Epileptic Encephalopathy Of Infancy Research Articles

Monogenic developmental and epileptic encephalopathies of infancy and childhood, a population cohort from Norway.

IntroductionDevelopmental and epileptic encephalopathies (DEE) is a group of epilepsies where the epileptic activity, seizures and the underlying neurobiology contributes to cognitive and behavioral impairments. Uncovering the causes of DEE is important in order to develop guidelines for treatment and follow-up. The aim of the present study was to describe the clinical picture and to identify genetic causes in a patient cohort with DEE without known etiology, from a Norwegian regional hospital.MethodsSystematic searches of medical records were performed at Drammen Hospital, Vestre Viken Health Trust, to identify patients with epilepsy in the period 1999–2018. Medical records were reviewed to identify patients with DEE of unknown cause. In 2018, patients were also recruited consecutively from treating physicians. All patients underwent thorough clinical evaluation and updated genetic diagnostic analyses.ResultsFifty-five of 2,225 patients with epilepsy had DEE of unknown etiology. Disease-causing genetic variants were found in 15/33 (45%) included patients. Three had potentially treatable metabolic disorders (SLC2A1, COQ4 and SLC6A8). Developmental comorbidity was higher in the group with a genetic diagnosis, compared to those who remained undiagnosed. Five novel variants in known genes were found, and the patient phenotypes are described.ConclusionThe results from this study illustrate the importance of performing updated genetic investigations and/or analyses in patients with DEE of unknown etiology. A genetic cause was identified in 45% of the patients, and three of these patients had potentially treatable conditions where available targeted therapy may improve patient outcome.

Pulse Methylprednisolone with Oral Prednisolone versus Adrenocorticotropic Hormone in Children with West Syndrome: a Randomized Controlled Trial.

Background and PurposeWest syndrome is an epileptic encephalopathy of infancy. According to guidelines, adrenocorticotrophic hormone (ACTH) is probably effective for the short-term management of infantile spasm, but there is little uniformity in treatment due to variable response. This study has been done to evaluate the efficacy of pulse methylprednisolone as compared to ACTH in children with West syndrome.MethodsChildren between 3 months to 24 months with the diagnosis of West syndrome were included and ACTH and pulse methyl prednisolone followed by oral prednisolone were given after randomization. Total duration of treatment was 6 weeks in both groups.ResultsTotal 87 children were enrolled; 12 patients lost in follow up. Finally, 43 received ACTH and 32 received pulse methylprednisolone. In pulse methylprednisolone group, 28.13% showed 50–80% response, 28.13% showed 80–99% response and 21.87% patients showed 100% response. In ACTH group, 41.86% showed 50–80% response, 25.58% showed 80–99% response and only 3 (6.97%) patients showed 100% response. Methylprednisolone treatment regimen did not cause significant or persistent adverse effects.ConclusionsPulse methylprednisolone followed by oral prednisolone for 6 weeks is as effective as ACTH. Thus, methylprednisolone therapy can be an important alternative to ACTH.

The link between brain acidosis, breathing and seizures: a novel mechanism of action for the ketogenic diet in a model of infantile spasms.

Infantile spasms (IS) syndrome is a catastrophic, epileptic encephalopathy of infancy that is often refractory to current antiepileptic therapies. The ketogenic diet (KD) has emerged as an alternative treatment for patients with medically intractable epilepsy, though the prospective validity and mechanism of action for IS remains largely unexplored. We investigated the KD's efficacy as well as its mechanism of action in a rodent model of intractable IS. The spasms were induced using the triple-hit paradigm and the animals were then artificially reared and put on either the KD (4:1 fats: carbohydrate + protein) or a control milk diet (CM; 1.7:1). 31Phosphorus magnetic resonance spectroscopy (31P MRS) and head-out plethysmography were examined in conjunction with continuous video-EEG behavioural recordings in lesioned animals and sham-operated controls. The KD resulted in a peripheral ketosis observed both in the blood and urine. The KD led to a robust reduction in the frequency of spasms observed, with approximately a 1.5-fold increase in the rate of survival. Intriguingly, the KD resulted in an intracerebral acidosis as measured with 31P MRS. In addition, the respiratory profile of the lesioned rats on the KD was significantly altered with slower, deeper and longer breathing, resulting in decreased levels of expired CO2. Sodium bicarbonate supplementation, acting as a pH buffer, partially reversed the KD's protective effects on spasm frequency. There were no differences in the mitochondrial respiratory profiles in the liver and brain frontal cortex measured between the groups, supporting the notion that the effects of the KD on breathing are not entirely due to changes in intermediary metabolism. Together, our results indicate that the KD produces its anticonvulsant effects through changes in respiration leading to intracerebral acidosis. These findings provide a novel understanding of the mechanisms underlying the anti-seizure effects of the KD in IS. Further research is required to determine whether the effects of the KD on breathing and intracerebral acid-base balance are seen in other paediatric models of epilepsy.

Role of Aberrant Spontaneous Neurotransmission in SNAP25-Associated Encephalopathies

SNARE (soluble N-ethylmaleimide sensitive factor attachment protein receptor) complex, composed of synaptobrevin, syntaxin, and SNAP25, forms the essential fusion machinery for neurotransmitter release. Recent studies have reported several mutations in the gene encoding SNAP25 as a causative factor for developmental and epileptic encephalopathies of infancy and childhood with diverse clinical manifestations. However, it remains unclear how SNAP25 mutations give rise to these disorders. Here, we show that although structurally clustered mutations in SNAP25 give rise to related synaptic transmission phenotypes, specific alterations in spontaneous neurotransmitter release are a key factor to account for disease heterogeneity. Importantly, we identified a single mutation that augments spontaneous release without altering evoked release, suggesting that aberrant spontaneous release is sufficient to cause disease in humans.

Malignant migratory partial seizures of infancy: description of clinical observations

Epileptic encephalopathies of infancy are difficult-to-treat destructive cases of epilepsy in infants and young children, which include the two clinical observations of Coppola Dulac syndrome (malignant migrating partial attacks of infancy) given in this article. Epileptic encephalopathies are a genetically heterogeneous group of disorders that are characterized by the presence of a convulsive syndrome and are accompanied by cognitive and behavioral disorders. As a result of intensive development of methods of molecular genetic research, ideas about the causes of epilepsy in children began to change, this fact led to the fact that the international League against epilepsy replaced the term idiopathic epilepsy with genetic epilepsy. To date, about 60 phenotypic variants of early epileptic encephalopathies have been registered in children, including those associated with mutations of genes that regulate the functions of voltage-dependent calcium and sodium channels. In our work, we consider clinical observations of genetic epileptic encephalopathies caused by mutations in the CACNA1A and SCN8A genes, respectively, which are channelopathy. Malignant migrating partial attacks of infancy (infant epilepsy with migrating focal attacks, Coppola Dulac syndrome) are manifested at an early age, from the first days to 6 months of life, and are characterized by typical multifocal attacks with a tendency to change hemispheres and involve opposite limbs. G. Coppola based on the analysis of their own observations, described in 1995 a new age dependent epileptic syndrome, introducing a definition for it migrating partial attacks of infancy. Currently, it is recommended to use the term infant epilepsy with migrating focal seizures. We present our own clinical and neurophysiological observations of this rare syndrome.

Abstract TP509: Patterns of Injury in Children With Perinatal Arterial Ischemic Stroke and Infantile Spasms

Perinatal arterial ischemic stroke (AIS) occurs in 1 in 4000 live births and is the most common stroke in children. Consequences include seizures and a spectrum of cognitive and motor disability. Infantile spasms (IS) is an epileptic encephalopathy of infancy with an incidence of 2 in 10,000 live births. Approximately 5% of IS is caused by perinatal AIS. Patterns of ischemic injury that may predispose infants to IS and predict treatment response have not yet been identified. This retrospective case series of infants with AIS and IS provides detailed descriptions of ischemic distribution, seizure presentation, treatment and outcomes. Inclusion criteria were: term birth, ischemic stroke or encephalomalacia in an arterial distribution identified or presumed to have occurred in the perinatal period, a diagnosis of infantile spasms. Patients with a watershed pattern of injury were excluded. The modified pediatric ASPECTS was used to qualify and quantify the type and distribution of stroke. Areas of injury were identified on MRI and scored from T2/Flair or DWI sequences. Eleven patients with AIS and IS were identified. Of nine who fit inclusion criteria, all had MCA territory involvement with 6/9 having basal ganglia injury. Five had ischemia identified retrospectively after developing IS and four presented as neonates. The highest ASPECTS (bilateral deep MCA) was associated with the worst outcome in motor function and epilepsy control. However, the second-highest ASPECTS (unilateral MCA, bilateral ACA) had mild motor deficits and no seizure recurrence after IS resolution. The three lowest ASPECTS (<10) involved unilateral cortical MCA strokes sparing the deep structures, and also had the best motor outcome and seizure control. The co-occurrence of perinatal AIS and IS often results in significant neurologic disability. Although there was no defined pattern of regional homogeneity, there was a trend towards basal ganglia injury with progression of epilepsy after IS. This study highlights that size of ischemic injury may be less important than location as a predictor of motor outcome and seizure intractability. Future research will focus on identifying areas of injury that may confer increased risk of IS compared to stroke patients who remain seizure-free.

The genetic landscape of the epileptic encephalopathies of infancy and childhood

The genetic landscape of the epileptic encephalopathies of infancy and childhood

Strain- and age-dependent hippocampal neuron sodium currents correlate with epilepsy severity in Dravet syndrome mice

Heterozygous loss-of-function SCN1A mutations cause Dravet syndrome, an epileptic encephalopathy of infancy that exhibits variable clinical severity. We utilized a heterozygous Scn1a knockout (Scn1a+/−) mouse model of Dravet syndrome to investigate the basis for phenotype variability. These animals exhibit strain-dependent seizure severity and survival. Scn1a+/− mice on strain 129S6/SvEvTac (129.Scn1a+/−) have no overt phenotype and normal survival compared with Scn1a+/− mice bred to C57BL/6J (F1.Scn1a+/−) that have severe epilepsy and premature lethality. We tested the hypothesis that strain differences in sodium current (INa) density in hippocampal neurons contribute to these divergent phenotypes. Whole-cell voltage-clamp recording was performed on acutely-dissociated hippocampal neurons from postnatal days 21–24 (P21–24) 129.Scn1a+/− or F1.Scn1a+/− mice and wild-type littermates. INa density was lower in GABAergic interneurons from F1.Scn1a+/− mice compared to wild-type littermates, while on the 129 strain there was no difference in GABAergic interneuron INa density between 129.Scn1a+/− mice and wild-type littermate controls. By contrast, INa density was elevated in pyramidal neurons from both 129.Scn1a+/− and F1.Scn1a+/− mice, and was correlated with more frequent spontaneous action potential firing in these neurons, as well as more sustained firing in F1.Scn1a+/− neurons. We also observed age-dependent differences in pyramidal neuron INa density between wild-type and Scn1a+/− animals. We conclude that preserved INa density in GABAergic interneurons contributes to the milder phenotype of 129.Scn1a+/− mice. Furthermore, elevated INa density in excitatory pyramidal neurons at P21–24 correlates with age-dependent onset of lethality in F1.Scn1a+/− mice. Our findings illustrate differences in hippocampal neurons that may underlie strain- and age-dependent phenotype severity in a Dravet syndrome mouse model, and emphasize a contribution of pyramidal neuron excitability.

Activation of Slack Channels Alters their Interactions with the Pp1 Targeting Protein Phactr1

Slack Na+-activated K+ channels contribute to neuronal adaptation during sustained stimulation and regulate the temporal accuracy of action potentials. The C-terminus of Slack interacts with the mRNA-binding protein FMRP (Fragile X Mental Retardation protein). Using yeast-two hybrid and co-immunopurification experiments we have established the Slack binds Phactr1, a Protein Phosphatase 1 targeting protein. This interaction likely regulates the modulation of Slack by protein kinase C (PKC), which increases current amplitude and slows the rate of activation rate by phosphorylation of a specific serine (S407) in the Slack cytoplasmic C-terminus. Using resonance wavelength grating optical biosensors, we have determined that phosphorylation of Slack at S407 by PKC produces a sustained decrease in mass near the plasma membrane. The decrease in mass requires the very C-terminal domain of Slack, previously shown to be required for Slack/FMRP interactions. To determine whether the decrease in mass results from the translocation of either FMRP or Phactr1 from the channel upon activation, RNAi was used to suppress expression of FMRP, Phactr1 and other potential partners. The presence of Phactr1, but not FMRP, was found selectively to be required to observe a decrease in mass. Gain-of-function human mutations in Slack channels that mimic constitutive phosphorylation at S407 cause malignant migrating partial seizures of infancy (MMPSI), an epileptic encephalopathy of infancy that combines seizures with severe developmental delay. Activation of PKC does not produce a change of mass in these mutant channels, suggesting that Phactr1 fails to associate/dissociate. Our results suggest that activation of Slack alters its interaction with Phactr1, which may influence the phosphorylation state of Slack, but also of associated proteins such as FMRP, providing a link between channel activation and downstream signaling pathway that regulate normal neuronal development and intellectual ability.

Progress of the syndrome of malignant migrating partial seizures in infancy

The syndrome of malignant migrating partial seizures in infancy (MMPSI) is one of the most severe epileptic encephalopathies of infancy onset.It has been firstly reported by Coppola in 1995.There have been approximately 80 cases reported worldwide by now,but there is no case reported in our country.The etiology for MMPSI is still unknown,the diagnosis is difficult,and conventional antiepileptic drugs have little efficacy.This paper reviews the possible causes,clinical characteristics,diagnosis and treatment of MMPSI. Key words: Epilepsy; Malignant migrating partial seizures in infancy; Epileptic encephalopathy; Electroencephalogram

Phospholipase C beta 1 deficiency is associated with early-onset epileptic encephalopathy

The epileptic encephalopathies of infancy and childhood are a collection of epilepsy disorders characterized by refractory, severe seizures and poor neurological outcome, in which the mechanism of disease is poorly understood. We report the clinical presentation and evolution of epileptic encephalopathy in a patient, associated with a loss-of-function mutation in the phospholipase C-β 1 gene. We ascertained a consanguineous family containing a male infant who presented with early-onset epileptic encephalopathy for detailed clinical phenotyping and molecular genetic investigation. In addition, a cohort of 12 consanguineous families of children with infantile spasms were analysed for linkage to the phospholipase C-β 1 gene locus. The male infant presented with tonic seizures in early infancy and subsequently developed infantile spasms. Over time, he developed drug-resistant epilepsy associated with severe neurological regression and failure to thrive. Molecular genetic investigation revealed a homozygous loss-of-function 0.5-Mb deletion, encompassing the promoter element and exons 1, 2 and 3 of phospholipase C-β 1 in the index case. Linkage to the phospholipase C-β 1 locus was excluded in the 12 other consanguineous families, consistent with genetic heterogeneity in this disorder. Although phospholipase C-β 1 deficiency has not previously been reported in humans, the Plcb1 homozygote knockout mouse displays early-onset severe tonic seizures and growth retardation, thus recapitulating the human phenotype. Phospholipase C-β 1 has important functions in both hippocampal muscarinic acetylcholine receptor signalling and in cortical development. Thus, the discovery of a phospholipase C-β 1 mutation allows us to propose a novel potential underlying mechanism in early-onset epileptic encephalopathy.

The Epileptic Encephalopathies of Infancy and Childhood

The epileptic encephalopathies comprise a group of devastating seizure syndromes which begin in infancy and early childhood and usually result in intractable epilepsy. While some syndromes are relatively easily diagnosed early in their course, others take time to evolve, hampering an early, confident diagnosis. Epileptic encephalopathies are associated with slowing of cognitive function and evolution of severe behavioral disorders, which are often more distressing to families than the epilepsy. While an underlying etiology may explain some of this co-morbidity, many children have no identifiable etiology found for their seizures. In these "idiopathic" cases, recurrent subtle seizures, frequent epileptiform discharge and non-convulsive status epilepticus probably all play a role in deterioration of cognitive function and evolution of behavior disorders. This paper will review the most common epileptic encephalopathy syndromes, discuss the cognitive and behavioral co-morbidities and review current therapeutic options.

Encephalopathie myoclonique precoce avec epilepsie

The authors describe the electroclinical and evolutive aspects of 4 cases (including 2 brothers) of myoclonic epileptic encephalopathy beginning between 2 days and 10 weeks of life. From the onset of myoclonic jerks, polymorphous fits (partial seizures, tonic seizures) and multifocal electrical abnormalities are associated. Repeated spasms and 'suppression-burst' patterns appear later. The neurological status deteriorates progressively, leading within a few months to decerebration posture with opisthotonus. In spite of thorough neuroradiological, biochemical, cytological to metabolic investigations, etiology remains unknown. However, the electroclinical and evolutive patterns are similar to that of metabolic diseases, especially non-ketotic hyperglycemia. The authors discuss the relations between their observations and those in the literature and the nosological problems of this particular epileptic encephalopathy of infancy.