Sudden Unexpected Death in Epilepsy: Addressing the Challenges

Smithson, W. Henry; Colwell, Brigitte; Hanna, Jane

doi:10.1007/s11910-014-0502-4

Cited by 19 publications

(14 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Hippocampal malrotational abnormalities were noted in 9.7% of SUDEP cases; the degree of abnormality varied, with some apparent macroscopically and others only visible microscopically, with hyper‐convolutional folds of CA1/subiculum in the hippocampal body [23]. MRI studies have shown hippocampal malrotation in people with epilepsy [24], but a frequency of 19% has been reported in series of healthy volunteers [3]. The significance of hippocampal malrotation in epilepsy, or as a pathological risk factor for SUDEP, is therefore uncertain.…”

Section: Discussionmentioning

confidence: 99%

“…In 2002, the findings from a national UK audit highlighted sudden and unexpected deaths in epilepsy as ‘deaths in the shadows’, being systemically under‐recognized, under‐reported and poorly investigated by health professionals [1]. Sudden unexpected death in epilepsy (SUDEP) is now recognized as a leading cause of premature death in young adults with epilepsy with an estimated incidence of 1.16 cases per 1000 people with epilepsy per year [2] and is currently the focus of international initiatives aiming to address causes and identify preventative strategies [3]. In the UK, an estimated 500 annual epilepsy‐related deaths are considered to be SUDEP (Joint Epilepsy Council UK, 2011).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Audit of practice in sudden unexpected death in epilepsy (SUDEP) post mortems and neuropathological findings

Thom

Michalak

Wright³

et al. 2015

Neuropathology Appl Neurobio

View full text Add to dashboard Cite

AimsSudden unexpected death in epilepsy (SUDEP) is one of the leading causes of death in people with epilepsy. For classification of definite SUDEP, a post mortem (PM), including anatomical and toxicological examination, is mandatory to exclude other causes of death. We audited PM practice as well as the value of brain examination in SUDEP.MethodsWe reviewed 145 PM reports in SUDEP cases from four UK neuropathology centres. Data were extracted for clinical epilepsy details, circumstances of death and neuropathological findings.ResultsMacroscopic brain abnormalities were identified in 52% of cases. Mild brain swelling was present in 28%, and microscopic pathologies relevant to cause or effect of seizures were seen in 89%. Examination based on whole fixed brains (76.6% of all PMs), and systematic regional sampling was associated with higher detection rates of underlying pathology (P < 0.01). Information was more frequently recorded regarding circumstances of death and body position/location than clinical epilepsy history and investigations.ConclusionOur findings support the contribution of examination of the whole fixed brain in SUDEP, with high rates of detection of relevant pathology. Availability of full clinical epilepsy‐related information at the time of PM could potentially further improve detection through targeted tissue sampling. Apart from confirmation of SUDEP, complete neuropathological examination contributes to evaluation of risk factors as well as helping to direct future research into underlying causes.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Audit of practice in sudden unexpected death in epilepsy (SUDEP) post mortems and neuropathological findings

Thom

Michalak

Wright³

et al. 2015

Neuropathology Appl Neurobio

View full text Add to dashboard Cite

show abstract

“…2-5) suggested the presence of arrhythmogenic substrates in Scn8a N1768D/+ mice. Previous work indicated that changes in autonomic tone may precede SUDEP in patients (35)(36)(37) and mice (24). We simulated a catecholaminergic surge by i.p.…”

Section: Bradycardia In Scn8amentioning

confidence: 99%

Cardiac arrhythmia in a mouse model of sodium channel SCN8A epileptic encephalopathy

Frasier

Wagnon

Bao

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Patients with early infantile epileptic encephalopathy (EIEE) are at increased risk for sudden unexpected death in epilepsy (SUDEP). De novo mutations of the sodium channel gene SCN8A, encoding the sodium channel Na v 1.6, result in EIEE13 (OMIM 614558), which has a 10% risk of SUDEP. Here, we investigated the cardiac phenotype of a mouse model expressing the gain of function EIEE13 patient mutation p.Asn1768Asp in Scn8a (Na v 1.6-N1768D). We tested Scn8a N1768D/+ mice for alterations in cardiac excitability. We observed prolongation of the early stages of action potential (AP) repolarization in mutant myocytes vs. controls. Scn8a N1768D/+ myocytes were hyperexcitable, with a lowered threshold for AP firing, increased incidence of delayed afterdepolarizations, increased calcium transient duration, increased incidence of diastolic calcium release, and ectopic contractility. Calcium transient duration and diastolic calcium release in the mutant myocytes were tetrodotoxin-sensitive. A selective inhibitor of reverse mode Na/Ca exchange blocked the increased incidence of diastolic calcium release in mutant cells. Scn8a N1768D/+ mice exhibited bradycardia compared with controls. This difference in heart rate dissipated after administration of norepinephrine, and there were no differences in heart rate in denervated ex vivo hearts, implicating parasympathetic hyperexcitability in the Scn8a N1768D/+ animals. When challenged with norepinephrine and caffeine to simulate a catecholaminergic surge, Scn8a N1768D/+ mice showed ventricular arrhythmias. Two of three mutant mice under continuous ECG telemetry recording experienced death, with severe bradycardia preceding asystole. Thus, in addition to central neuron hyperexcitability, Scn8a N1768D/+ mice have cardiac myoycte and parasympathetic neuron hyperexcitability. Simultaneous dysfunction in these systems may contribute to SUDEP associated with mutations of Scn8a. sodium channel | epilepsy | arrhythmia | channelopathy | mutation

show abstract

“…Moreover, the seizures became more frequent and/or severe during the course of the experiment, ultimately resulting in a terminal seizure and death ( Fig.3a). Seizures have similarly been associated with death in humans, resulting in a condition denoted Sudden Unexpected Death During Epilepsy (SUDEP) (30,31). Importantly, we failed to detect seizures over the same time period in Xrcc1 Nes-Cre mice in which one or both Parp1 alleles were deleted ( Fig.3a).…”

Section: Parp1 Hyperactivation At Unrepaired Single-strand Breaks Trimentioning

confidence: 83%

“…These data are the first to demonstrate a molecular mechanism by which unrepaired DNA strand breaks trigger neurological seizures. Seizures are potentially lethal events, associated with a condition denoted Sudden Unexpected Death During Epilepsy (SUDEP) (30,31). Indeed, Xrcc1 Nes-Cre mice exhibit a dramatically shorted lifespan, which we have now established by video imaging is due to episodic epilepsy leading ultimately to a fatal seizure.…”

Section: Discussionmentioning

confidence: 99%

Aberrant PARP1 Activity Couples DNA Breaks to Deregulated Presynaptic Calcium Signalling and Lethal Seizures

Komulainen

et al. 2018

Preprint

View full text Add to dashboard Cite

Defects in DNA strand break repair can trigger seizures that are often intractable and life-threatening. However, the molecular mechanism/s by which unrepaired DNA breaks trigger seizures are unknown. Here, we show that hyperactivity of the DNA break sensor protein poly(ADP-ribose) polymerase-1 is widespread in DNA single-strand break repair defective XRCC1-mutant mouse brain, including the hippocampus and cortex. We demonstrate elevated seizure-like activity in XRCC1-mutant hippocampus in vitro and increased seizures in vivo, and weshow that Parp1 deletion reduces or prevents both. We also show that the increased seizures in Xrcc1 mutant mice result in juvenile mortality, and that Parp1 deletion extends the lifespan of these mice up to 25-fold. Parp1 hyperactivation is thus a major molecular mechanism by which unrepaired endogenous DNA strand breaks trigger disease pathology, including neurological seizures and death. These data implicate inhibitors of PARP activity as a possible therapeutic approach for the treatment of single-strand break induced neurodegenerative disease. DNA single-strand breaks (SSBs) are the commonest lesions arising in cells and can result directly from damage to deoxyribose, indirectly as an obligate intermediate of DNA base or ribonucleotide excision repair, and as abortive intermediates of topoisomerase activity. SSBs are rapidly detected by the enzymes poly(ADP-ribose)polymerase-1 (PARP1) and/or poly(ADP-ribose) polymerase-2 (PARP2); two enzymes that bind to DNA breaks and subsequently modify themselves and other proteins at the site of the break with polymeric chains of ADP-ribose (1-3). This polymer, denoted poly(ADP-ribose), triggers recruitment the DNA single-strand break repair (SSBR) scaffold protein XRCC1 and its protein partners which subsequently can process any damaged DNA termini at the break and complete SSBR (4-6).If not repaired rapidly, SSBs can result in replication fork stalling and/or collapse (7-10) and can block the progression of RNA polymerases during gene transcription (11,12). Moreover, mutations in proteins involved in SSBR are associated in humans with cerebella ataxia, neurodevelopmental defects, and episodic seizures (13)(14)(15)(16)(17)(18)(19). To date, all of the identified SSBR-defective human diseases are mutated in either

show abstract

Sudden Unexpected Death in Epilepsy: Addressing the Challenges

Cited by 19 publications

References 50 publications

Audit of practice in sudden unexpected death in epilepsy (SUDEP) post mortems and neuropathological findings

Audit of practice in sudden unexpected death in epilepsy (SUDEP) post mortems and neuropathological findings

Cardiac arrhythmia in a mouse model of sodium channel SCN8A epileptic encephalopathy

Aberrant PARP1 Activity Couples DNA Breaks to Deregulated Presynaptic Calcium Signalling and Lethal Seizures

Contact Info

Product

Resources

About