Pulmonary and cardiac pathology in sudden unexpected death in epilepsy (SUDEP)

Nascimento, Fábio A.; Tseng, Zian H.; Palmière, Cristian; Maleszewski, Joseph J.; Shiomi, Takayuki; McCrillis, Aileen; Devinsky, Orrin

doi:10.1016/j.yebeh.2017.05.013

Cited by 57 publications

(60 citation statements)

References 43 publications

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“…4,5 SUDEP ranks second only to stroke among neurologic diseases, in terms of potential years of life lost. 6,7 Because there are no known effective treatments, there is a pressing need to find drugs that could prevent SUDEP. 6,7 Because there are no known effective treatments, there is a pressing need to find drugs that could prevent SUDEP.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Introductionmentioning

confidence: 99%

“…5 The major pathophysiologic mechanisms that have been implicated in SUDEP include respiratory failure, cardiac arrhythmia and cerebral shutdown. 6,7 Because there are no known effective treatments, there is a pressing need to find drugs that could prevent SUDEP.…”

Section: Introductionmentioning

confidence: 99%

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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“…When this occurs in a person with epilepsy, distinguishing between an arrhythmogenic and an epileptogenic death is often impossible. Cardiomegaly, coronary artery disease, and cardiac fibrosis occur in SUDEP and other epilepsy deaths . The incidence and severity of cardiac, brain, and other systemic pathologies increases with age, increasing the frequency of Possible SUDEP classification in older individuals .…”

Section: Results and Recommendationsmentioning

confidence: 99%

“…However, if the decedent's airway is obstructed by water, whether the body is below water, and the death certificate indicates drowning, the best classification is Possible SUDEP. Pulmonary | 1223 congestion or edema and heavy lungs (>1000 g combined) are common in SUDEP cases without suspected drowning 8 and in drowning victims without epilepsy 7 ; thus, these findings cannot differentiate SUDEP with subsequent submersion from drowning for another reason. Nashef's third Possible SUDEP example, a patient with uncontrolled epilepsy found dead in daytime where autopsy revealed aspiration of gastric contents of unspecified amount.…”

Section: Definite Sudep Plus Comorbidity Versus Possible Sudepmentioning

confidence: 99%

“…Cardiomegaly, coronary artery disease, and cardiac fibrosis occur in SUDEP and other epilepsy deaths. 8 The incidence and severity of cardiac, brain, and other systemic pathologies increases with age, increasing the frequency of Possible SUDEP classification in older individuals. 5,6 An unresolved critical issue is distinguishing competing versus contributing COD based on degree of cardiac (and other) pathology.…”

Section: Definite Sudep Plus Comorbidity Versus Possible Sudepmentioning

confidence: 99%

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Resolving ambiguities in SUDEP classification

Devinsky¹,

Bundock

Hesdorffer

et al. 2018

Epilepsia

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Accurate and consistent classification of cause of death among individuals with epilepsy remains a dire public health concern. SUDEP is likely underestimated in national health statistics. Greater standardization of criteria among epilepsy researchers, medical examiners, and epidemiologists to determine cause and classify death will lead to more accurate tracking of SUDEP and other epilepsy-related mortalities.

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The brain–heart interaction in epilepsy: implications for diagnosis, therapy, and SUDEP prevention

Costagliola

Orsini

Coll

et al. 2021

Ann Clin Transl Neurol

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The influence of the central nervous system and autonomic system on cardiac activity is being intensively studied, as it contributes to the high rate of cardiologic comorbidities observed in people with epilepsy. Indeed, neuroanatomic connections between the brain and the heart provide links that allow cardiac arrhythmias to occur in response to brain activation, have been shown to produce arrhythmia both experimentally and clinically. Moreover, seizures may induce a variety of transient cardiac effects, which include changes in heart rate, heart rate variability, arrhythmias, asystole, and other ECG abnormalities, and can trigger the development of Takotsubo syndrome. People with epilepsy are at a higher risk of death than the general population, and sudden unexpected death in epilepsy (SUDEP) is the most important direct epilepsy-related cause of death. Although the cause of SUDEP is still unknown, cardiac abnormalities during and between seizures could play a significant role in its pathogenesis, as highlighted by studies on animal models of SUDEP and registration of SUDEP events. Recently, genetic mutations in genes co-expressed in the heart and brain, which may result in epilepsy and cardiac comorbidity/increased risk for SUDEP, have been described. Recognition and a better understanding of brainheart interactions, together with new advances in sequencing techniques, may provide new insights into future novel therapies and help in the prevention of cardiac dysfunction and sudden death in epileptic individuals.

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Pulmonary and cardiac pathology in sudden unexpected death in epilepsy (SUDEP)

Cited by 57 publications

References 43 publications

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

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

Resolving ambiguities in SUDEP classification

The brain–heart interaction in epilepsy: implications for diagnosis, therapy, and SUDEP prevention

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