Sudden unexpected death in epilepsy: The neuro-cardio-respiratory connection

Manolis, Theodora A.; Manolis, Antonis A.; Melita, Helen; Manolis, Antonis S

doi:10.1016/j.seizure.2018.12.007

Cited by 77 publications

(53 citation statements)

References 135 publications

(177 reference statements)

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“…Temporal lobe epilepsy features prominently in SUDEP series in adults 1,10 . The main risk factor is the number of generalized tonic‐clonic seizures; 11 arrhythmias during seizures also associate with risk of SUDEP 10,12 . The pathophysiological changes underlying this effect remain unresolved, yet an understanding is fundamental to the development of therapeutic interventions to minimize the risk of SUDEP.…”

Section: Introductionmentioning

confidence: 99%

Cardiac effects of repeated focal seizures in rats induced by intrahippocampal tetanus toxin: Bradyarrhythmias, tachycardias, and prolonged interictal QT interval

2020

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Objective: To determine electrical changes in the heart in a chronic, nonstatus model of epilepsy. Methods: Electrocorticography (ECoG) and electrocardiography (ECG) of nine animals (five made epileptic by intrahippocampal injection of tetanus neurotoxin (TeNT) and four controls), are monitored continuously by radiotelemetry for up to 7 weeks. Results: Epileptic animals develop a median of 168 seizures, with postictal tachycardias reaching a mean of 487 beats/min and lasting a mean of 661 seconds. Ictal changes in heart rate include tachycardia and in the case of convulsive seizures, bradyarrhythmias resembling Mobitz type 1 second-degree atrioventricular block; notably the P-R interval increased before block. Postictally, the amplitude of T wave increases. Interictally, QT dependence on RR is modest and conventional QT corrections prove ineffective. Interictal QT intervals, measured at a heart rate of 400 bpm, increased from 65 to 75 ms, an increase dependent on seizure incidence over the preceding 10-14 days. Significance: Repeated seizures induce a sustained tachycardia and increase in QT interval of the ECG and evoke arrhythmias including periods of atrioventricular block during Racine type 4 and 5 seizures. These changes in cardiac function may predispose to development in fatal arrhythmias and sudden death in humans with epilepsy. K E Y W O R D S cardiac dysfunction, epilepsy, QT correction, QT prolongation | 799 JEFFERYS Et al. |

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Section: Introductionmentioning

confidence: 99%

Cardiac effects of repeated focal seizures in rats induced by intrahippocampal tetanus toxin: Bradyarrhythmias, tachycardias, and prolonged interictal QT interval

2020

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“…With Vglut2:Ndufs4cKO mice, the lethality was associated with severe motor and respiratory alterations, whereas with Gad2:Ndufs4cKO mice, sudden unexpected death was associated with epilepsy (SUDEP) [32][33][34] with no overt clinical alteration beyond the weight loss.…”

Section: Discussionmentioning

confidence: 99%

Defined neuronal populations drive fatal phenotype in Leigh Syndrome

Bolea

Gella

Sanz

et al. 2019

Preprint

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Dysfunctions of the mitochondrial energy-generating machinery cause a series of progressive, untreatable and usually fatal diseases collectively known as mitochondrial disease. High energyrequiring organs such as the brain are especially affected, leading to developmental delay, ataxia, respiratory failure, hypotonia, seizures and premature death. While neural affectation is a critical component of the pathology, only discrete neuronal populations are susceptible. However, their molecular identity and their contribution to the disease remain unknown. Mice lacking the mitochondrial Complex I subunit NDUFS4 (Ndufs4KO mice) recapitulate the classical signs of Leigh Syndrome (LS), the most common presentation of mitochondrial disease with predominant CNS affectation. Here, we identify the critical role of two genetically-defined neuronal populations driving the fatal phenotype in Ndufs4KO mice. Selective inactivation of Ndufs4 in Vglut2expressing glutamatergic neurons causes brainstem inflammation, motor and respiratory deficits, and early death. On the other hand, Ndufs4 deletion in GABAergic neurons leads to basal ganglia inflammation without motor or respiratory involvement, but accompanied by severe refractory epileptic seizures preceding premature death. These results provide novel insight in the cell typespecific contribution to LS pathology and open new avenues to understand the underlying cellular mechanisms of mitochondrial disease.

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“…SUDEP is defined as a sudden, unexpected, witnessed or unwitnessed, non-traumatic and non-drowning death in patients with epilepsy, with or without evidence of a seizure excluding documented status epilepticus, in which postmor-tem examination does not reveal a toxicological or anatomical cause of death [11]. SUDEP incidence is estimated to be from 0.3 to 6 persons per 1000 adult person-years [2]; however, SUDEP may be under-diagnosed due to the fact that the 10 th revision of International Classification of Disease does not include term SUDEP as a cause of death [1,10].…”

Section: Epilepsy and Sudepmentioning

confidence: 99%

“…The etiology of SUDEP remains unclear. Effective seizure control was shown to be a preventive strategy for premature death in epilepsy [2], however, approximately 30% of patients do not respond to treatment with common anticonvulsants [3].…”

Section: Introductionmentioning

confidence: 99%

Epilepsy and hypertension: The possible link for sudden unexpected death in epilepsy?

et al. 2021

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Epilepsy affects about 50 million people worldwide. Sudden unexpected death in epilepsy (SUDEP) is the main cause of death in epilepsy accounting for up to 17% of all deaths in epileptic patients, and therefore remains a major public health problem. SUDEP likely arises from a combination and interaction of multiple risk factors (such as being male, drug resistance, frequent generalized tonic-clonic seizures) making risk prediction and mitigation challenging. While there is a general understanding of the physiopathology of SUDEP, mechanistic hypotheses linking risk factors with a risk of SUDEP are still lacking. Identifying cross-talk between biological systems implicated in SUDEP may facilitate the development of improved models for SUDEP risk assessment, treatment and clinical management. In this review, the aim was to explore an overlap between the pathophysiology of hypertension, cardiovascular disease and epilepsy, and discuss its implication for SUDEP. Presented herein, evidence in literature in support of a cross-talk between the renin-angiotensin system (RAS) and sympathetic nervous system, both known to be involved in the development of hypertension and cardiovascular disease, and as one of the underlying mechanisms of SUDEP. This article also provides a brief description of local RAS in brain neuroinflammation and the role of centrally acting RAS inhibitors in epileptic seizure alleviation.

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Sudden unexpected death in epilepsy: The neuro-cardio-respiratory connection

Cited by 77 publications

References 135 publications

Cardiac effects of repeated focal seizures in rats induced by intrahippocampal tetanus toxin: Bradyarrhythmias, tachycardias, and prolonged interictal QT interval

Cardiac effects of repeated focal seizures in rats induced by intrahippocampal tetanus toxin: Bradyarrhythmias, tachycardias, and prolonged interictal QT interval

Defined neuronal populations drive fatal phenotype in Leigh Syndrome

Epilepsy and hypertension: The possible link for sudden unexpected death in epilepsy?

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