brainstems were studied comprising four groups: 14 SUDEP, six epilepsy controls, seven Dravet syndrome cases and 13 non-epilepsy controls. Serial sections through the medulla (from obex 1 to 10 mm) were stained for Nissl, somatostatin, neurokinin 1 receptor (for pre-Bötzinger complex neurons) and galanin, tryptophan hydroxylase and serotonin transporter (neuromodulatory systems). Using stereology total neuronal number and densities, with respect to obex level, were measured. Whole slide scanning image analysis was used to quantify immunolabelling indices as well as co-localization between markers. Significant findings included reduction in somatostatin neurons and neurokinin 1 receptor labelling in the ventrolateral medulla in sudden death in epilepsy compared to controls (P < 0.05). Galanin and tryptophan hydroxylase labelling was also reduced in sudden death cases and more significantly in the ventrolateral medulla region than the raphe (P < 0.005 and P < 0.05). With serotonin transporter, reduction in labelling in cases of sudden death in epilepsy was noted only in the raphe (P ≤ 0.01); however, co-localization with tryptophan hydroxylase was significantly reduced in the ventrolateral medulla. Epilepsy controls and cases with Dravet syndrome showed less significant alterations with differences from non-epilepsy controls noted only for somatostatin in the ventrolateral medulla (P < 0.05). Variations in labelling with respect to obex level were noted of potential relevance to the rostro-caudal organization of respiratory nuclear groups, including tryptophan hydroxylase, where the greatest statistical difference noted between all epilepsy cases and controls was at obex 9-10 mm (P = 0.034), the putative level of the pre-Bötzinger complex. Furthermore, there was evidence for variation with duration of epilepsy for somatostatin and neurokinin 1 receptor. Our findings suggest alteration to neuronal populations in the medulla in SUDEP with evidence for greater reduction in neuromodulatory neuropeptidergic and mono-aminergic systems, including for galanin, and serotonin. Other nuclei need to be investigated to evaluate if this is part of more widespread brainstem pathology. Our findings could be a result of previous seizures and may represent a pathological risk factor for SUDEP through impaired respiratory homeostasis during a seizure.
Highlights
Sudden and unexpected death in epilepsy (SUDEP) is the leading cause of death in young adults with intractable epilepsy (Dlouhy et al, 2016)
We hypothesized that pathological changes in brainstem respiratory nuclei could occur in SUDEP and our aim was to study the ventrolateral medulla (VLM) region, which encloses the putative human homologue of the pre-BotC nucleus (Tada et al, 2009; Schwarzacher et al, 2011; Presti et al, 2014) and medullary raphe in a series of SUDEP post-mortem cases compared with control groups
Cases included: (i) Fourteen SUDEP from the Epilepsy Society Brain and Tissue Bank (ESBTB) at UCL and from Brain UK via the pathology department at Derriford Hospital, Plymouth. These were further categorized into nine definite SUDEP, the remaining five being probable or possible SUDEP (Nashef et al, 2012); (ii) Seven cases with Dravet syndrome obtained from ESBTB and the University of Melbourne Australia [as previously reported (Catarino et al, 2011), between 1992 and 2010]
Summary
Sudden and unexpected death in epilepsy (SUDEP) is the leading cause of death in young adults with intractable epilepsy (Dlouhy et al, 2016). The pre-BotC is further modulated to regulate respiratory rhythm in response to physiological and metabolic demands and during sleep-wake cycles via higher cortical and other brainstem nuclei (Ramirez et al, 2012; Smith et al, 2013). The latter are regulated by peripheral and sensory inputs and chemoreceptors and, through the serotonergic neurons of the medullary raphe, provide excitatory drive in response to hypoxia and hypercarbia (Richerson, 2004; Benarroch, 2014). In sudden infant death syndrome (SIDS), which has clinical parallels with SUDEP, alterations to medullary serotonergic neuronal populations have been shown (Paterson et al, 2006; Kinney et al, 2009)
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