A ketogenic diet protects DBA/1 and Scn1aR1407X/+ mice against seizure-induced respiratory arrest independent of ketosis.

Published on Nov 1, 2021in Epilepsy & Behavior2.937
· DOI :10.1016/J.YEBEH.2021.108334
Megan Crotts2
Estimated H-index: 2
(UI: University of Iowa),
YuJaung Kim2
Estimated H-index: 2
(UI: University of Iowa)
+ 2 AuthorsFrida A. Teran4
Estimated H-index: 4
(UI: University of Iowa)
Source
Abstract
Abstract null null Patients with uncontrolled epilepsy have a high risk of sudden unexpected death in epilepsy (SUDEP). Seizure-induced respiratory arrest (S-IRA) is thought to be the determining cause of death in many cases of SUDEP. The goal of the present study was to use Scn1aR1407X/+ (Dravet Syndrome, DS) and DBA/1 mice to determine: (1) the effect of a ketogenic diet (KD) on S-IRA and (2) the relationship between serum ketones and the protective effect of a KD. Ketogenic diet treatment significantly decreased spontaneous seizure-induced mortality in DS mice compared to control (8% vs 39%, p = 0.0021). This protective effect was not abolished when ketosis was prevented by supplementing the KD with glucose (10% mortality, p = 0.0007). In DBA/1 mice, the latency to onset of S-IRA due to audiogenic seizures was delayed from 7.6 to 20.8 seconds by a KD on treatment day (TD) 7 compared to control (p
References54
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#1Anthony Marincovich (UI: University of Iowa)H-Index: 2
#2Eduardo Bravo (UI: University of Iowa)H-Index: 8
Last. George B. Richerson (UI: University of Iowa)H-Index: 55
view all 4 authors...
Abstract Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death in patients with refractory epilepsy. Human studies and animal models suggest that respiratory arrest is the initiating event leading to death in many cases of SUDEP. It has previously been reported that the onset of apnea can coincide with the spread of seizures to the amygdala, and apnea can be reproduced by electrical stimulation of the amygdala. The aim of the current work was to determine if the amygdala ...
Source
Ketogenic diet (KD) has been used to treat epilepsy for 100 years. It is a high-fat, low-carbohydrate, and sufficient-protein-for-growth diet that mimics the metabolic changes occurring during starvation. Except for classic KD, its modified counterparts, including modified Atkins diet and low-glycemic-index treatment, have gained grounds to increase palatability and adherence. Strong evidence exists that the KD offers protection against seizures in difficult-to-treat epilepsy and possesses long-...
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#1Alexandra N. Petrucci (UI: University of Iowa)H-Index: 3
#2Katelyn G. Joyal (UI: University of Iowa)H-Index: 2
Last. Gordon F. Buchanan (UI: University of Iowa)H-Index: 23
view all 4 authors...
Abstract Epilepsy is a highly prevalent disease characterized by recurrent, spontaneous seizures. Approximately one-third of epilepsy patients will not achieve seizure freedom with medical management and become refractory to conventional treatments. These patients are at greatest risk for sudden unexpected death in epilepsy (SUDEP). The exact etiology of SUDEP is unknown, but a combination of respiratory, cardiac, neuronal electrographic dysfunction, and arousal impairment is thought to underlie...
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#1J. Helen Cross (NIHR: National Institute for Health Research)H-Index: 65
#2Roberto Caraballo (Garrahan Hospital)H-Index: 42
Last. Lieven Lagae (Katholieke Universiteit Leuven)H-Index: 77
view all 6 authors...
Over time, with careful delineation of Dravet syndrome, we have gained experience in treatments most likely to lead to improvement in seizures, as well as those that should be avoided. Sodium valproate, clobazam, stiripentol, and topiramate are all medications that may lead to benefit, as well as the ketogenic diet. Bromides may be utilized in resistant cases. However, equally important are outlining prompt rescue treatment for prolonged seizures and avoidance of precipitants. Newer agents inclu...
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#1Angela M. Poff (USF: University of South Florida)H-Index: 13
#2Jong M. Rho (UCSD: University of California, San Diego)H-Index: 54
Last. Dominic P. D’Agostino (USF: University of South Florida)H-Index: 25
view all 3 authors...
The ketogenic diet (KD) is a high-fat, low-carbohydrate treatment for medically intractable epilepsy. One of the hallmark features of the KD is the production of ketone bodies which have long been believed, but not yet proven, to exert direct anti-seizure effects. The prevailing view has been that ketosis is an epiphenomenon during KD treatment, mostly due to clinical observations that blood ketone levels do not correlate well with seizure control. Nevertheless, there is increasing experimental ...
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#1Frida A. Teran (UI: University of Iowa)H-Index: 4
#2YuJaung Kim (UI: University of Iowa)H-Index: 2
Last. George B. RichersonH-Index: 55
view all 6 authors...
Sudden unexpected death in epilepsy (SUDEP) is a major cause of mortality in patients with drug-resistant epilepsy. Most SUDEP cases occur in bed at night and are preceded by a generalized tonic-clonic seizure (GTCS) and. Dravet syndrome (DS) is a severe childhood-onset epilepsy commonly caused by mutations in the SCN1A gene. Affected individuals suffer from refractory seizures and an increased risk of SUDEP. Here, we demonstrate that mice with the Scn1aR1407X/+ loss-of-function mutation experie...
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#1Timothy A. Simeone (Creighton University)H-Index: 19
#2Kristina A. Simeone (Creighton University)H-Index: 15
Last. Jong M. Rho (U of C: University of Calgary)H-Index: 54
view all 4 authors...
Abstract Although the mechanisms underlying the anti-seizure effects of the high-fat ketogenic diet (KD) remain unclear, a long-standing question has been whether ketone bodies (i.e., β-hydroxybutyrate, acetoacetate and acetone), either alone or in combination, contribute mechanistically. The traditional belief has been that while ketone bodies reflect enhanced fatty acid oxidation and a general shift toward intermediary metabolism, they are not likely to be the key mediators of the KD's clinica...
Source
#1YuJaung KimH-Index: 2
#2Eduardo BravoH-Index: 8
Last. George B. Richerson (UI: University of Iowa)H-Index: 55
view all 10 authors...
: Dravet syndrome (DS) is a severe childhood-onset epilepsy commonly due to mutations of the sodium channel gene SCN1A. Patients with DS have a high risk of sudden unexplained death in epilepsy (SUDEP), widely believed to be due to cardiac mechanisms. Here we show that patients with DS commonly have peri-ictal respiratory dysfunction. One patient had severe and prolonged postictal hypoventilation during video EEG monitoring and died later of SUDEP. Mice with an Scn1aR1407X/+ loss-of-function mut...
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#1Kristina A. Simeone (Creighton University)H-Index: 15
#2Jodi Hallgren (Creighton University)H-Index: 2
Last. Timothy A. Simeone (Creighton University)H-Index: 19
view all 12 authors...
SummaryObjective Increased breathing rate, apnea, and respiratory failure are associated with sudden unexpected death in epilepsy (SUDEP). We recently demonstrated the progressive nature of epilepsy and mortality in Kcna1−/− mice, a model of temporal lobe epilepsy and SUDEP. Here we tested the hypothesis that respiratory dysfunction progresses with age in Kcna1−/− mice, thereby increasing risk of respiratory failure and sudden death (SD). Methods Respiratory parameters were determined in conscio...
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#1Zhibin Chen (University of Melbourne)H-Index: 15
#2Martin J. BrodieH-Index: 92
Last. Patrick KwanH-Index: 68
view all 4 authors...
Importance A study published in 2000 showed that more than one-third of adults with epilepsy have inadequate control of seizures with antiepileptic drugs (AEDs). This study evaluates overall treatment outcomes in light of the introduction of more than 1 dozen new AEDs in the past 2 decades. Objective To assess long-term treatment outcome in patients with newly diagnosed and treated epilepsy. Design, Setting, and Participants This longitudinal observational cohort study was conducted at the Epile...
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