Time of Day and a Ketogenic Diet Influence Susceptibility to SUDEP in Scn1aR1407X/+ Mice

Teran, Frida A.; Kim, YuJaung; Crotts, Megan S.; Bravo, Eduardo; Emaus, Katlynn J.; Richerson, George B.

doi:10.3389/fneur.2019.00278

Cited by 35 publications

(43 citation statements)

References 41 publications

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“…Previous studies demonstrated that increased seizure burden during the worsening stage correlates with increased risk for SUDEP Teran et al, 2019). Here, we add that reduced PSD also correlates with increased risk for SUDEP ( Fig.…”

Section: Reduced Eeg Power At the Worsening Stage Of Dravetsupporting

confidence: 69%

“…1A), such longitudinal analysis inherently disregards these mice that die prematurely. Moreover, as frequent seizures have been shown to increase the risk of sudden unexpected death in epilepsy (SUDEP) Teran et al, 2019), this analysis also intrinsically selects mice with milder epilepsy or better compensatory mechanisms, which enable survival to the stabilization stage. A comparison of the PSD between mice that died prematurely and those that survived to the stabilization stage demonstrated decreased power in mice which eventually died during the worsening stage ( Fig.…”

Section: The Risk For Premature Death Correlates With Lower Psdmentioning

confidence: 99%

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Early EEG and behavioral alterations in Dravet mice

Fadila

Quinn

Maia

et al. 2020

Preprint

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Dravet Syndrome (Dravet) is a severe childhood epileptic encephalopathy. The disease begins around the age of six months, with a febrile stage, characterized by febrile seizures with otherwise normal development. By the end of the first year of life, the disease progresses to the worsening stage, featuring recurrent intractable seizures and the appearance of additional comorbidities, including global developmental delay, cognitive deficits, hyperactivity and motor problems. Later, in early school years, Dravet reaches the stabilization stage, in which seizure burden decreases, while Dravet-associated comorbidities persist. Dravet syndrome mouse models (DS) faithfully recapitulate the three stages of the human syndrome. Here, we performed power spectral analyses of background EEG activity in DS and their wild-type (WT) littermates, demonstrating disease stagerelated alterations. Specifically, while the febrile stage activity resembled that of WT mice, we observed a marked reduction in total power during the worsening stage and a smaller reduction during the stabilization stage. Moreover, low EEG power at the worsening stage correlated with increased risk for premature death, suggesting that such measurements can potentially be used as a marker for Dravet severity. With normal development at the febrile stage and the presentation of developmental delay at the worsening stage, the contribution of recurrent seizures to the emergence of Dravet-associated comorbidities is still debated.Thus, we further characterized the behavior of WT and DS mice during the different stages of Dravet. At the febrile stage, despite their normal background EEG patterns, DS mice already demonstrated motor impairment and hyperactivity in the open field, that persisted to the worsening and stabilization stages. Conversely, clear evidence for deficits in working memory emerged later in life, during the worsening stage. These results indicate that despite the mild epilepsy at the febrile stage, DS development is already altered, suggesting that the pathophysiological mechanisms governing the appearance of some Dravet behavioral comorbidities may be independent of the epileptic phenotype. Highlights • Reduction in background EEG power in Dravet• Low EEG power correlates with the risk of premature death• Motor deficits and hyperactivity are evident as early as the febrile stage • Cognitive deficits and detection of increased anxiety begin at the worsening stage 10 min, and were selected from throughout the entire recording. Spikes were detected using LabChart 8 software (ADInstruments, Sydney, Australia). The threshold was set to 7 standard divisions, and their maximal allowed duration was set to 250 ms. Early motor activityWT and DS mice were tested from P8 to P11. Mice were individually placed in the middle of a 13 cm wide circle and the latency to cross the drawn borders of the circle was measured. The test was repeated three times and averaged. If the mouse was unable to cross the border of the circle within 1 min, the test was terminated. ...

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Section: Reduced Eeg Power At the Worsening Stage Of Dravetsupporting

confidence: 69%

Section: The Risk For Premature Death Correlates With Lower Psdmentioning

confidence: 99%

Early EEG and behavioral alterations in Dravet mice

Fadila

Quinn

Maia

et al. 2020

Preprint

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“…Previous studies demonstrated that the occurrence of premature death during the severe stage of the epilepsy correlates with higher seizure burden. 22,25 Within this cohort of DS mice, 56% of the mice died during the 4th week of life. Thus, we wondered whether worse performance at the pre-epileptic stage would correlate with a higher risk for premature death.…”

Section: Dravetmentioning

confidence: 99%

Convulsive seizures and some behavioral comorbidities are uncoupled in the Scn1a^A1783V Dravet syndrome mouse model

et al. 2020

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Objective: Dravet syndrome (Dravet) is a severe childhood epileptic encephalopathy. The disease begins with a febrile stage, characterized by febrile seizures with otherwise normal development. Progression to the worsening stage features recurrent intractable seizures and the presentation of additional nonepileptic comorbidities, including global developmental delay, hyperactivity, and motor deficits. Later in life, at the stabilization stage, seizure burden decreases, whereas Dravet-associated comorbidities persist. To date, it remains debated whether the nonepileptic comorbidities result from severe epilepsy or represent an independent phenotypic feature. Methods: Dravet mice (DS) faithfully recapitulate many clinical aspects of Dravet. Using wild-type (WT) and DS at different ages, we monitored multiple behavioral features as well as background electroencephalogram (EEG) activity during the different stages of Dravet epilepsy. Results: Behavioral tests of WT and DS demonstrated that some deficits manifest already at the pre-epileptic stage, prior to the onset of convulsive seizures. These include motor impairment and hyperactivity in the open field. Deficits in cognitive functions were detected at the onset of severe spontaneous seizures. Power spectral analysis of background EEG activity, measured through development, showed that DS exhibit normal background oscillations at the pre-epileptic stage, a marked reduction in total power during the onset of severe epilepsy, and a subsequent smaller reduction later in life. Importantly, low EEG power at the stage of severe frequent convulsive seizures correlated with increased risk for premature death. Significance: Our data provide a comprehensive developmental trajectory of Dravet epilepsy and Dravet-associated comorbidities in mice, under controlled settings, demonstrating that the convulsive seizures and some nonepileptic comorbidities may be uncoupled. Moreover, we report the existence of an inverse correlation, on average, between the power of background EEG and the severity of epileptic phenotypes, suggesting that such measurements may potentially serve as a biomarker for Dravet severity. K E Y W O R D S background EEG, Dravet syndrome, hyperactivity, motor impairment, power spectral density 2290 | FADILA et AL. SUPPORTING INFORMATION Additional supporting information may be found online in the Supporting Information section. How to cite this article: Fadila S, Quinn S, Turchetti Maia A, et al. Convulsive seizures and some behavioral comorbidities are uncoupled in the Scn1a A1783V Dravet syndrome mouse model.

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“…79,80 The ketogenic diet, an alternative seizure treatment for refractory epilepsy, reduces the mortality in SCN1A R1407X/þ mice without modifying seizure frequency or light-dark predilection. 35 Moreover, the ketogenic diet reduces seizure number and extends longevity in KCNA1-null mice, in a gender-and age-dependent manner. [41][42][43] In addition, rest deficiency seen in KCNA1-null mice is reduced with ketogenic diet treatment.…”

Section: Arousal Sleep and Time Of Daymentioning

confidence: 99%

Scurrying to Understand Sudden Expected Death in Epilepsy: Insights From Animal Models

Buchanan

2019

Epilepsy Curr

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Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with refractory epilepsy, accounting for up to 17% of deaths in patients with epilepsy. The pathophysiology of SUDEP has remained unclear, largely because it is unpredictable and commonly unwitnessed. This poses a great challenge to studies in patients. Recently, there has been an increase in animal studies to try to better understand the pathophysiology of SUDEP. In this current review, we focus on developments through seizure-induced death models and the preventative strategies they may reveal.

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Time of Day and a Ketogenic Diet Influence Susceptibility to SUDEP in Scn1aR1407X/+ Mice

Cited by 35 publications

References 41 publications

Early EEG and behavioral alterations in Dravet mice

Early EEG and behavioral alterations in Dravet mice

Convulsive seizures and some behavioral comorbidities are uncoupled in the Scn1a^A1783V Dravet syndrome mouse model

Scurrying to Understand Sudden Expected Death in Epilepsy: Insights From Animal Models

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Time of Day and a Ketogenic Diet Influence Susceptibility to SUDEP in Scn1aR1407X/+ Mice

Cited by 35 publications

References 41 publications

Early EEG and behavioral alterations in Dravet mice

Early EEG and behavioral alterations in Dravet mice

Convulsive seizures and some behavioral comorbidities are uncoupled in the Scn1aA1783V Dravet syndrome mouse model

Scurrying to Understand Sudden Expected Death in Epilepsy: Insights From Animal Models

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Convulsive seizures and some behavioral comorbidities are uncoupled in the Scn1a^A1783V Dravet syndrome mouse model