The ventrolateral medulla and medullary raphe in sudden unexpected death in epilepsy

Patodia, Smriti; Somani, Alyma; O'Hare, Megan; Venkateswaran, Ranjana; Liu, Joan; Michalak, Zuzanna; Ellis, Matthew; Scheffer, Ingrid E.; Diehl, Beate; Sisodiya, Sanjay M.; Thom, Maria

doi:10.1093/brain/awy078

Cited by 85 publications

(101 citation statements)

References 54 publications

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“…The latter region corresponds well to the region in which alterations of neuromodulatory, neuropeptidergic, and monoaminergic systems have been shown in a histopathological study of patients who died of SUDEP (Patodia et al, 2018). Furthermore, the results of the individual and combined regional analyses suggest that it was not merely the extent of the brainstem abnormalities but in particular volume loss in the region of the mesencephalon/raphe nuclei and the upper medulla oblongata at the level of the obex that was most highly correlated with the time between last MRI and SUDEP.…”

Section: Discussionsupporting

confidence: 53%

Brainstem network disruption: A pathway to sudden unexplained death in epilepsy?

Mueller

Nei

Bateman

et al. 2018

Human Brain Mapping

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Observations in witnessed Sudden Unexpected Death in Epilepsy (SUDEP) suggest that a fatal breakdown of the central autonomic control could play a major role in SUDEP. A previous MR study found volume losses in the mesencephalon in focal epilepsy that were more severe and extended into the lower brainstem in two patients who later died of SUDEP. The aims of this study were to demonstrate an association (1) between brainstem volume loss and impaired autonomic control (reduced heart rate variability [HRV]); (2) between brainstem damage and time to SUDEP in patients who later died of SUDEP. Two populations were studied: (1) Autonomic system function population (ASF, 18 patients with focal epilepsy, 11 controls) with HRV measurements and standardized 3 T MR exams. (2) SUDEP population (26 SUDEP epilepsy patients) with clinical MRI 1-10 years before SUDEP. Deformation-based morphometry of the brainstem was used to generate profile similarity maps from the resulting Jacobian determinant maps that were further characterized by graph analysis to identify regions with excessive expansion indicating significant volume loss or atrophy. The total number of regions with excessive expansion in ASF was negatively correlated with HRV (r = -.37, p = .03), excessive volume loss in periaqueductal gray/medulla oblongata autonomic nuclei explained most of the HRV associated variation (r/r = -.82/.67, p < .001). The total number of regions with excessive expansion in SUDEP was negatively correlated with time to SUDEP (r = -.39, p = .03), excessive volume loss in the raphe/medulla oblongata at the obex level explained most of the variation of the time between MRI to SUDEP (r/r = -.60/.35,p = .001). Epilepsy is associated with brainstem atrophy that impairs autonomic control and can increase the risk for SUDEP if it expands into the mesencephalon.

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Section: Discussionsupporting

confidence: 53%

Brainstem network disruption: A pathway to sudden unexplained death in epilepsy?

Mueller

Nei

Bateman

et al. 2018

Human Brain Mapping

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“…50 DBA/1 mice exhibit a genetic deficiency of serotonin synthesis due to reduced expression of tryptophan hydroxylase 2. 54 Taken together, these findings suggest the potential usefulness of fenfluramine in the prevention of SUDEP in patients with epilepsy. 10 In addition to confirming the importance of serotonin observed in previous studies in DBA/1 mice, the present findings also extend the evidence for the anticonvulsant 39,51 and potential SUDEP-preventing effects of enhancing central serotonergic neurotransmission.…”

Section: Discussionmentioning

confidence: 79%

Fenfluramine, a serotonin‐releasing drug, prevents seizure‐induced respiratory arrest and is anticonvulsant in the DBA/1 mouse model of SUDEP

Tupal

Faingold

2019

Epilepsia

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Summary Objective Prevention of sudden unexpected death in epilepsy (SUDEP) is a critical goal for epilepsy therapy. The DBA/1 mouse model of SUDEP exhibits an elevated susceptibility to seizure‐induced death in response to electroconvulsive shock, hyperthermia, convulsant drug, and acoustic stimulation. The serotonin hypothesis of SUDEP is based on findings that treatments which modify serotonergic function significantly alter susceptibility to seizure‐induced sudden death in several epilepsy models, including DBA/1 mice. Serotonergic abnormalities have also recently been observed in human SUDEP. Fenfluramine is a drug that enhances serotonin release in the brain. Recent studies have found that the addition of fenfluramine improved seizure control in patients with Dravet syndrome, which has a high incidence of SUDEP. Therefore, we investigated the effects of fenfluramine on seizures and seizure‐induced respiratory arrest (S‐IRA) in DBA/1 mice. Methods The dose and time course of the effects of fenfluramine (i.p.) on audiogenic seizures (Sz) induced by an electric bell in DBA/1 mice were determined. Videos of Sz‐induced behaviors were recorded for analysis. Statistical significance (P < 0.05) was evaluated using the chi‐square test. Results Sixteen hours after administration of 15 mg/kg of fenfluramine, a high incidence of selective block of S‐IRA susceptibility (P < 0.001) occurred in DBA/1 mice without blocking any convulsive behavior. Thirty minutes after 20‐40 mg/kg of fenfluramine, significant reductions of seizure incidence and severity, as well as S‐IRA susceptibility occurred, which were long‐lasting (≥48 hours). The median effective dose (ED50) of fenfluramine for significantly reducing Sz at 30 minutes was 21 mg/kg. Significance This study presents the first evidence for the effectiveness of fenfluramine in reducing seizure incidence, severity, and S‐IRA susceptibility in a mammalian SUDEP model. The ability of fenfluramine to block S‐IRA selectively suggests the potential usefulness of fenfluramine in prophylaxis of SUDEP. These results further confirm and extend the serotonin hypothesis of SUDEP.

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“…We recently observed reduced somatostatin and galanin in the ventrolateral medulla in a postmortem SUDEP series, and our aim was to carry out an investigation of neuropeptides in the amygdala. By including a group of SUDEP cases with a history of one or more seizures followed by recovery in the 24‐hour period prior to SUDEP, we aimed to address whether the occurrence of recent seizures also had any impact on amygdala neuropeptide levels.…”

Section: Introductionmentioning

confidence: 99%

Neuropeptide depletion in the amygdala in sudden unexpected death in epilepsy: A postmortem study

et al. 2020

Self Cite

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Objective Sudden unexpected death in epilepsy (SUDEP) is typically unwitnessed but can be preceded by seizures in the period prior to death. Peri‐ictal respiratory dysfunction is a likely mechanism for some SUDEP, and central apnea has been shown following amygdala stimulation. The amygdala is enriched in neuropeptides that modulate neuronal activity and can be transiently depleted following seizures. In a postmortem SUDEP series, we sought to investigate alterations of neuropeptidergic networks in the amygdala, including cases with recent poor seizure control. Methods In 15 SUDEP cases, 12 epilepsy controls, and 10 nonepilepsy controls, we quantified the labeling index (LI) for galanin, neuropeptide Y (NPY), and somatostatin (SST) in the lateral, basal, and accessory basal nuclei and periamygdala cortex with whole slide scanning image analysis. Within the SUDEP group, seven had recent generalized seizures with recovery 24 hours prior to death (SUDEP‐R). Results Galanin, NPY, and SST LIs were significantly lower in all amygdala regions in SUDEP cases compared to epilepsy controls (P < .05 to P < .0005), and galanin LI was lower in the lateral nucleus compared to nonepilepsy controls (P < .05). There was no difference in the LI in the SUDEP‐R group compared to other SUDEP. Higher LI was noted in epilepsy controls than nonepilepsy controls; this was significant for NPY in lateral and basal nuclei (P < .005 and P < .05). Significance A reduction in galanin in the lateral nucleus in SUDEP could represent acute depletion, relevant to postictal amygdala dysfunction. In addition, increased amygdala neuropeptides in epilepsy controls support their seizure‐induced modulation, which is relatively deficient in SUDEP; this could represent a vulnerability factor for amygdala dysfunction in the postictal period.

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The ventrolateral medulla and medullary raphe in sudden unexpected death in epilepsy

Cited by 85 publications

References 54 publications

Brainstem network disruption: A pathway to sudden unexplained death in epilepsy?

Brainstem network disruption: A pathway to sudden unexplained death in epilepsy?

Fenfluramine, a serotonin‐releasing drug, prevents seizure‐induced respiratory arrest and is anticonvulsant in the DBA/1 mouse model of SUDEP

Neuropeptide depletion in the amygdala in sudden unexpected death in epilepsy: A postmortem study

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