Sudden unexpected death in epilepsy: From the lab to the clinic setting

Terra, Vera Cristina; Cysneiros, Roberta Monterazzo; Cavalheiro, Ésper A.; Scorza, Fúlvio Alexandre

doi:10.1016/j.yebeh.2012.12.018

Cited by 41 publications

(28 citation statements)

References 97 publications

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“…Both DBA/1 and DBA/2 mice have been shown to be relevant animal models for studying SUDEP [25, 26]. First, both strains exhibit S-IRA after generalized convulsive seizures, leading to subsequent death if resuscitation is not rapidly instituted [16, 27].…”

Section: Dba Mice As Relevant Sudep Modelsmentioning

confidence: 99%

Abnormalities of serotonergic neurotransmission in animal models of SUDEP

Feng

Faingold

2017

Epilepsy & Behavior

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Sudden unexpected death in epilepsy (SUDEP) is a devastating event, and both DBA/1 and DBA/2 mice have been shown to be relevant animal models for studying SUDEP. DBA mice exhibit seizure-induced respiratory arrest (S-IRA), leading to cardiac arrest and subsequent sudden death after generalized audiogenic seizures (AGS). This sequence of terminal events is also observed in the majority of witnessed human SUDEP cases. Several pathophysiological mechanisms, including respiratory/cardiac dysfunction, have been proposed to contribute to human SUDEP. Several (but not all) selective serotonin (5-HT) reuptake inhibitors (SSRIs), including fluoxetine, can reversibly block S-IRA, and abnormal expression of 5-HT receptors is found in the brainstem of DBA mice. DBA mice, which do not initially show S-IRA, exhibit S-IRA after treatment with a non-selective 5-HT antagonist. These studies suggest that abnormalities of 5-HT neurotransmission are involved in the pathogenesis of S-IRA in DBA mice. 5-HT transmission plays an important role in normal respiration, and DBA mice exhibiting S-IRA can be resuscitated using a rodent ventilator. It is important and interesting to know if fluoxetine blocks S-IRA in DBA mice by enhancing respiratory ventilation. To test this, the effects of breathing stimulants, doxapram and 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (PK-THPP) were compared to fluoxetine on S-IRA in DBA/1 mice. Although fluoxetine reduces the incidence of S-IRA in DBA/1 mice, as reported previously, the same dose of fluoxetine fails to enhance baseline respiratory ventilation in the absence of AGS. Doxapram and PK-THPP augment the baseline ventilation in DBA/1 mice. However, these breathing stimulants are ineffective in preventing S-IRA in DBA/1 mice. These data suggest that fluoxetine blocks S-IRA in DBA/1 mice by cellular/molecular mechanisms other than enhancement of basal ventilation. Future research directions are also discussed.

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Section: Dba Mice As Relevant Sudep Modelsmentioning

confidence: 99%

Abnormalities of serotonergic neurotransmission in animal models of SUDEP

Feng

Faingold

2017

Epilepsy & Behavior

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“…SUDEP accounts for about 7.5-17 % of all deaths in epilepsy, increasing the rate of sudden death (SD) 24-fold when compared to the general population [2,3].…”

Section: Introductionmentioning

confidence: 99%

Genetic investigation of sudden unexpected death in epilepsy cohort by panel target resequencing

et al. 2015

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Sudden unexpected death in epilepsy (SUDEP) is defined as the abrupt, no traumatic, witnessed or unwitnessed death, occurring in benign circumstances, in an individual with epilepsy, with or without evidence for a seizure and excluding documented status epilepticus (seizure duration ≥ 30 min or seizures without recovery), and in which postmortem examination does not reveal a cause of death. Although the physiopathological mechanisms that underlie SUDEP remain to be clarified, the genetic background has been described to play a role in this disorder. Pathogenic variants in genes associated with epilepsy and encoding cardiac ion channels could explain the SUDEP phenotype. To test this we use the next-generation sequencing technology to sequence a cohort of SUDEP cases and its translation into clinical and forensic fields. A panel target resequencing was used to study 14 SUDEP cases from both postmortem (2 cases) and from living patients (12 cases). Genes already associated with SUDEP and also candidate genes had been investigated. Overall, 24 rare genetic variants were identified in 13 SUDEP cases. Four cases showed rare variants with complete segregation in the SCN1A, FBN1, HCN1, SCN4A, and EFHC1 genes, and one case with a rare variant in KCNQ1 gene showed incomplete pattern of inheritance. In four cases, rare variants were detected in CACNA1A, SCN11A and SCN10A, and KCNQ1 genes, but familial segregation was not possible due to lack of DNA from relatives. Finally, in the four remaining cases, the rare variants did not segregate in the family. This study confirms the link between epilepsy, sudden death, and cardiac disease. In addition, we identified new potential candidate genes for SUDEP: FBN1, HCN1, SCN4A, EFHC1, CACNA1A, SCN11A, and SCN10A. Further confirmation in larger cohorts will be necessary especially if genetic screening for SUDEP is applied to forensic and clinical medicine. Nevertheless, this study supports the emerging concept of a genetically determined cardiocerebral channelopathy.

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“…The specific mechanisms of SUDEP remain unclear, and a broad range of triggers or predisposing factors have been identified, including the presence of generalised tonic-clonic seizures, a early onset of the disease, abnormalities of the cardiovascular system, symptomatic epilepsies and nocturnal seizures. 3,4 In Scotland, Fatal Accident Inquiries (FAIs) into sudden epilepsy-related deaths of three young women resulted in a recommendation by the sheriff (Scottish equivalent of judge) that most people diagnosed with epilepsy should be informed of SUDEP at diagnosis, or in exceptional circumstances, very shortly thereafter. 5 The recommendation of disclosure at the time of diagnosis is also reflected in clinical guidelines 6,7 ; however, there has been significant disagreement among clinicians around informing patients and families about SUDEP, with many not routinely disclosing SUDEP information.…”

Section: Introductionmentioning

confidence: 99%