Yi-Chen Lai

Early cardiac electrographic and molecular remodeling in a model of status epilepticus and acquired epilepsy

A myriad of acute and chronic cardiac alterations are associated with status epilepticus (SE) including increased sympathetic tone, rhythm and ventricular repolarization disturbances. Despite these observations, the molecular processes underlying SE‐associated myocardial remodeling remain to be identified. Here we determined early SE‐associated myocardial electrical and molecular alterations using a model of SE and acquired epilepsy.

Efficacy and safety of ketogenic diet for treatment of pediatric convulsive refractory status epilepticus

PURPOSE To describe the efficacy and safety of ketogenic diet (KD) for convulsive refractory status epilepticus (RSE). METHODS RSE patients treated with KD at the 6/11 participating institutions of the pediatric Status Epilepticus Research Group from January-2011 to December-2016 were included. Patients receiving KD prior to the index RSE episode were excluded. RSE was defined as failure of ≥2 anti-seizure medications, including at least one non-benzodiazepine drug. Ketosis was defined as serum beta-hydroxybutyrate levels >20 mg/dl (1.9 mmol/l). Outcomes included proportion of patients with electrographic (EEG) seizure resolution within 7 days of starting KD, defined as absence of seizures and ≥50% suppression below 10 μV on longitudinal bipolar montage (suppression-burst ratio ≥50%); time to start KD after onset of RSE; time to achieve ketosis after starting KD; and the proportion of patients weaned off continuous infusions 2 weeks after KD initiation. Treatment-emergent adverse effects (TEAEs) were also recorded. RESULTS Fourteen patients received KD for treatment of RSE (median age 4.7 years, interquartile range [IQR] 5.6). KD was started via enteral route in 11/14 (78.6%) patients. KD was initiated a median of 13 days (IQR 12.5) after the onset of RSE, at 4:1 ratio in 8/14 (57.1%) patients. Ketosis was achieved within a median of 2 days (IQR 2.0) after starting KD. EEG seizure resolution was achieved within 7 days of starting KD in 10/14 (71.4%) patients. Also, 11/14 (78.6%) patients were weaned off their continuous infusions within 2 weeks of starting KD. TEAEs, potentially attributable to KD, occurred in 3/14 (21.4%) patients, including gastro-intestinal paresis and hypertriglyceridemia. Three month outcomes were available for 12/14 (85.7%) patients, with 4 patients being seizure-free, and 3 others with decreased seizure frequency compared to pre-RSE baseline. CONCLUSIONS This series suggests efficacy and safety of KD for treatment of pediatric RSE.

Mitochondrial Dysfunction Mediated by Poly(ADP-Ribose) Polymerase-1 Activation Contributes to Hippocampal Neuronal Damage Following Status Epilepticus

Mitochondrial dysfunction plays a central role in the neuropathology associated with status epilepticus (SE) and is implicated in the development of epilepsy. While excitotoxic mechanisms are well-known mediators affecting mitochondrial health following SE, whether hyperactivation of poly(ADP-ribose) polymerase-1 (PARP-1) also contributes to SE-induced mitochondrial dysfunction remains to be examined. Here we first evaluated the temporal evolution of poly-ADP-ribosylated protein levels in hippocampus following kainic acid-induced SE as a marker for PARP-1 activity, and found that PARP-1 was hyperactive at 24 h following SE. We evaluated oxidative metabolism and found decreased NAD+ levels by enzymatic cycling, and impaired NAD+-dependent mitochondrial respiration as measured by polarography at 24 h following SE. Stereological estimation showed significant cell loss in the hippocampal CA1 and CA3 subregions 72 h following SE. PARP-1 inhibition using N-(6-Oxo-5,6-dihydro-phenanthridin-2-yl)- N,N-dimethylacetamide (PJ-34) in vivo administration was associated with preserved NAD+ levels and NAD+-dependent mitochondrial respiration, and improved CA1 neuronal survival. These findings suggest that PARP-1 hyperactivation contributes to SE-associated mitochondrial dysfunction and CA1 hippocampal damage. The deleterious effects of PARP-1 hyperactivation on mitochondrial respiration are in part mediated through intracellular NAD+ depletion. Therefore, modulating PARP-1 activity may represent a potential therapeutic target to preserve intracellular energetics and mitochondrial function following SE.

Factors associated with treatment delays in pediatric refractory convulsive status epilepticus

Objective To identify factors associated with treatment delays in pediatric patients with convulsive refractory status epilepticus (rSE). Methods This prospective, observational study was performed from June 2011 to March 2017 on pediatric patients (1 month to 21 years of age) with rSE. We evaluated potential factors associated with increased treatment delays in a Cox proportional hazards model. Results We studied 219 patients (53% males) with a median (25th–75th percentiles [p25–p75]) age of 3.9 (1.2–9.5) years in whom rSE started out of hospital (141 [64.4%]) or in hospital (78 [35.6%]). The median (p25–p75) time from seizure onset to treatment was 16 (5–45) minutes to first benzodiazepine (BZD), 63 (33–146) minutes to first non-BZD antiepileptic drug (AED), and 170 (107–539) minutes to first continuous infusion. Factors associated with more delays to administration of the first BZD were intermittent rSE (hazard ratio [HR] 1.54, 95% confidence interval [CI] 1.14–2.09; p = 0.0467) and out-of-hospital rSE onset (HR 1.5, 95% CI 1.11–2.04; p = 0.0467). Factors associated with more delays to administration of the first non-BZD AED were intermittent rSE (HR 1.78, 95% CI 1.32–2.4; p = 0.001) and out-of-hospital rSE onset (HR 2.25, 95% CI 1.67–3.02; p < 0.0001). None of the studied factors were associated with a delayed administration of continuous infusion. Conclusion Intermittent rSE and out-of-hospital rSE onset are independently associated with longer delays to administration of the first BZD and the first non-BZD AED in pediatric rSE. These factors identify potential targets for intervention to reduce time to treatment.

Epilepsy is associated with ventricular alterations following convulsive status epilepticus in children

Convulsive status epilepticus can exert profound cardiovascular effects in adults, including ventricular depolarization–repolarization abnormalities. Whether status epilepticus adversely affects ventricular electrical properties in children is less understood. Therefore, we sought to characterize ventricular alterations and the associated clinical factors in children following convulsive status epilepticus.

Changes in synaptic AMPA receptor concentration and composition in chronic temporal lobe epilepsy

&NA; Excitotoxicity caused by excessive stimulation of glutamate receptors, resulting in pathologically increased Ca2+‐concentrations, is a decisive factor in neurodegenerative diseases. We investigated long‐term changes in synaptic contents of AMPA receptor subunits that play important roles in calcium regulation in chronic epilepsy. Such plastic changes may be either adaptive or detrimental. We used a kainic acid (KA)‐based rat model of chronic temporal lobe epilepsy (TLE). Using hippocampal synaptosomes, we found significant reductions in the concentration of the AMPA receptor subunits GluA1 and GluA2, and the NMDA receptor subunit NR2B. The relative size of GluA1 and GluA2 reductions were almost identical, at 28% and 27%, respectively. In order to determine whether the synaptic reduction of the AMPA receptor subunits actually reflected the pool of receptors present along the postsynaptic density (PSD), as opposed to cytoplasmic or extrasynaptic pools, we performed postembedding immunogold electron microscopy (EM) of GluA1 and GluA2 in Schaffer collateral synapses in the hippocampal CA1 area. We found significant reductions, at 32% and 52% of GluA1 and GluA2 subunits, respectively, along the PSD, indicating that these synapses undergo lasting changes in glutamatergic neurotransmission during chronic TLE. When compared to the overall concentration and composition of AMPA receptors expressed in the brain, there was a relative increase in GluA2‐lacking AMPA receptor subunits following chronic epilepsy. These changes in synaptic AMPA receptor subunits may possibly contribute to further aggravate the excitotoxic vulnerability of the neurons as well as have significant implications for hippocampal cognitive functions. HighlightsRat model of chronic TLE shows reduction of AMPA receptors in hippocampal synapses.At the PSD, GluA1 and GluA2 were reduced by 32% and 52%, respectively.Overall, GluA2‐lacking AMPA receptor concentration is increased in chronic TLE.The mean length of the PSD is reduced in chronic temporal lobe epilepsy.

Myocardial remodeling and susceptibility to ventricular tachycardia in a model of chronic epilepsy

Sympathetic predominance and ventricular repolarization abnormalities represent epilepsy‐associated cardiac alterations and may underlie seizure‐induced ventricular arrhythmias. Myocardial ion channel and electrical remodeling have been described early in epilepsy development and may contribute to ventricular repolarization abnormalities and excitability. Using the pilocarpine‐induced acquired epilepsy model we sought to examine whether altered myocardial ion channel levels and electrophysiological changes also occur in animals with long‐standing epilepsy.

Platform Session – Electroencephalography/Epilepsy: Clinical characteristics and outcomes of pediatric super refractory status epilepticus

Introduction There is limited literature on pediatric super refractory status epilepticus (SRSE). We aimed to identify clinical variables associated with the occurrence of SRSE and to describe variability in SRSE treatment in a cohort of children admitted to pediatric intensive care units (ICU) with refractory status epilepticus (RSE). Methods This prospective, observational study was performed at 14 US hospitals. Inclusion criteria: (1) hospital admission between June 2011 and September 2017, (2) convulsive RSE defined as focal or generalized convulsive seizures at onset that continued after administration of at least 2 anti-seizure drugs (ASDs), including one non-benzodiazepine ASD or use of continuous infusion (CI) and (3) age 1 month to 21 years. We divided the cohort into SRSE and non-SRSE groups. SRSE was defined as continuous or intermittent seizures lasting ⩾ 24 h following initiation of CI. We used Fisher’s exact test and Wilcoxon rank sum test in the univariate analysis. Results The initial cohort included 264 patients with a median (p25–p75) age of 4 (1.23–9.50) years. Thirty-five patients (19 males) were identified as SRSE cases, with a median age of 4.5 (1.91–8.45) years. Univariate analysis did not show significant differences between the groups for: sex, age, etiology, prior SE, diagnosis of epilepsy, in-hospital seizure onset, generalized tonic-clonic seizures or continuous SE. SRSE patients had delayed first line treatment initiation (71(15–135.5) vs. 16(5–40.5) min; p = 0.017), longer ICU stay (17(9–42) vs. 3(1.86–8.66) days; p  Conclusion SRSE patients had delayed first-line treatment administration in comparison to non-SRSE patients. Once SRSE was established, children had significantly higher morbidity and mortality. Treatment approaches were heterogeneous, probably reflecting limited evidence to guide clinical decision-making in SRSE. (Funded by the Pediatric Epilepsy Research Foundation and Epilepsy Research Fund ).

The calcium sensor synaptotagmin 1 is expressed and regulated in hippocampal postsynaptic spines

Synaptotagmin 1 is a presynaptic calcium sensor, regulating SNARE‐mediated vesicle exocytosis of transmitter. Increasing evidence indicate roles of SNARE proteins in postsynaptic glutamate receptor trafficking. However, a possible postsynaptic expression of synaptotagmin 1 has not been demonstrated previously. Here, we used postembedding immunogold electron microscopy to determine the subsynaptic localization of synaptotagmin 1 in rat hippocampal CA1 Schaffer collateral synapses. We report for the first time that synaptotagmin 1 is present in rat hippocampal postsynaptic spines, both on cytoplasmic vesicles and at the postsynaptic density. We further investigated whether postsynaptic synaptotagmin 1 is regulated during synaptic plasticity. In a rat model of chronic temporal lobe epilepsy, we found that presynaptic and postsynaptic concentrations of the protein are reduced compared to control animals. This downregulation may possibly be an adaptive measure to decrease both presynaptic and postsynaptic calcium sensitivity in excitotoxic conditions.

501: QT INTERVAL ADAPTATION TO HEART RATE IS IMPAIRED IN PEDIATRIC EPILEPSY FOLLOWING STATUS EPILEPTICUS

Crit Care Med 2015 • Volume 43 • Number 12 (Suppl.) of Transcranial Color-Coded Doppler ultrasonography (TCCD) has showed increased in blood flow velocities in the basal cerebral arteries. It is unclear whether this indicates cerebral hyperperfusion, vasospasm or both. Methods: A prospectively observational study was conducted between October 2014 and May 2015. We evaluated women admitted to our intensive-care unit with eclampsia diagnosis. Daily TCCD was performed, the evaluation consist in assessing the mean flow velocity (MFV) of the right middle cerebral artery (RMCA), left middle cerebral artery (LMCA), extracraneal internal carotid artery to calculate the Lindegaard Ratio (LR). All patients underwent Magnetic Resonance Imaging (RMI). Results: The diagnosis occurred in 8 patients. The mean age was 25 + 10.4 yr, with body mass index 28.2 + 4.9 kg/m2. The patients showed moderately elevated mean arterial pressure (MAP) during admission (105 +10 mmHg) and (104 + 18 at 24 hr and 107 +13 mmHg at 48 hr). Also, MFV at admission RMCA 81.6 + 34.1 cm/s with LR 3.3, LMCA 80.8 + 27.4 cm/s with LR 3.4. At 24 hr RMCA 96,9 + 33.2 cm/s with LR 2.8, LMCA 108.6 + 54.9 with LR 2.9 and at 48 hr RMCA 113 + 25 with LR 3.4 LMCA 105 + 24.8 cm/s with LR 2.2. None of the results were statically significant in interhemispheric difference at admission (p= 0.22), 24hr (p=0.2) and 48hr (p= 0.21). Although a trend to increase MFV after 48hr of index event, none were statically significant (RCMA p= 0.2, LMCA p= 0.22). Neuroimaging showed characteristic changes of PRES in all patients. Conclusions: The data indicate that cerebral hemodynamics are impaired in eclampsia patients with a trend to increase after 48 hr of the index event. The finding of PRES in all patients confirms that it could be a core component of eclamptic patients.