Suppression Burst Research Articles

Synchronous heart rate reduction with suppression-burst pattern in KCNT1-related developmental and epileptic encephalopathies.

Suppression-burst (SB) is an electroencephalographic pattern observed in neonatal- and infantile-onset developmental and epileptic encephalopathies (DEEs), which are associated with high mortality in early life. However, the relation of SB electroencephalogram (SB-EEG) with autonomic function requires clarification. We investigated the relationship between heart rate (HR) and phasic transition during SB-EEG in DEEs to explore the mechanism of early death. Seven patients (two with KCNT1-DEE) with neonatal- and infantile-onset DEE who presented with SB-EEG were retrospectively identified. Five-minute SB-EEGs were analyzed with simultaneous recording of electrocardiograms. Mean HR, suppression duration, and burst period were calculated by measuring RR intervals. Two patients with KCNT1-DEE exhibited synchronous HR fluctuations, with an HR decrease during suppression and an increase during burst. The HR decrease was larger (-6.1% and -7.7%) and the median duration of suppression was longer (4.0 and 8.2s) in patients with KCNT1-DEE than the other five (range: -2.9% to 0.9% and 0.7-1.7s, respectively). A strong negative correlation was confirmed between suppression duration and HR reduction rates in one patient with KCNT1-DEE. SB phases may influence HR regulation in patients with KCTN1-DEE.

Ketogenic Diet in the Treatment of Super-Refractory Status Epilepticus at a Pediatric Intensive Care Unit: A Single-Center Experience.

Background: To evaluate the use of the ketogenic diet (KD) for treatment of super-refractory status epilepticus (SRSE) at a pediatric intensive care unit (PICU).Design: A retrospective analysis of all pediatric patients treated for SRSE with the KD at our center was performed using patient data from our prospective longitudinal KD database.Setting: SRSE is defined as refractory SE that continues or recurs 24 h or more after initiation of anesthetic drugs. We describe the clinical and electroencephalographic (EEG) findings of all children treated with KD at our PICU. The KD was administered as add-on after failure of standard treatment. Response was defined as EEG seizure resolution (absence of seizures and suppression–burst ratio ≥50%).Patients: Eight consecutive SRSE patients (four females) treated with KD were included. Median age at onset of SRSE was 13.6 months (IQR 0.9–105), and median age at KD initiation was 13.7 months (IQR 1.9 months to 8.9 years). Etiology was known in 6/8 (75%): genetic in 4 (50%), structural in 1 (12.5%), and autoimmune/inflammatory in 1 (12.5%).Main Results: Time from onset of SRSE to initiation of KD was median 6 days (IQR 1.3–9). Time until clinically relevant ketosis (beta-hydroxybutyrate (BHB) >2 mmol/L in serum) was median 68.0 h (IQR 27.3–220.5). Higher ketosis was achieved when a higher proportion of enteral feeds was possible. Four (50%) patients responded to KD treatment within 7 days. During follow-up (median 4.2 months, IQR 1.6–12.3), 5/8 patients—three of them responders—died within 3–12 months after SRSE.Conclusions: In eight patients with SRSE due to severe etiologies including Alpers syndrome, we report an initial 50% response to KD. KD was used early in SRSE and sufficient levels of ketosis were reached early in most patients. Higher ketosis was achieved with combined enteral and parenteral feedings.

Clinical characteristics of KCNQ2 encephalopathy

PurposeKCNQ2 mutations are associated with benign familial neonatal epilepsy (BFNE) or developmental and epileptic encephalopathy (DEE). In this study, we aimed to delineate the phenotype of KCNQ2 encephalopathy and evaluate the treatment response. MethodsThirteen patients of KCNQ2 encephalopathy were included in the study. Characteristics of KCNQ2 mutations, electroclinical features, clinical course, and response to the treatment were analyzed. ResultsAge range of the thirteen patients was between 3 months and 20.9 years. The onset of seizures in 11 patients ranged from 1 to 3 days of age, while in the other two patients it was 7 and 40 days, respectively. Most common initial seizure types were tonic seizures. Initial EEGs were suppression burst pattern in seven patients and slow and disorganized background with multifocal epileptiform discharges in six patients. Initial epilepsy syndrome was Ohtahara syndrome in seven patients, neonatal focal seizure in five patients, and focal epilepsy beyond neonatal period in one patient. Sodium channel blockers including oxcarbazepine (OXC) (n = 3), lamotrigine (LTG) (n = 3), phenytoin (PHT) (n = 2), topiramate (TPM) (n = 2), and zonisamide (ZNS) (n = 1) were tried and found effective in eleven patients. Ultimately, 12 of 13 patients became seizure-free. However, developmental outcomes were poor. ConclusionsSodium channel blockers are effective in seizure control in these patients with KCNQ2 encephalopathy. Early recognition of KCNQ2 encephalopathy and early use of sodium channel blockers might be helpful in seizure control.

The clinical utility of intraoperative electrocorticography in pediatric epilepsy surgical strategy and planning.

In this study, the authors aimed to determine 1) whether the use of intraoperative electrocorticography (ECoG) affects outcomes and complication rates of children undergoing resective epilepsy surgery; 2) which patient- and epilepsy-related variables might influence ECoG-based surgical strategy; and 3) what the predictors of epilepsy surgery outcomes are. Over a period of 12 years, data were collected on pediatric patients who underwent tailored brain resections in the Motol Epilepsy Center. In patients in whom an abnormal ECoG pattern (e.g., spiking, suppression burst, or recruiting rhythm) was not observed beyond presurgically planned resection margins, the authors did not modify the surgical plan (group A). In those with significant abnormal ECoG findings beyond resection margins, the authors either did (group B) or did not (group C) modify the surgical plan, depending on the proximity of the eloquent cortex or potential extent of resection. Using Fisher's exact test and the chi-square test, the 3 groups were compared in relation to epilepsy surgery outcomes and complication rate. Next, multivariate models were constructed to identify variables associated with each of the groups and with epilepsy surgery outcomes. Patients in group C achieved significantly lower rates of seizure freedom compared to groups A (OR 30.3, p < 0.001) and B (OR 35.2, p < 0.001); groups A and B did not significantly differ (p = 0.78). Patients in whom the surgical plan was modified suffered from more frequent complications (B vs A+C, OR 3.8, p = 0.01), but these were mostly minor (duration < 3 months; B vs A+C, p = 0.008). In all cases, tissue samples from extended resections were positive for the presence of the original pathology. Patients with intended modification of the surgical plan (groups B+C) suffered more often from daily seizures, had a higher age at first seizure, had intellectual disability, and were regarded as MR-negative (p < 0.001). Unfavorable surgical outcome (Engel class II-IV) was associated with focal cortical dysplasia, incomplete resection based on MRI and/or ECoG findings, negative MRI finding, and inability to modify the surgical plan when indicated. Intraoperative ECoG serves as a reliable tool to guide resection and may inform the prognosis for seizure freedom in pediatric patients undergoing epilepsy surgery. ECoG-based modification of the surgical plan is associated with a higher rate of minor complications. Children in whom ECoG-based modification of the surgical plan is indicated but not feasible achieve significantly worse surgical outcomes.

Neonatal SCN2A encephalopathy: A peculiar recognizable electroclinical sequence

IntroductionSodium voltage-gated channel alpha subunit 2 (SCN2A) gene encodes the Nav1.2 subunit of voltage-gated sodium channel in pyramidal neurons. SCN2A gain-of-function mutations are identified more and more often with gene panels and whole exome sequencing. Phenotype ranges from benign neonatal or infantile seizures to severe epileptic encephalopathy. Although large series of patients targeting genetic background point out two main phenotypes with SCN2A encephalopathy, Ohtahara syndrome and malignant migrating partial seizures in infancy (EMPSI), we noticed that in fact, a peculiar clinical and electroencephalogram (EEG) sequence distinct from these syndromes should suggest the diagnosis early. Patients and methodsWe report three new cases with de novo SCN2A mutations – 166237617C>A p.(Asp1487Glu), c.407T>G p.(Met136Arg), and c.4633A>G p.(Met1545Val) – diagnosed by direct sequencing or genes panel, their follow-up ranging from 4 to 5 years. ResultsFor all three patients, seizures started at two days of life and consisted of apnea and cyanosis with partial clonic or tonic, alternating on both sides with, up to 100/day, evolving to generalized tonic–clonic seizures (GTCS) and epileptic spasms by three months. First EEG showed a discontinuous pattern, evolving to multifocal spikes, by 3 (two patients) and 6 months (one). Seizure frequency decreased progressively by the middle or end of the first year of life. Only less frequent GTCS persisted during the second year of life for two patients. Improvement was observed in two patients with sodium channel blocker (phenytoin) used at age of 1 month for one patient and at 2 years for another one. All patients remained with severe psychomotor delay. DiscussionAll three infants share a condition different from Ohtahara syndrome in which tonic spasms predominate and suppression–burst pattern is obvious, and from EMPSI, in which partial migrating discharges involve successively the various parts of the brain including occipital regions with oculoclonic seizures, but there is neither discontinuous pattern nor therapeutic response to sodium channel blockers. ConclusionNeonatal SCN2A encephalopathy has a recognizable phenotype starting soon after birth with alternating partial motor seizures evolving to infantile spasms and a discontinuous EEG pattern. Seizures improve spontaneously in the first year of life. This electroclinical sequence should indicate the search of SCN2A mutation and suggest the administration of sodium channel blockers.

Report on three additional patients and genotype-phenotype correlation in SLC25A22-related disorders group.

Early infantile epileptic encephalopathy (EIEE) is a heterogeneous group of severe forms of age-related developmental and epileptic encephalopathies with onset during the first weeks or months of life. The interictal electroencephalogram (EEG) shows a "suppression burst" (SB) pattern. The prognosis is usually poor and most children die within the first two years or survive with very severe intellectual disabilities. EIEE type 3 is caused by variants affecting function, in SLC25A22, which is also responsible for epilepsy of infancy with migrating focal seizures (EIMFS). We report a family with a less severe phenotype of EIEE type 3. We performed exome sequencing and identified two unreported variants in SLC25A22 in the compound heterozygous state: NM_024698.4: c.[813_814delTG];[818 G>A] (p.[Ala272Glnfs*144];[Arg273Lys]). Functional studies in cultured skin fibroblasts from a patient showed that glutamate oxidation was strongly defective, based on a literature review. We clustered the 18 published patients (including those from this family) into three groups according to the severity of the SLC25A22-related disorders. In an attempt to identify genotype-phenotype correlations, we compared the variants according to the location depending on the protein domains. We observed that patients with two variants located in helical transmembrane domains presented a severe phenotype, whereas patients with at least one variant outside helical transmembrane domains presented a milder phenotype. These data are suggestive of a continuum of disorders related to SLC25A22 that could be called SLC25A22-related disorders. This might be a first clue to enable geneticists to outline a prognosis based on genetic molecular data regarding the SLC25A22 gene.

Successful treatment of intractable life-threatening seizures with perampanel in the first case of early myoclonic encephalopathy with a novel de novo SCN1A mutation

PurposeEarly myoclonic encephalopathy (EME) is a form of developmental and epileptic encephalopathy with myoclonic seizures and a suppression burst on electroencephalogram, which occurs during the neonatal or early infantile period and is characterized by highly intractable seizures and severe development impairment. Although multiple genetic aetiologies of EME have been identified, no SCN1A mutation has been reported. MethodsWe described a female patient with EME due to an SCN1A mutation. ResultsShe developed frequent myoclonic and apnoeic seizures during the neonatal period. As her seizures were refractory to many antiepileptic drugs, she underwent a tracheotomy and has since been treated with continuous mechanical ventilation. Eventually, perampanel was added, which resulted in the cessation of the apnoeic seizures. Genetic analysis revealed a heterozygous de novo missense mutation in the SCN1A gene (c.2588 T > C:p.Leu863Ser). ConclusionThis is the first patient with EME due to anSCN1A mutation to be successfully treated with perampanel. Recently, perampanel was reported to be effective in treating Dravet syndrome, including cases with an SCN1A mutation. Perampanel may contribute to seizure reduction in patients with intractable epilepsy carrying the SCN1A mutation.

Different types of suppression-burst patterns in patients with epilepsy of infancy with migrating focal seizures (EIMFS)

PurposeIn rare cases, patients with epilepsy of infancy withmigrating focal seizures (EIMFS) exhibit suppression-burst (SB) patterns on electroencephalography (EEG), similar to the findings observed in patients with Ohtahara syndrome and early myoclonic encephalopathy. In this report, we discuss six cases of EIMFS in which patients exhibited two types of SB patterns. MethodsWe evaluated six patients with EIMFS who had been admitted to the NHO Shizuoka Institute of Epilepsy and Neurological Disorders between 2011 and 2018. We retrospectively examined clinical characteristics and EEG findings for each patient. In all patients, the first EEG was performed within 1 month after seizure onset. Afterwards, EEG examinations were performed at irregular intervals (ranging from 1 to 5 months). ResultsAge at seizure onset ranged from 2 days to 3 months. SB was first detected within 1 month of age in two patients, and within the range of 3–14 months in the remaining four patients. Among the latter four patients, SB patterns persisted at the final EEG recording in three patients (34–54 months). In all patients, SB patterns were observed during sleep only. Interhemispheric asynchrony in SB was observed in the two patients who exhibited SB within 1 month of age, while synchronous SB patterns were observed in the remaining four patients. ConclusionsOur findings indicate that EIMFS may be associated with two types of SB patterns (early-onset and late-onset), which can be distinguished based on the stage of emergence and level of synchrony.

Chapter 1 - Generalized epilepsies

Idiopathic generalized epilepsies (IGE) are characterized by normal background EEG activity and generalized interictal spike-and-wave discharges in the absence of any evidence of brain lesion. Absence epilepsies are the prototypes of IGEs. In childhood and juvenile absence epilepsies, by definition, all patients manifest absence seizures associated with an EEG pattern of generalized spike-wave (GSW) discharges. In juvenile myoclonic epilepsy, myoclonic jerks, usually affecting shoulders and arms bilaterally and appearing upon awakening, are the most characteristic clinical feature. Myoclonic jerks are accompanied on the EEG by generalized spike/polyspike-and-wave (GSW, GPWS) complexes at 3.5-6Hz. Idiopathic generalized epilepsy with generalized tonic-clonic seizures only is a broad and nonspecific category including all patients with generalized tonic-clonic seizures and an interictal EEG pattern of GSW discharges. Despite the strong heritability and the recent advances in genetic technology, the genetic basis of IGEs remains largely elusive and only in a small minority of patients with classic IGE phenotypes is a monogenic cause identified. Early myoclonic encephalopathy (EME), early infantile encephalopathy with suppression bursts, West syndrome, and Lennox-Gastaut syndrome, once classified among the generalized epilepsies, are now considered to be epileptic encephalopathies. Among them, only Lennox-Gastaut syndrome is characterized by prominent generalized clinical and EEG features.

Identification of a Loss-of-Function Mutation in the Context of Glutaminase Deficiency and Neonatal Epileptic Encephalopathy

The identification and understanding of the monogenic causes of neurodevelopmental disorders are of high importance for personalized treatment and genetic counseling. To identify and characterize novel genes for a specific neurodevelopmental disorder characterized by refractory seizures, respiratory failure, brain abnormalities, and death in the neonatal period; describe the outcome of glutaminase deficiency in humans; and understand the underlying pathological mechanisms. We performed exome sequencing of cases of neurodevelopmental disorders without a clear genetic diagnosis, followed by genetic and bioinformatic evaluation of candidate variants and genes. Establishing pathogenicity of the variants was achieved by measuring metabolites in dried blood spots by a hydrophilic interaction liquid chromatography method coupled with tandem mass spectrometry. The participants are 2 families with a total of 4 children who each had lethal, therapy-refractory early neonatal seizures with status epilepticus and suppression bursts, respiratory insufficiency, simplified gyral structures, diffuse volume loss of the brain, and cerebral edema. Data analysis occurred from October 2017 to June 2018. Early neonatal epileptic encephalopathy with glutaminase deficiency and lethal outcome. A total of 4 infants from 2 unrelated families, each of whom died less than 40 days after birth, were included. We identified a homozygous frameshift variant p.(Asp232Glufs*2) in GLS in the first family, as well as compound heterozygous variants p.(Gln81*) and p.(Arg272Lys) in GLS in the second family. The GLS gene encodes glutaminase (Enzyme Commission 3.5.1.2), which plays a major role in the conversion of glutamine into glutamate, the main excitatory neurotransmitter of the central nervous system. All 3 variants probably lead to a loss of function and thus glutaminase deficiency. Indeed, glutamine was increased in affected children (available z scores, 3.2 and 11.7). We theorize that the potential reduction of glutamate and the excess of glutamine were a probable cause of the described physiological and structural abnormalities of the central nervous system. We identified a novel autosomal recessive neurometabolic disorder of loss of function of glutaminase that leads to lethal early neonatal encephalopathy. This inborn error of metabolism underlines the importance of GLS for appropriate glutamine homeostasis and respiratory regulation, signal transduction, and survival.

PLPBP mutations cause variable phenotypes of developmental and epileptic encephalopathy.

SummaryObjectiveVitamin B6–dependent epilepsies are treatable disorders caused by variants in several genes, such as ALDH7A1,PNPO, and others. Recently, biallelic variants in PLPBP, formerly known as PROSC, were identified as a novel cause of vitamin B6–dependent epilepsies. Our objective was to further delineate the phenotype of PLPBP mutation.MethodsWe identified 4 unrelated patients harboring a total of 4 variants in PLPBP, including 3 novel variants, in a cohort of 700 patients with developmental and epileptic encephalopathies. Clinical information in each case was collected.ResultsEach patient had a different clinical course of epilepsy, with seizure onset from the first day of life to 3 months of age. Generalized tonic–clonic seizures were commonly noted. Myoclonic seizures or focal seizures were also observed in 2 patients. Interictal electroencephalography showed variable findings, such as suppression burst, focal or multifocal discharges, and diffuse slow activity. Unlike previous reports, all the patients had some degree of intellectual disability, although some of them had received early treatment with vitamin B6, suggesting that different mutation types influence the severity and outcome of the seizures.Significance PLPBP variants should be regarded as among the causative genes of developmental and epileptic encephalopathy, even when it occurs after the neonatal period. Early diagnosis and proper treatment with pyridoxine or pyridoxal phosphate is essential to improve the neurologic prognosis in neonates or young children with poorly controlled seizures.

Electro-clinical characteristics and prognostic significance of post anoxic myoclonus

ObjectiveTo systematically examine the electro-clinical characteristics of post anoxic myoclonus (PAM) and their prognostic implications in comatose cardiac arrest (CA) survivors. MethodsFifty-nine CA survivors who developed myoclonus within 72 h of arrest and underwent continuous EEG monitoring were included in the study. Retrospective chart review was performed for all relevant clinical variables including time of PAM onset (“early onset” when within 24 h) and semiology (multi-focal, facial/ocular, whole body and limbs only). EEG findings including background, reactivity, epileptiform patterns and EEG correlate to myoclonus were reviewed at 6, 12, 24, 48 and 72 h after the return of spontaneous circulation (ROSC). Outcome was categorized as either with recovery of consciousness (Cerebral Performance Category (CPC) 1–3) or without recovery of consciousness (CPC 4–5) at the time of discharge. ResultsSeven of the 59 patients (11.9%) regained consciousness, including 6/51 (11.8%) with early onset PAM. Patients with recovery of consciousness had shorter time to ROSC, and were more likely to have preserved brainstem reflexes and normal voltage background at all times. No patient with suppression burst or low voltage background (N = 52) at any point regained consciousness. In the subset where precise electro-clinical correlation was possible, all (5/5) those with recovery of consciousness had multi-focal myoclonus and most (4/5) had midline-maximal spikes over a continuous background. No patient with any other semiology (N = 21) regained consciousness. ConclusionsEarly onset PAM is not always associated with lack of recovery of consciousness. EEG can help discriminate between patients who may or may not regain consciousness by the time of hospital discharge.

Munc18-1 haploinsufficiency impairs learning and memory by reduced synaptic vesicular release in a model of Ohtahara syndrome

Ohtahara syndrome, also known as type 4 of Early Infantile Epileptic Encephalopathy with suppression bursts (EIEE-4) is currently an untreatable disorder that presents with seizures and impaired cognition. EIEE-4 patients have mutations most frequently in the STXBP1 gene encoding a Sec protein, munc18-1. The exact molecular mechanism of how these munc18-1 mutations cause impaired cognition, remains elusive. The leading haploinsufficiency hypothesis posits that mutations in munc18-1 render the protein unstable leading to its degradation. Expression driven by the healthy allele is not sufficient to maintain the physiological function resulting in haploinsufficiency. The aim of this study has been to understand how munc18-1 haploinsufficiency causes cognitive impairment seen in EIEE-4. Here we present results from behavioral to cellular effects from a mouse model of munc18-1 haploinsufficiency. Munc18-1 heterozygous knock-out mice showed impaired spatial learning and memory in behavior tests as well as reduced synaptic plasticity in hippocampal CA1 long-term potentiation. Cultured munc18-1 heterozygous hippocampal neurons had significantly slower rate of synaptic vesicle release and decreased readily releasable vesicle pool compared to wild-type control neurons in fluorescent FM dye assays. These results demonstrate that reduced munc18-1 levels are sufficient to impair learning and memory by reducing neurotransmitter release. Therefore, our study implicates munc18-1 haploinsufficiency as a primary cause of cognitive impairment seen in EIEE-4 patients.

Neurostimulant use is associated with improved survival in comatose patients after cardiac arrest regardless of electroencephalographic substrate

AimIdentify EEG patterns that predict or preclude favorable response in comatose post-arrest patients receiving neurostimulants. MethodsWe examined a retrospective cohort of consecutive electroencephalography (EEG)-monitored comatose post-arrest patients. We classified the last day of EEG recording before neurostimulant administration based on continuity (continuous/discontinuous), reactivity (yes/no) and malignant patterns (periodic discharges, suppression burst, myoclonic status epilepticus or seizures; yes/no). In subjects who did not receive neurostimulants, we examined the last 24h of available recording. For our primary analysis, we used logistic regression to identify EEG predictors of favorable response to treatment (awakening). ResultsIn 585 subjects, mean (SD) age was 57 (17) years and 227 (39%) were female. Forty-seven patients (8%) received a neurostimulant. Neurostimulant administration independently predicted improved survival to hospital discharge in the overall cohort (adjusted odds ratio (aOR) 4.00, 95% CI 1.68–9.52) although functionally favorable survival did not differ. No EEG characteristic predicted favorable response to neurostimulants. In each subgroup of unfavorable EEG characteristics, neurostimulants were associated with increased survival to hospital discharge (discontinuous background: 44% vs 7%, P=0.004; non-reactive background: 56% vs 6%, P<0.001; malignant patterns: 63% vs 5%, P<0.001). ConclusionEEG patterns described as ominous after cardiac arrest did not preclude survival or awakening after neurostimulant administration. These data are limited by their observational nature and potential for selection bias, but suggest that EEG patterns alone should not affect consideration of neurostimulant use.

High phenotypic intra-familial variability of pyridoxine-dependent epilepsy

Objective: The present study aims to further characterize the phenotypic spectrum of antiquitin (ALDH7A1 gene) deficiency and underlines a high phenotypic intra-familial variability of this condition. ALDH7A1 gene is known to be responsible for autosomal recessive pyridoxine-dependent epilepsy (OMIM 266100). Phenotypic spectrum of ALDH7A1 mutations is very heterogeneous ranging from refractory epilepsy through brain malformation and neurodevelopmental delay, to multisystem neonatal disorder. Results: We present the case of two siblings, children of first-cousin parents, found to harbour a homozygous ALDH7A1 mutation. A boy (7th pregnancy) was born at term. At 3 hours of life he presented drug- resistant seizures. EEG showed a suppression burst pattern and several multifocal critical patterns. Brain MRI was normal. Targeted next-generation sequencing panels for epileptic encephalopathy disclosed a homozygous missense mutation in the gene encoding for ALDH7A1 (antiquitin) responsible for pyridoxine-dependent epilepsy. Supplementation with pyridoxine and lysine- restricted diet led to complete seizure control and to improvement of psychomotor development in the next months. The same mutation was searched and found in a stocked sample of DNA from peripheral blood of the older sister dead 3 years before. His daughter (3rd pregnancy) presented severe brain malformation diagnosed at fetal ultrasound. At birth, MRI showed microcephaly associated to diffuse cortical thinning, agenesis of the corpus callosum and cerebellar hypoplasia. She presented refractory seizures on day two. EEG showed a suppression burst pattern with multifocal epileptiform discharges. CGH-array was negative. Health conditions got worst and she died at 6 months of life. Both parents were tested and found to be heterozygous carriers. Mother had 2 miscarriages and an abortion for anencephaly. Two other children (one boy and one girl) were healthy. Conclusions: Our data show a high phenotypic intra-familial variability of pyridoxine-dependent epilepsy and a possible association of ALDH7A1 gene mutations to severe brain malformations.

Neonatal Hypoxic-Ischemic Encephalopathy and Hypothermia Therapy: Solving Questions about Monitoring and Prognosis

Introduction: The hypoxic-ischemic encephalopathy is a significant cause of neurologic morbidity and mortality in the newborn. One of the standards of management is the hypothermia therapy that allows a reduction in the brain injury extension, making important to define the settings involving the admission to such therapy. The hypothermia therapy protocol demands an strict compliance of the inclusion criteria, one of them, the APGAR score at a determinate moment, no protocol includes its score at different times, the APGAR score helps the clinician to decide the therapeutic approach of this patients, and the tenth minute score has received priority over the other minute’s score, nevertheless many patients will lose the opportunity to be admitted for hypothermia therapy when this score is taken, although the ACOG has determined that it is the minute 5 APGAR that has the value to define neonatal asphyxia, most European and American protocols take the 10 minute APGAR score; besides it is possible that the newborn in the first 6 hours does not demonstrate the secondary damage, or energy failure that are generated up to 48 hours later, in which the use of hypothermia therapy has truly a therapeutic effect. Then it is imperative to analyze the early outcomes according to the APGAR in the minute 5 and 10 in patients admitted for hypothermia therapy. Methods: A descriptive study, and retrospective analysis of a cohort of 62 patients born in term with hypoxic ischemic encephalopathy, admitted at the intensive care unit of Clinica Universitaria Bolivariana, Medellin, Colombia, between 2014-2016. Results: The cohort of newborns exhibits a mortality of 8.1%, which was significantly associated with the presence of complications during hypothermia. The most frequent pattern found in the electroencephalographic line during the first day was suppression burst 45.2%, and heading to the end of the protocol, 51.6% achieved normalization; imaging findings such as the subcortical ischemia was the mostly found in 25.8%, but the hemorrhagic ones were only found in 12.9%. During a bivariate analysis a correlation between different outcomes were found, the most important of them, was the one among the presence of status during the electroencephalographic monitoring with an APGAR score under 5 at the fifth minute. Conclusions: It is important to take on consideration the five-minute APGAR score because of its relation with epileptic status development, which in our cohort was more frequent without clinical manifestation than with it during monitoring. This is important because of the negative prognosis that this implies in the short term, in addition the patients that presented epileptic status post medication had correlation with persistent abnormalities at the discharge, that is why the five-minute APGAR score under five can predict the neurological examination at the discharge and the epileptic status development as a predictive marker. This also creates a suspect that the recommendation to use hypothermia therapy without electroencephalographic monitoring is a dangerous practice, and makes it difficult to assess the response to it.

Continuous EEG monitoring enhances multimodal outcome prediction in hypoxic–ischemic brain injury

ObjectiveHypoxic brain injury is the largest contributor to disability and mortality after cardiac arrest. We aim to identify electroencephalogram (EEG) characteristics that can predict outcome on cardiac arrest patients treated with targeted temperature management (TTM). MethodsWe retrospectively examined clinical, EEG, functional outcome at discharge, and in-hospital mortality for 373 adult subjects with return of spontaneous circulation after cardiac arrest. Poor outcome was defined as a Cerebral Performance Category score of 3–5. Pure suppression–burst (SB) was defined as SB not associated with status epilepticus (SE), seizures, or generalized periodic discharges. ResultsIn-hospital mortality was 68.6% (N=256). Presence of both unreactive EEG background and SE was associated with a positive predictive value (PPV) of 100% (95% confidence interval: 0.96–1) and a false-positive rate (FPR) of 0% (95% CI: 0–0.11) for poor functional outcome. A prediction model including demographics data, admission exam, presence of status epilepticus, pure SB, and lack of EEG reactivity had an area under the curve of 0.92 (95% CI: 0.87–0.95) for poor functional outcome prediction, and 0.96 (95% CI: 0.94–0.98) for in-hospital mortality. Presence of pure SB (N=87) was confounded by anesthetics use in 83.9% of the cases, and was not an independent predictor of poor functional outcome, having a FPR of 23% (95% CI: 0.19–0.28). ConclusionsAn unreactive EEG background and SE predicted poor functional outcome and in-hospital mortality in cardiac arrest patients undergoing TTM. Prognostic value of pure SB is confounded by use of sedative agents, and its use on prognostication decisions should be made with caution.

West Syndrome, Severe Developmental Retardation, and Intermittent Horizontal Saccade Failure: An Expanded Spectrum of STXBP1-Epileptic Encephalopathy

Background/Purpose: Mutations in the STXBP1 gene, encoding the syntaxin binding protein 1, have been described in Ohtahara syndrome or early infantile epileptic encephalopathy with suppression burst pattern and in other early epileptic encephalopathies, like West syndrome.

The Dorsal Visual System Predicts Future and Remembers Past Eye Position.

Eye movements are essential to primate vision but introduce potentially disruptive displacements of the retinal image. To maintain stable vision, the brain is thought to rely on neurons that carry both visual signals and information about the current direction of gaze in their firing rates. We have shown previously that these neurons provide an accurate representation of eye position during fixation, but whether they are updated fast enough during saccadic eye movements to support real-time vision remains controversial. Here we show that not only do these neurons carry a fast and accurate eye-position signal, but also that they support in parallel a range of time-lagged variants, including predictive and post dictive signals. We recorded extracellular activity in four areas of the macaque dorsal visual cortex during a saccade task, including the lateral and ventral intraparietal areas (LIP, VIP), and the middle temporal (MT) and medial superior temporal (MST) areas. As reported previously, neurons showed tonic eye-position-related activity during fixation. In addition, they showed a variety of transient changes in activity around the time of saccades, including relative suppression, enhancement, and pre-saccadic bursts for one saccade direction over another. We show that a hypothetical neuron that pools this rich population activity through a weighted sum can produce an output that mimics the true spatiotemporal dynamics of the eye. Further, with different pooling weights, this downstream eye position signal (EPS) could be updated long before (<100 ms) or after (<200 ms) an eye movement. The results suggest a flexible coding scheme in which downstream computations have access to past, current, and future eye positions simultaneously, providing a basis for visual stability and delay-free visually-guided behavior.

Neonatal Seizures and Inborn Errors of Metabolism: An Update

Early identification of an underlying inborn error of metabolism in newborns with otherwise unexplained seizures may address appropriate disease-specific treatment and provide important tools about the choice of the antiepileptic drugs. Neonatal seizures usually present as prolonged or recurrent, often configuring epileptic status. Striking features of an underlying metabolic disorder include abnormal neurological examination, lethargy and/ or symptoms of acute decompensation. Ex adiuvantibus, trial with intravenous pyridoxine administration could be attempted in refractory unexplained neonatal seizures. Peculiar EEG patterns such as Suppression Burst may address diagnosis and laboratory work-up being most frequently associated to specific metabolic disorders.