Neuromonitoring of Pediatric and Adult Extracorporeal Membrane Oxygenation Patients: The Importance of Continuous Bedside Tools in Driving Neuroprotective Clinical Care.

Extracorporeal membrane oxygenation (ECMO) is a form of temporary cardiopulmonary bypass for patients with acute respiratory or cardiac failure refractory to conventional therapy. Its usage has become increasingly widespread and while reported survival after ECMO has increased in the past 25 years, the incidence of neurological injury has not declined, leading to the pressing question of how to improve time-to-detection and diagnosis of neurological injury. The neurological status of patients on ECMO is clinically difficult to evaluate due to multiple factors including illness, sedation, and pharmacological paralysis. Thus, increasing attention has been focused on developing tools and techniques to measure and monitor the brain of ECMO patients to identify dynamic risk factors and monitor patients' neurophysiological state as a function in time. Such tools may guide neuroprotective interventions and thus prevent or mitigate brain injury. Current means to continuously monitor and prevent neurological injury in ECMO patients are rather limited; most techniques provide indirect or postinsult recognition of irreversible brain injury. This review will explore the indications, advantages, and disadvantages of standard-of-care, emerging, and investigational technologies for neurological monitoring on ECMO, focusing on bedside techniques that provide continuous assessment of neurological health.

Combination of triheptanoin with the ketogenic diet in Glucose transporter type 1 deficiency (G1D).

Fuel influx and metabolism replenish carbon lost during normal neural activity. Ketogenic diets studied in epilepsy, dementia and other disorders do not sustain such replenishment because their ketone body derivatives contain four carbon atoms and are thus devoid of this anaplerotic or net carbon donor capacity. Yet, in these diseases carbon depletion is often inferred from cerebral fluorodeoxyglucose-positron emission tomography. Further, ketogenic diets may prove incompletely therapeutic. These deficiencies provide the motivation for complementation with anaplerotic fuel. However, there are few anaplerotic precursors consumable in clinically sufficient quantities besides those that supply glucose. Five-carbon ketones, stemming from metabolism of the food supplement triheptanoin, are anaplerotic. Triheptanoin can favorably affect Glucose transporter type 1 deficiency (G1D), a carbon-deficiency encephalopathy. However, the triheptanoin constituent heptanoate can compete with ketogenic diet-derived octanoate for metabolism in animals. It can also fuel neoglucogenesis, thus preempting ketosis. These uncertainties can be further accentuated by individual variability in ketogenesis. Therefore, human investigation is essential. Consequently, we examined the compatibility of triheptanoin at maximum tolerable dose with the ketogenic diet in 10 G1D individuals using clinical and electroencephalographic analyses, glycemia, and four- and five-carbon ketosis. 4 of 8 of subjects with pre-triheptanoin beta-hydroxybutyrate levels greater than 2 mM demonstrated a significant reduction in ketosis after triheptanoin. Changes in this and the other measures allowed us to deem the two treatments compatible in the same number of individuals, or 50% of persons in significant beta-hydroxybutyrate ketosis. These results inform the development of individualized anaplerotic modifications to the ketogenic diet.ClinicalTrials.gov registration NCT03301532, first registration: 04/10/2017.

Electroencephalographic (EEG) Biomarkers in Genetic Neurodevelopmental Disorders.

Collectively, neurodevelopmental disorders are highly prevalent, but more than a third of neurodevelopmental disorders have an identifiable genetic etiology, each of which is individually rare. The genes associated with neurodevelopmental disorders are often involved in early brain development, neuronal signaling, or synaptic plasticity. Novel treatments for many genetic neurodevelopmental disorders are being developed, but disease-relevant clinical outcome assessments and biomarkers are limited. Electroencephalography (EEG) is a promising noninvasive potential biomarker of brain function. It has been used extensively in epileptic disorders, but its application in neurodevelopmental disorders needs further investigation. In this review, we explore the use of EEG in 3 of the most prevalent genetic neurodevelopmental disorders-Angelman syndrome, Rett syndrome, and fragile X syndrome. Quantitative analyses of EEGs, such as power spectral analysis or measures of connectivity, can quantify EEG signatures seen on qualitative review and potentially correlate with phenotypes. In both Angelman syndrome and Rett syndrome, increased delta power on spectral analysis has correlated with clinical markers of disease severity including developmental disability and seizure burden, whereas spectral power analysis on EEG in fragile X syndrome tends to demonstrate abnormalities in gamma power. Further studies are needed to establish reliable relationships between quantitative EEG biomarkers and clinical phenotypes in rare genetic neurodevelopmental disorders.

EEG and clinical characteristics of neonatal parechovirus encephalitis.

RATIONALE: Human parechoviruses (HPeVs) are single -stranded ribonucleic (RNA) viruses belonging to the picornaviridae family with characteristics similar to enteroviruses. They either cause mild respiratory and gastrointestinal or no symptoms in older children and adults but can be a major cause of central nervous system (CNS) infection in the neonatal period and demonstrate a seasonal predilection. Starting in March 2022, we saw eight patients with polymerase chain reaction (PCR) proven HPeV encephalitis with seizures and some electroencephalographic (EEG) features raising concerns for neonatal genetic epilepsy. Although cerebrospinal fluid (CSF) and imaging findings have been previously described, there is little emphasis on seizure presentation and EEG findings of HPeV in the literature. We wish to highlight the EEG and seizure semiology of HPeV encephalitis that may mimic a genetic neonatal epilepsy syndrome. METHODS: Retrospective chart review of all neonates seen at Children's Health Dallas, UTSW Medical Center between 03/18/2022-06/01/2022 with HPeV encephalitis. RESULTS: Term neonates (postmenstrual age 37-40 weeks) presented with a variable combination of fever, lethargy, irritability, poor oral intake, erythematous rash, and focal seizures. One patient with a single episode of limpness and pallor did not undergo EEG due to a low suspicion for seizures. CSF indices were normal in all patients. EEG was abnormal in all patients where performed (n = 7). EEG features included dysmaturity (7/7, 100 %); excessive discontinuity (6/7, 86 %); excessive asynchrony (6/7, 86 %); multifocal sharp transients (7/7, 100 %). Focal/multifocal seizures were captured in 6/7 (86 %); tonic in 3/7 (42 %) and described as migrating in 2 patients. Subclinical seizures were noted in 6/7 (86 %) with status epilepticus in 5/7 (71 %) patients. In 2/7 (28 %) the EEG showed a burst suppression pattern with poor state variation and voltages of < 5-10 uV/mm during the inter-burst intervals. Repeat EEG (3-11 days post initial EEG) showed improvement in 3 of 4 patients. No patient had ongoing seizures beyond day two of admission (22.5 h after EEG initiation). MRI showed extensive restricted diffusion in the supratentorial white matter, thalami, and less frequently the cortex, mimicking imaging findings of a metabolic or hypoxic-ischemic encephalopathy (7/8). Seizures responded within 36 h of presentation to treatment with acute bolus doses of medications. One patient died due to diffuse cerebral edema and status epilepticus. Six patients had a normal clinical exam at discharge. All patients started on maintenance antiseizure medication (ASM) were sent home on either a single medication or two medications (phenobarbital and levetiracetam) with plans to wean phenobarbital after discharge. CONCLUSIONS: HPeV is a rare cause of seizures and encephalopathy in neonates. Prior studies have emphasized specific patterns of white matter injury on imaging. We demonstrate that HPeV also commonly presents with clonic or tonic seizures with or without apnea and often subclinical multifocal and migrating focal seizures that could mimic a genetic neonatal epilepsy syndrome. Interictal EEG shows a dysmature background with excessive asynchrony, discontinuity, burst-suppression pattern, and multifocal sharp transients. However, we note that 100 % of patients responded quickly to standard ASM, and did not have seizures after hospital discharge- a factor that can help distinguish it from a genetic epilepsy syndrome.

Metabolic modulation of synaptic failure and thalamocortical hypersynchronization with preserved consciousness in Glut1 deficiency.

Individuals with glucose transporter type I deficiency (G1D) habitually experience nutrient-responsive epilepsy associated with decreased brain glucose. However, the mechanistic association between blood glucose concentration and brain excitability in the context of G1D remains to be elucidated. Electroencephalography (EEG) in G1D individuals revealed nutrition time-dependent seizure oscillations often associated with preserved volition despite electrographic generalization and uniform average oscillation duration and periodicity, suggesting increased facilitation of an underlying neural loop circuit. Nonlinear EEG ictal source localization analysis and simultaneous EEG/functional magnetic resonance imaging converged on the thalamus-sensorimotor cortex as one potential circuit, and 18F-deoxyglucose positron emission tomography (18F-DG-PET) illustrated decreased glucose accumulation in this circuit. This pattern, reflected in a decreased thalamic to striatal 18F signal ratio, can aid with the PET imaging diagnosis of the disorder, whereas the absence of noticeable ictal behavioral changes challenges the postulated requirement for normal thalamocortical activity during consciousness. In G1D mice, 18F-DG-PET and mass spectrometry also revealed decreased brain glucose and glycogen, but preserved tricarboxylic acid cycle intermediates, indicating no overall energy metabolism failure. In brain slices from these animals, synaptic inhibition of cortical pyramidal neurons and thalamic relay neurons was decreased, and neuronal disinhibition was mitigated by metabolic sources of carbon; tonic-clonic seizures were also suppressed by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor inhibition. These results pose G1D as a thalamocortical synaptic disinhibition disease associated with increased glucose-dependent neuronal excitability, possibly in relation to reduced glycogen. Together with findings in other metabolic defects, inhibitory neuron dysfunction is emerging as a modulable mechanism of hyperexcitability.

Epilepsy Course and Developmental Trajectories in STXBP1-DEE.

Background and Objectives: Clinical manifestations in STXBP1 developmental and epileptic encephalopathy (DEE) vary in severity and outcome, and the genotypic spectrum is diverse. We aim to trace the neurodevelopmental trajectories in individuals with STXBP1-DEE and dissect the relationship between neurodevelopment and epilepsy. Methods: Retrospective standardized clinical data were collected through international collaboration. A composite neurodevelopmental score system compared the developmental trajectories in STXBP1-DEE. Results: Forty-eight patients with de novo STXBP1 variants and a history of epilepsy were included (age range at the time of the study: 10 months to 35 years, mean 8.5 years). At the time of inclusion, 65% of individuals (31/48) had active epilepsy, whereas 35% (17/48) were seizure free, and 76% of those (13/17) achieved remission within the first year of life. Twenty-two individuals (46%) showed signs of developmental impairment and/or neurologic abnormalities before epilepsy onset. Age at seizure onset correlated with severity of developmental outcome and the developmental milestones achieved, with a later seizure onset associated with better developmental outcome. In contrast, age at seizure remission and epilepsy duration did not affect neurodevelopmental outcomes. Overall, we did not observe a clear genotype-phenotype correlation, but monozygotic twins with de novo STXBP1 variant showed similar phenotype and parallel disease course. Discussion: The disease course in STXBP1-DEE presents with 2 main trajectories, with either early seizure remission or drug-resistant epilepsy, and a range of neurodevelopmental outcomes from mild to profound intellectual disability. Age at seizure onset is the only epilepsy-related feature associated with neurodevelopment outcome. These findings can inform future dedicated natural history studies and trial design.

EEG is A Predictor of Neuroimaging Abnormalities in Pediatric Extracorporeal Membrane Oxygenation.

The goal of this project was to evaluate if severity of electroencephalogram (EEG) during or shortly after being placed on extracorporeal membrane oxygenation (ECMO) would correlate with neuroimaging abnormalities, and if that could be used as an early indicator of neurologic injury. This was a retrospective chart review spanning November 2009 to May 2018. Patients who had an EEG recording during ECMO or within 48 hours after being decannulated (early group) or within 3 months of being on ECMO (late group) were included if they also had ECMO-related neuroimaging. In the early EEG group, severity of the EEG findings of mild, moderate, and severe EEG correlated to mild, moderate, and severe neuroimaging scores. Patients on venoarterial (VA) ECMO were noted to have higher EEG and neuroimaging severity; this was statistically significant. There was no association in the late EEG group to neuroimaging abnormalities. Our study highlights that EEG severity can be an early predictor for neuroimaging abnormalities that can be identified by computed tomography (CT) and or magnetic resonance imaging (MRI). This can provide guidance for both the medical team and families, allowing for a better understanding of overall prognosis.

Spatially clustering de novo variants in CYFIP2, encoding the cytoplasmic FMRP interacting protein 2, cause intellectual disability and seizures.

CYFIP2, encoding the evolutionary highly conserved cytoplasmic FMRP interacting protein 2, has previously been proposed as a candidate gene for intellectual disability and autism because of its important role linking FMRP-dependent transcription regulation and actin polymerization via the WAVE regulatory complex (WRC). Recently, de novo variants affecting the amino acid p.Arg87 of CYFIP2 were reported in four individuals with epileptic encephalopathy. We here report 12 independent patients harboring a variety of de novo variants in CYFIP2 broadening the molecular and clinical spectrum of a novel CYFIP2-related neurodevelopmental disorder. Using trio whole-exome or -genome sequencing, we identified 12 independent patients carrying a total of eight distinct de novo variants in CYFIP2 with a shared phenotype of intellectual disability, seizures, and muscular hypotonia. We detected seven different missense variants, of which two occurred recurrently (p.(Arg87Cys) and p.(Ile664Met)), and a splice donor variant in the last intron for which we showed exon skipping in the transcript. The latter is expected to escape nonsense-mediated mRNA decay resulting in a truncated protein. Despite the large spacing in the primary structure, the variants spatially cluster in the tertiary structure and are all predicted to weaken the interaction with WAVE1 or NCKAP1 of the actin polymerization regulating WRC-complex. Preliminary genotype-phenotype correlation indicates a profound phenotype in p.Arg87 substitutions and a more variable phenotype in other alterations. This study evidenced a variety of de novo variants in CYFIP2 as a novel cause of mostly severe intellectual disability with seizures and muscular hypotonia.

Does Autoimmunity have a Role in Myoclonic Astatic Epilepsy? A Case Report of Voltage Gated Potassium Channel Mediated Seizures.

BACKGROUND: There is expanding knowledge about the phenotypic variability of patients with voltage gated potassium channel complex (VGKC) antibody mediated neurologic disorders. The phenotypes are diverse and involve disorders of the central and peripheral nervous systems. The central nervous system manifestations described in the literature include limbic encephalitis, status epilepticus, and acute encephalitis. PATIENT DESCRIPTION: We report a 4.5 year-old boy who presented with intractable Myoclonic Astatic Epilepsy (MAE) or Doose syndrome and positive VGKC antibodies in serum. Treatment with steroids led to resolution of seizures and electrographic normalization. CONCLUSION: This case widens the spectrum of etiologies for MAE to include autoimmunity, in particular VGKC auto-antibodies and CNS inflammation, as a primary or contributing factor. There is an evolving understanding of voltage gated potassium channel complex mediated autoimmunity in children and the role of inflammation and autoimmunity in MAE and other intractable pediatric epilepsy syndromes remains to be fully defined. A high index of suspicion is required for diagnosis and appropriate management of antibody mediated epilepsy syndromes.

The safety and tolerability of newer antiepileptic drugs in children and adolescents.

Childhood epilepsy continues to be intractable in more than 25% of patients diagnosed with epilepsy. The introduction of new anti-epileptic drugs (AEDs) provides more options for treatment of children with epilepsy. We review the safety and tolerability of seven new AEDs (levetiracetam, lamotrigine, oxcarbazepine, rufinamide, topiramate, vigabatrin and zonisamide) focusing on their side effect profiles and safety in children and adolescents. Many considerations that are specific for children such as the impact of AEDs on the developing brain are not addressed during the development of new AEDs. They are usually approved as adjunctive therapies based upon clinical trials involving adult patients with partial epilepsy. However, 2 of the AEDs reviewed here (rufinamide and vigabatrin) have FDA approval in the U.S. for specific Pediatric epilepsy syndromes, which are discussed below. The Pediatrician or Neurologists decision on the use of a new AED is an evolutionary process largely dependent on the patient characteristics, personal/peer experiences and literature about efficacy and safety profiles of these medications. Evidence based guidelines are limited due to a lack of randomized controlled trials involving pediatric patients for many of these new AEDs.

Successful management of refractory neonatal seizures with midazolam.

Seizures are indicative of underlying neurologic dysfunction in neonates. Repeated seizures may be deleterious to the brain even without disturbances of ventilation or perfusion. First-line antiepileptic drugs such as phenobarbital and phenytoin are not very effective in controlling seizures in neonates. Rapid control of status epilepticus with midazolam has been demonstrated in 2 previous studies with complete clinical and electrographic response in neonates who did not respond to phenobarbital and phenytoin. We report our experience with 3 neonates with status epilepticus. Seizures in all 3 neonates did not respond to phenobarbital and phenytoin but responded to midazolam infusion. Midazolam may be considered a safe and effective antiepileptic drug in refractory neonatal seizures of diverse etiologies.

Apneic seizures: a sign of temporal lobe hemorrhage in full-term neonates.

Intracranial hemorrhage is a common cause of neonatal seizures in full-term infants. However, only some infants with intracranial hemorrhage come to clinical attention. A right temporal lobe hemorrhage with resulting apneic seizures was described previously in one neonate. In this case report, we review three full-term male neonates with no significant perinatal complications who presented with apneic events and temporal lobe hemorrhage. One neonate had apnea as the sole manifestation of a seizure that was confirmed electrographically. One neonate had motor manifestations of seizures, in addition to apnea, that were confirmed as seizures electrographically. The third neonate had pure apneic events before initiation of electroencephalogram monitoring which were presumed to be seizures, because the electroencephalogram demonstrated epileptiform abnormalities. At follow-up, all three children were neurodevelopmentally normal. This case report emphasizes that, although uncommon, full-term neonates may present with apnea as the initial manifestation of temporal lobe hemorrhage. Because apnea could be a manifestation of a seizure, continuous electroencephalogram monitoring should be considered in a full-term neonate with unexplained apnea.

The safety of levetiracetam.

Levetiracetam is an antiepileptic drug approved for use as an adjunct agent in partial-onset seizures in adults and children aged > or = 4 years. It was also approved as adjunctive therapy in the treatment of adults and adolescents aged > or = 12 years with juvenile myoclonic epilepsy. A parenteral intravenous formulation has recently become available allowing for its use when oral administration is temporarily not feasible. Available literature has demonstrated and supported that levetiracetam has an acceptable safety profile and this review discusses the safety profile of levetiracetam, with attention to special populations. The most common adverse effects are somnolence, asthenia and dizziness, which usually appear early after initiation of levetiracetam therapy and generally resolve without medication withdrawal. The most serious adverse effects are behavioral in nature and are more common in children and in patients with a prior history of behavioral problems.