Ketogenic diet treatment of children in the intensive care unit: Safety, tolerability, and effectiveness.

PURPOSE: The ketogenic diet (KD) is initiated emergently in the intensive care unit (ICU) for patients with super refractory status epilepticus (SRSE) and epileptic encephalopathies (EE). However, few data are available regarding safety, effectiveness, and long-term outcomes. METHODS: We performed a retrospective cohort study of consecutive patients with KD initiated in the ICU from 2010 to 2018 for SRSE and EE. We characterized time to ketosis, adverse effects, and seizure outcomes. Responders were defined as having ≥50 % reduction in seizure frequency compared to prior to KD initiation. RESULTS: We identified 29 patients. KD was initiated for SRSE in 12 patients, EE in 8 patients, and EE with SRSE in 9 patients. KD was initiated after a median of 9 days. Ketosis was achieved 2 days faster in fasted patients (p < 0.0001). All patients had at least 1 KD-related adverse effect, most often hypoglycemia, constipation, or acidosis. There was ≥50 % reduction in seizure frequency compared to prior to KD initiation by 1 week in 17/28 patients, seizure-freedom by 2 weeks in 7/28 patients, and weaned off anesthetics in 11/17 patients. All KD-responders at 1 month had continued response at 6 months. Mortality at 1 year was 24 %. There was no difference in KD response or mortality between KD indication groups. CONCLUSION: Emergent KD initiation in the ICU is feasible, safe, and often effective for SRSE and EE. Expected adverse effects were common but treatable. Morbidity and mortality in this group was high. A ≥ 50 % reduction in seizure is achieved in most responders by 1-2 weeks.

Comprehensive Migraine Initiative in the Pediatric Emergency Department Improves Treatment Outcomes.

OBJECTIVE: To compare pediatric migraine treatment efficacy in the emergency department before and after the implementation of a comprehensive migraine initiative, consisting of a standardized treatment protocol, provider educational series and standardized physician documentation template. BACKGROUND: Pediatric migraine is common, accounting for 1% of pediatric emergency department visits. Yet there is large variability in treatment practices, with few studies looking into measures of both clinical effectiveness and timeliness of treatment following implementation of standardized protocols. METHODS: A single-center retrospective chart review of pediatric patients presenting to the emergency department with migraine before and after implementation of an institutional headache initiative designed to more effectively and efficiently deliver care to pediatric migraine patients. RESULTS: The study yielded 110 patients each in the intervention and preintervention groups. There were no significant differences in patient characteristics with respect to age, gender, or initial pain score. Compared with the preintervention group, the intervention group demonstrated a significant reduction in headache pain score prior to discharge (decrease of 5.9 vs 4.8 in preintervention group, P value .006) with a greater percentage of patients achieving ≥50% reduction in pain (82% vs 67% in preintervention group, P value .039). Additionally, we found a significantly decreased time to treatment in the intervention group compared with the preintervention group (1.8 vs 2.1 hours, P value .046). CONCLUSION: Through the use of a standardized treatment protocol, improved provider education, and ease of documentation, this comprehensive migraine initiative improved efficacy and efficiency of migraine treatment in the pediatric emergency department.

The probability of seizures during continuous EEG monitoring in high-risk neonates.

OBJECTIVE: We evaluated the impact of monitoring indication, early electroencephalography (EEG), and clinical features on seizure risk in all neonates undergoing continuous EEG (cEEG) monitoring following a standardized monitoring protocol. METHODS: All cEEGs from unique neonates 34-48 weeks postmenstrual age monitored from 1/2011-10/2017 (n = 291) were included. We evaluated the impact of cEEG monitoring indication (acute neonatal encephalopathy [ANE], suspicious clinical events [SCEs], or other high-risk conditions [OHRs]), age, medication status, and early EEG abnormalities (including the presence of epileptiform discharges and abnormal background continuity, amplitude, asymmetry, asynchrony, excessive sharp transients, and burst suppression) on time to first seizure and overall seizure risk using Kaplan-Meier survival curves and multivariable Cox proportional hazards models. RESULTS: Seizures occurred in 28% of high-risk neonates. Discontinuation of monitoring after 24 hours of seizure-freedom would have missed 8.5% of neonates with seizures. Overall seizure risk was lower in neonates monitored for ANE compared to OHR (P = .004) and trended lower compared to SCE (P = .097). The time course of seizure presentation varied by group, where the probability of future seizure was less than 1% after 17 hours of seizure-free monitoring in the SCE group, but required 42 hours in the OHR group, and 73 hours in the ANE group. The presence of early epileptiform discharges increased seizure risk in each group (ANE: adjusted hazard ratio [aHR] 4.32, 95% confidence interval [CI] 1.23-15.13, P = .022; SCE: aHR 10.95, 95% CI 4.77-25.14, P < 1e-07; OHR: aHR 56.90, 95% CI 10.32-313.72, P < 1e-05). SIGNIFICANCE: Neonates who undergo cEEG are at high risk for seizures, and risk varies by monitoring indication and early EEG findings. Seizures are captured in nearly all neonates undergoing monitoring for SCE within 24 hours of cEEG monitoring. Neonates monitored for OHR and ANE can present with delayed seizures and require longer durations of monitoring. Early epileptiform discharges are the best early EEG feature to predict seizure risk.

Functional consequences of 17q21.31/WNT3-WNT9B amplification in hPSCs with respect to neural differentiation.

Human pluripotent stem cell (hPSC) lines exhibit repeated patterns of genetic variation, which can alter in vitro properties as well as suitability for clinical use. We examined associations between copy-number variations (CNVs) on chromosome 17 and hPSC mesodiencephalic dopaminergic (mDA) differentiation. Among 24 hPSC lines, two karyotypically normal lines, BG03 and CT3, and BG01V2, with trisomy 17, exhibited amplification of the WNT3/WNT9B region and rapid mDA differentiation. In hPSC lines with amplified WNT3/WNT9B, basic fibroblast growth factor (bFGF) signaling through mitogen-activated protein kinase (MAPK)/ERK amplifies canonical WNT signaling by phosphorylating LRP6, resulting in enhanced undifferentiated proliferation. When bFGF is absent, noncanonical WNT signaling becomes dominant due to upregulation of SIAH2, enhancing JNK signaling and promoting loss of pluripotency. When bFGF is present during mDA differentiation, stabilization of canonical WNT signaling causes upregulation of LMX1A and mDA induction. Therefore, CNVs in 17q21.31, a "hot spot" for genetic variation, have multiple and complex effects on hPSC cellular phenotype.

Is there an ideal way to discontinue the ketogenic diet?

It is unclear what the ideal weaning speed of the ketogenic diet should be and the resultant risk of seizure worsening. A retrospective chart review was performed of children who discontinued the ketogenic diet at Johns Hopkins Hospital from January 2000 to June 2010. Speed of discontinuation was categorized into immediate (<1 week), quick (1-6 weeks), or slow (>6 weeks) rates. One hundred and eighty-three children were identified. Children with both a longer diet duration (p=0.004) and lower seizure frequency (p<0.001) were weaned more slowly by our group. There was no significant difference in the incidence of seizures worsening between discontinuation rates. However, there was an increased risk of seizures worsening in those specifically with a 50-99% seizure reduction (30% vs. 8%, p<0.0001) and for that level of seizure improvement, in those who were receiving more anticonvulsants (1.4 vs. 0.8, p=0.01). In summary, there does not appear to be an increased risk of seizure exacerbation with rapid ketogenic diet discontinuations. Those who improved 50-99% and were receiving more anticonvulsants were at the highest risk overall. Discontinuing the ketogenic diet over weeks rather than months appears safe.

Cocaine causes deficits in radial migration and alters the distribution of glutamate and GABA neurons in the developing rat cerebral cortex.

Prenatal cocaine exposure induces cytoarchitectural changes in the embryonic neocortex; however, the biological mechanisms and type of cortical neurons involved in these changes are not known. Previously, we found that neural progenitor proliferation in the neocortical ventricular zone (VZ) is inhibited by cocaine; here, we examine the changes in cortical neurogenesis and migration of glutamate and GABA neurons induced by prenatal cocaine exposure. Pregnant rats received 20 mg/kg of cocaine intraperitoneally twice at an interval of 12 h during three periods of neocortical neurogenesis. Neocortical area and distribution of developing neurons were examined by counting Tuj1+, glutamate+, or GABA+ cells in different areas of the cerebral cortex. Cocaine decreased neocortical area by reducing the size of the Tuj1+ layer, but only when administered during early periods of neocortical neurogenesis. The number of glutamatergic neurons was increased in the VZ but was decreased in the outer cortical laminae. Although the number of GABA+ neurons in the VZ of both the neocortex and ganglionic eminences was unchanged, GABA+ cells decreased in all other neocortical laminae. Tangential migration of GABA+ cells was also disrupted by cocaine. These findings suggest that in utero cocaine exposure disturbs radial migration of neocortical neurons, possibly because of decreased radial glia guiding support through enhanced differentiation of neocortical VZ progenitors. Cocaine interrupts radial migration of both glutamatergic and GABAergic neurons within the neocortex, in addition to the tangential migration of GABAergic neurons from the subcortical telecephalon. This may result in abnormal neocortical cytoarchitecture and concomitant adverse functional effects.

The adenosine A2A antagonist MSX-3 reverses the effort-related effects of dopamine blockade: differential interaction with D1 and D2 family antagonists.

RATIONALE: Brain dopamine (DA) participates in the modulation of instrumental behavior, including aspects of behavioral activation and effort-related choice behavior. Rats with impaired DA transmission reallocate their behavior away from food-seeking behaviors that have high response requirements, and instead select less effortful alternatives. Although accumbens DA is considered a critical component of the brain circuitry regulating effort-related choice behavior, emerging evidence demonstrates a role for adenosine A(2A) receptors. OBJECTIVE: Adenosine A(2A) receptor antagonism has been shown to reverse the effects of DA antagonism. The present experiments were conducted to determine if this effect was dependent upon the subtype of DA receptor that was antagonized to produce the changes in effort-related choice. MATERIALS AND METHODS: The adenosine A(2A) receptor antagonist MSX-3 (0.5-2.0 mg/kg IP) was assessed for its ability to reverse the effects of the D1 family antagonist SCH39166 (ecopipam; 0.2 mg/kg IP) and the D2 family antagonist eticlopride (0.08 mg/kg IP), using a concurrent lever pressing/chow feeding procedure. RESULTS: MSX-3 produced a substantial dose-related reversal of the effects of eticlopride on lever pressing and chow intake. At the highest dose of MSX-3, there was a complete reversal of the effects of eticlopride on lever pressing. In contrast, MSX-3 produced only a minimal attenuation of the effects of SCH39166, as measured by regression and effect size analyses. CONCLUSIONS: The greater ability of MSX-3 to reverse the effects of D2 vs. D1 blockade may be related to the colocalization of D2 and adenosine A(2A) receptors on the same population of striatal neurons.

Nucleus accumbens adenosine A2A receptors regulate exertion of effort by acting on the ventral striatopallidal pathway.

Goal-directed actions are sensitive to work-related response costs, and dopamine in nucleus accumbens is thought to modulate the exertion of effort in motivated behavior. Dopamine-rich striatal areas such as nucleus accumbens also contain high numbers of adenosine A(2A) receptors, and, for that reason, the behavioral and neurochemical effects of the adenosine A(2A) receptor agonist CGS 21680 [2-p-(2-carboxyethyl) phenethylamino-5'-N-ethylcarboxamidoadenosine] were investigated. Stimulation of accumbens adenosine A(2A) receptors disrupted performance of an instrumental task with high work demands (i.e., an interval lever-pressing schedule with a ratio requirement attached) but had little effect on a task with a lower work requirement. Immunohistochemical studies revealed that accumbens neurons that project to the ventral pallidum showed adenosine A(2A) receptors immunoreactivity. Moreover, activation of accumbens A(2A) receptors by local injections of CGS 21680 increased extracellular GABA levels in the ventral pallidum. Combined contralateral injections of CGS 21680 into the accumbens and the GABA(A) agonist muscimol into ventral pallidum (i.e., "disconnection" methods) also impaired response output, indicating that these structures are part of a common neural circuitry regulating the exertion of effort. Thus, accumbens adenosine A(2A) receptors appear to regulate behavioral activation and effort-related processes by modulating the activity of the ventral striatopallidal pathway. Research on the effort-related functions of these forebrain systems may lead to a greater understanding of pathological features of motivation, such as psychomotor slowing, anergia, and fatigue in depression.