New-onset refractory status epilepticus and febrile infection-related epilepsy syndrome.

PURPOSE OF REVIEW: The concept and understanding of new-onset refractory status epilepticus (NORSE), and its subtype with prior fever known as febrile infection-related epilepsy syndrome (FIRES) have evolved in the recent past. This review aims to summarize the recent developments in the pathophysiology, diagnosis and management of these challenging conditions. RECENT FINDINGS: NORSE and FIRES can have many different causes. Although the list of possible causes is still growing, they mostly fall in the categories of autoimmune encephalitis and genetic disorders. However, despite extensive investigations, most cases of NORSE and FIRES remain cryptogenic. Recent studies have pointed towards the key role of autoinflammation as a unifying pathophysiological mechanism in these cases. These findings also support the use of immunomodulatory treatment in this setting. Consensus recommendations on the management of NORSE and FIRES have recently been published. SUMMARY: NORSE and FIRES remain challenging conditions to diagnose and treat. Recent findings from clinical and basic research and new recommendations, reviewed in this article, contribute to an emerging framework for management and future research.

Febrile infection-related Epilepsy Syndrome (FIRES): a severe encephalopathy with status epilepticus. Literature review and presentation of two new cases.

FIRES is defined as a disorder that requires a prior febrile infection starting between 2 weeks and 24 h before the onset of the refractory status epilepticus with or without fever at the onset of status epilepticus. The patients, previously normal, present in the acute phase recurrent seizures and status epilepticus followed by a severe course with usually persistent seizures and residual cognitive impairment. Boundary with "new onset refractory status epilepticus (NORSE) has not clearly established. Pathogenetic hypothesis includes inflammatory or autoimmune mechanism with a possible genetic predisposition for an immune response dysfunction.Various types of treatment have been proposed for the treatment of the acute phase of the disorder to block the rapid seizures evolution to status epilepticus and to treat status epilepticus itself. Prognosis is usually severe both for control of the seizures and for cognitive involvement.FIRES is an uncommon but severe disorder which must be carefully considered in the differential diagnosis with other epileptic encephalopathy.

CDKL5 deficiency disorder: molecular insights and mechanisms of pathogenicity to fast-track therapeutic development.

CDKL5 deficiency disorder (CDD) is an X-linked brain disorder of young children and is caused by pathogenic variants in the cyclin-dependent kinase-like 5 (CDKL5) gene. Individuals with CDD suffer infantile onset, drug-resistant seizures, severe neurodevelopmental impairment and profound lifelong disability. The CDKL5 protein is a kinase that regulates key phosphorylation events vital to the development of the complex neuronal network of the brain. Pathogenic variants identified in patients may either result in loss of CDKL5 catalytic activity or are hypomorphic leading to partial loss of function. Whilst the progressive nature of CDD provides an excellent opportunity for disease intervention, we cannot develop effective therapeutics without in-depth knowledge of CDKL5 function in human neurons. In this mini review, we summarize new findings on the function of CDKL5. These include CDKL5 phosphorylation targets and the consequence of disruptions on signaling pathways in the human brain. This new knowledge of CDKL5 biology may be leveraged to advance targeted drug discovery and rapid development of treatments for CDD. Continued development of effective humanized models will further propel our understanding of CDD biology and may permit the development and testing of therapies that will significantly alter CDD disease trajectory in young children.

Combined immunoglobulin and plasmapheresis treatment for Febrile Infection-Related Epilepsy Syndrome (FIRES).

Febrile infection-related epilepsy syndrome (FIRES) is a rarely observed and destructive syndrome progressing with resistant seizures or refractory status epilepticus. In this report we present in a treatment procedure with plasmapheresis of a pediatric patient with FIRES and currently unknown etiology in order to contribute to the literature.

A case of febrile infection-related epilepsy syndrome (FIRES) in young adult: still a diagnostic and therapeutic challenge.

A new onset of status epilepticus in a previously healthy adult preceded by a recent minor febrile infection represents a diagnostic and therapeutic challenge in clinical practice. Considering the broad spectrum of epileptic encephalopathies caused by autoimmune mechanisms, differential diagnosis for new-onset refractory status epilepticus (NORSE) should include febrile infection-related epilepsy syndrome (FIRES), in order to not underestimate the underlying etiological condition triggering epilepsy in non-epileptic patients (Hon et al. in Recent Pat Inflamm Allergy Drug Discov 12:128-135, 2018). We report a case of acute encephalopathy with refractory seizures after a febrile illness (FIRES) in a young adult with complete remission of symptoms as well as dramatic improvement of EEG abnormalities following intravenous immunoglobulin and proper antiepileptic medications. We conducted an extensive workup including lumbar puncture, blood tests, EEG serial monitoring, MRI brain, total body CT scan, and PET brain with FDG to shed light on the etiology of the disease.

Genetic Epilepsy Syndromes.

PURPOSE OF REVIEW: This article reviews the clinical features, typical EEG findings, treatment, prognosis, and underlying molecular etiologies of the more common genetic epilepsy syndromes. Genetic generalized epilepsy, self-limited focal epilepsy of childhood, self-limited neonatal and infantile epilepsy, select developmental and epileptic encephalopathies, progressive myoclonus epilepsies, sleep-related hypermotor epilepsy, photosensitive occipital lobe epilepsy, and focal epilepsy with auditory features are discussed. Also reviewed are two familial epilepsy syndromes: genetic epilepsy with febrile seizures plus and familial focal epilepsy with variable foci. RECENT FINDINGS: Recent years have seen considerable advances in our understanding of the genetic factors underlying genetic epilepsy syndromes. New therapies are emerging for some of these conditions; in some cases, these precision medicine approaches may dramatically improve the prognosis. SUMMARY: Many recognizable genetic epilepsy syndromes exist, the identification of which is a crucial skill for neurologists, particularly those who work with children. Proper diagnosis of the electroclinical syndrome allows for appropriate treatment choices and counseling regarding prognosis and possible comorbidities.

CDKL5 deficiency disorder: clinical features, diagnosis, and management.

CDKL5 deficiency disorder (CDD) was first identified as a cause of human disease in 2004. Although initially considered a variant of Rett syndrome, CDD is now recognised as an independent disorder and classified as a developmental epileptic encephalopathy. It is characterised by early-onset (generally within the first 2 months of life) seizures that are usually refractory to polypharmacy. Development is severely impaired in patients with CDD, with only a quarter of girls and a smaller proportion of boys achieving independent walking; however, there is clinical variability, which is probably genetically determined. Gastrointestinal, sleep, and musculoskeletal problems are common in CDD, as in other developmental epileptic encephalopathies, but the prevalence of cerebral visual impairment appears higher in CDD. Clinicians diagnosing infants with CDD need to be familiar with the complexities of this disorder to provide appropriate counselling to the patients' families. Despite some benefit from ketogenic diets and vagal nerve stimulation, there has been little evidence that conventional antiseizure medications or their combinations are helpful in CDD, but further treatment trials are finally underway.

New-onset refractory status epilepticus (NORSE) and febrile infection-related epilepsy syndrome (FIRES) of unknown aetiology: A comparison of the incomparable?

PURPOSE: The discussion is ongoing whether new-onset refractory status epilepticus (NORSE) in adults and febrile infection-related epilepsy syndrome (FIRES) in children are one syndrome if the aetiology is unknown. In this study we will compare an adult cohort with NORSE and a paediatric cohort with FIRES in order to determine if they are similar or different. METHODS: We retrospectively compared 18 adults with NORSE versus 48 children with FIRES, both cohorts without identifiable cause despite extensive investigations. We analyzed demographic and clinical data using Mann-Whitney-U and χ2- tests. RESULTS: NORSE affected more women (78% vs. 42%; P = 0.009) than in FIRES. Median acute hospital stay was longer in FIRES (35 days [interquartile range, IQR=36] vs. 20 days [IQR=19]; P<0.001). FIRES was treated more frequently with coma therapy (82% vs. 28%; P<0.001) and with a higher median number of antiseizure medicines (7 [IQR=5] vs. 4 [IQR=2]; P<0.001). Children with FIRES showed a higher cerebrospinal fluid (CSF) cell count (10 cells/µl; P = 0.002) but a lower CSF protein level than adults with NORSE (48 mg/dl; P = 0.028). Immunotherapy was administered more frequently in FIRES (73% vs. 22%; P<0.001) than in NORSE. Group differences in number of antiseizure medicines after hospital stay (P = 0.229) and in overall mortality (P = 0.327) were not significant. CONCLUSION: In our explorative comparison, differences prevailed. NORSE and FIRES should be compared prospectively in age-matched cohorts.

Unraveling the enigma of new-onset refractory status epilepticus: a systematic review of aetiologies.

BACKGROUND AND PURPOSE: New-onset refractory status epilepticus (NORSE) is a clinical presentation, neither a specific diagnosis nor a clinical entity. It refers to a patient without active epilepsy or other pre-existing relevant neurological disorder, with a NORSE without a clear acute or active structural, toxic or metabolic cause. This study reviews the currently available evidence about the aetiology of patients presenting with NORSE and NORSE-related conditions. METHODS: A systematic search was carried out for clinical trials, observational studies, case series and case reports including patients who presented with NORSE, febrile-infection-related epilepsy syndrome or the infantile hemiconvulsion-hemiplegia and epilepsy syndrome. RESULTS: Four hundred and fifty records were initially identified, of which 197 were included in the review. The selected studies were retrospective case-control (n = 11), case series (n = 83) and case reports (n = 103) and overall described 1334 patients both of paediatric and adult age. Aetiology remains unexplained in about half of the cases, representing the so-called 'cryptogenic NORSE'. Amongst adult patients without cryptogenic NORSE, the most often identified cause is autoimmune encephalitis, either non-paraneoplastic or paraneoplastic. Infections are the prevalent aetiology of paediatric non-cryptogenic NORSE. Genetic and congenital disorders can have a causative role in NORSE, and toxic, vascular and degenerative conditions have also been described. CONCLUSIONS: Far from being a unitary condition, NORSE is a heterogeneous and clinically challenging presentation. The development and dissemination of protocols and guidelines to standardize diagnostic work-up and guide therapeutic approaches should be implemented. Global cooperation and multicentre research represent priorities to improve the understanding of NORSE.

Sevoflurane as bridge therapy for plasma exchange and Anakinra in febrile infection-related epilepsy syndrome.

Febrile infection-related epilepsy syndrome (FIRES) is a devastating immune inflammatory-mediated epileptic encephalopathy. Herein, we discuss a previously healthy 8-year-old boy with FIRES in whom high dosages of conventional and nonconventional anesthetics were ineffective in treating SE, as were ketogenic diet, intravenous corticosteroids, and immunoglobulins. After 29 days of prolonged SRSE, the patient was successfully treated with sevoflurane paired with plasma exchange, for a total of five days, thus obtaining a stable EEG suppression burst pattern with no adverse events. Anakinra at the dosage of 100 mg b.i.d. was started seven days after sevoflurane and plasma exchange had been discontinued and was effective in ensuring non-recurrence of SE. Sevoflurane as bridge therapy for immunosuppressive treatment could be considered an early, safe, and effective option in treating convulsive SE in which an autoimmune-inflammatory etiology can reasonably be hypothesized.

Current neurologic treatment and emerging therapies in CDKL5 deficiency disorder.

BACKGROUND: CDKL5 deficiency disorder (CDD) is associated with refractory infantile onset epilepsy, global developmental delay, and variable features that include sleep, behavioral disturbances, and movement disorders. Current treatment is primarily symptom-based and informed by experience in caring for this population. METHODS: We describe medication and non-medication approaches to treatment of epilepsy and additional key neurologic symptoms (sleep disturbances, behavioral issues, movement disorders, and swallowing dysfunction) in a cohort of 177 individuals meeting criteria for CDD, 154 evaluated at 4 CDKL5 Centers of Excellence in the USA and 40 identified through the NIH Natural History Study of Rett and Related Disorders. RESULTS: The four most frequently prescribed anti-seizure medications were broad spectrum, prescribed in over 50% of individuals. While the goal was not to ascertain efficacy, we obtained data from 86 individuals regarding response to treatment, with 2-week response achieved in 14-48% and sustained 3-month response in 5-36%, of those with known response. Additional treatments for seizures included cannabis derivatives, tried in over one-third of individuals, and clinical trial medications. In combination with pharmacological treatment, 50% of individuals were treated with ketogenic diet for attempted seizure control. Surgical approaches included vagus nerve stimulators, functional hemispherectomy, and corpus callosotomy, but numbers were too limited to assess response. Nearly one-third of individuals received pharmacologic treatment for sleep disturbances, 13% for behavioral dysregulation and movement disorders, and 43% had gastrostomy tubes. CONCLUSIONS: Treatment for neurologic features of CDD is currently symptom-based and empiric rather than CDD-specific, though clinical trials for CDD are emerging. Epilepsy in this population is highly refractory, and no specific anti-seizure medication was associated with improved seizure control. Ketogenic diet is commonly used in patients with CDD. While behavioral interventions are commonly instituted, information on the use of medications for sleep, behavioral management, and movement disorders is sparse and would benefit from further characterization and optimization of treatment approaches. The heterogeneity in treatment approaches highlights the need for systematic review and guidelines for CDD. Additional disease-specific and disease-modifying treatments are in development.

CDKL5 Deficiency Augments Inhibitory Input into the Dentate Gyrus That Can Be Reversed by Deep Brain Stimulation.

Cognitive impairment is a core feature of cyclin-dependent kinase-like 5 (CDKL5) deficiency, a neurodevelopmental disorder characterized by early epileptic seizures, intellectual disability, and autistic behaviors. Although loss of CDKL5 affects a number of molecular pathways, very little has been discovered about the physiological effects of these changes on the neural circuitry. We therefore studied synaptic plasticity and local circuit activity in the dentate gyrus of both Cdkl5-/y and Cdkl5+/- mutant mice. We found that CDKL5 haploinsufficiency in both male and female mice impairs hippocampus-dependent learning and memory in multiple tasks. In vivo, loss of CDKL5 reduced LTP of the perforant path to the dentate gyrus and augmented feedforward inhibition in this pathway; ex vivo experiments confirmed that excitatory/inhibitory input into the dentate gyrus is skewed toward inhibition. Injecting the GABAergic antagonist gabazine into the dentate improved contextual fear memory in Cdkl5-/y mice. Finally, chronic forniceal deep brain stimulation rescued hippocampal memory deficits, restored synaptic plasticity, and relieved feedforward inhibition in Cdkl5+/- mice. These results indicate that CDKL5 is important for maintaining proper dentate excitatory/inhibitory balance, with consequences for hippocampal memory.SIGNIFICANCE STATEMENT Cognitive impairment is a core feature of cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder. Although CDKL5 deficiency has been found to affect a number of molecular pathways, little is known about its physiological effects on the neural circuitry. We find that CDKL5 loss reduces hippocampal synaptic plasticity and augments feedforward inhibition in the perforant path to the dentate gyrus in vivo in Cdkl5 mutant mice. Chronic forniceal deep brain stimulation rescued hippocampal memory deficits, restored synaptic plasticity, and relieved feedforward inhibition in Cdkl5+/- mice, as it had previously done with Rett syndrome mice, suggesting that such stimulation may be useful for other neurodevelopmental disorders.

Epilepsy Syndromes in the First Year of Life and Usefulness of Genetic Testing for Precision Therapy.

The high pace of gene discovery has resulted in thrilling advances in the field of epilepsy genetics. Clinical testing with comprehensive gene panels, exomes, or genomes are now increasingly available and have led to a significant higher diagnostic yield in early-onset epilepsies and enabled precision medicine approaches. These have been instrumental in providing insights into the pathophysiology of both early-onset benign and self-limited syndromes and devastating developmental and epileptic encephalopathies (DEEs). Genetic heterogeneity is seen in many epilepsy syndromes such as West syndrome and epilepsy of infancy with migrating focal seizures (EIMFS), indicating that two or more genetic loci produce the same or similar phenotypes. At the same time, some genes such as SCN2A can be associated with a wide range of epilepsy syndromes ranging from self-limited familial neonatal epilepsy at the mild end to Ohtahara syndrome, EIFMS, West syndrome, Lennox-Gastaut syndrome, or unclassifiable DEEs at the severe end of the spectrum. The aim of this study was to review the clinical and genetic heterogeneity associated with epilepsy syndromes starting in the first year of life including: Self-limited familial neonatal, neonatal-infantile or infantile epilepsies, genetic epilepsy with febrile seizures plus spectrum, myoclonic epilepsy in infancy, Ohtahara syndrome, early myoclonic encephalopathy, West syndrome, Dravet syndrome, EIMFS, and unclassifiable DEEs. We also elaborate on the advantages and pitfalls of genetic testing in such conditions. Finally, we describe how a genetic diagnosis can potentially enable precision therapy in monogenic epilepsies and emphasize that early genetic testing is a cornerstone for such therapeutic strategies.

Epilepsy: Epileptic Syndromes and Treatment.

Epilepsy can now be diagnosed even in the presence of one unprovoked seizure or if the diagnosis of an epilepsy syndrome can be made. Epilepsy syndromes represent a specific set of seizure types and electroencephalographic and imaging features that tend to have age-dependent features, triggers, and prognosis. Epilepsy syndromes are the third and final level of epilepsy diagnosis, after classification of seizure and epilepsy types. Some epilepsy syndromes are self-limiting and pharmacoresponsive and others are pharmacoresistant and associated with poor developmental outcomes (epileptic and developmental encephalopathy). Features and management of 7 common age-dependent pediatric epilepsy syndromes are described.

Clinical profile and treatment outcome of epilepsy syndromes in children: A hospital-based study in Eastern Nepal.

Objective: It is often difficult to diagnose epilepsy syndromes in resource-limited settings. This study was aimed to investigate the prospect of ascertaining the diagnosis, clinical profile, and treatment outcomes of epilepsy syndromes (ESs) among children in a resource-limited setting. Methods: This was a descriptive study done from 01/07/2009 to 15/06/2017 among children (1-17 years of age) with unprovoked seizures presenting to the pediatric neurology clinic of a university hospital in eastern Nepal. Diagnosis, classification, and treatment of seizures were based upon International League Against Epilepsy guidelines. Results: Of 768 children with unprovoked seizures, 120 (15.6%) were diagnosed as ES. The age of onset of seizure was unique for each ES. Developmental delay and cerebral palsy were present in 47.5% and 28.3% children, respectively. Common ESs were West syndrome (WS)-26.7%, generalized tonic-clonic seizures alone (GTCSA)-21.7%, self-limited childhood epilepsy with centrotemporal spikes (SLCECTS)-12.5%, childhood absence epilepsy (CAE)-10.0%, Lennox-Gastaut syndrome (LGS)-10.0%, other developmental and epileptic encephalopathies (DEE)-5.8%, self-limited familial infantile epilepsy (SLFIE)-4.2%, and juvenile myoclonic epilepsy (JME)-3.3%. Among children with known outcomes (87/120), overall response to pharmacotherapy and to monotherapy was observed in 72.4% (63/87) and 57.5% (50/87) children, respectively. All children with GTCSA, SLFIE, genetic epilepsy with febrile seizure plus (GEFS+), CAE, SLCECTS, and JME responded to pharmacotherapy and they had normal computerized tomography scans of the brain. Seizures were largely pharmaco-resistant in progressive myoclonus epilepsy (PME)-100.0%, LGS-73.0%, WS-52.0%, and other DEEs-40%. Significance: A reasonable proportion (15.6%) of unprovoked seizures could be classified into specific ES despite limited diagnostic resources. WS was the most common ES. GTCSA, SLCECTS, CAE, and LGS were other common ESs. GTCSA, SLFIE, CAE, SLCECTS, GEFS+, and JME were largely pharmaco-responsive. PME, WS, and LGS were relatively pharmaco-resistant. Electro-clinical diagnosis of certain ES avoids the necessity of neuroimaging.

Developmental and epileptic encephalopathies: recognition and approaches to care.

The term "developmental and epileptic encephalopathy" (DEE) refers to when cognitive functions are influenced by both seizure and interictal epileptiform activity and the neurobiological process behind the epilepsy. Many DEEs are related to gene variants and the onset is typically during early childhood. In this setting, neurocognition, whilst not improved by seizure control, may benefit from some precision therapies. In patients with non-progressive diseases with cognitive impairment and co-existing epilepsy, in whom the epileptiform activity does not affect or has minimal effect on function, the term "developmental encephalopathy" (DE) can be used. In contrast, for those patients with direct impact on cognition due to epileptic or epileptiform activity, the term "epileptic encephalopathy" (EE) is preferred, as most can revert to their normal or near normal baseline cognitive state with appropriate intervention. These children need aggressive treatment. Clinicians must tailor care towards individual needs and realistic expectations for each affected person; those with DE are unlikely to gain from aggressive antiseizure medication whilst those with EE will gain. Patients with DEE might benefit from a precision medicine approach in order to reduce the overall burden of epilepsy.

Clinical manifestations and epilepsy treatment in Japanese patients with pathogenic CDKL5 variants.

OBJECTIVE: Patients with pathogenic cyclin-dependent kinase-like-5 gene (CDKL5) variants are designated CDKL5 deficiency disorder (CDD). This study aimed to delineate the clinical characteristics of Japanese patients with CDD and elucidate possible appropriate treatments. METHODS: We recruited patients with pathogenic or likely pathogenic CDKL5 variants from a cohort of approximately 1,100 Japanese patients with developmental and epileptic encephalopathies, who underwent genetic analysis. We retrospectively reviewed clinical, electroencephalogram, neuroimaging, and genetic information. RESULTS: We identified 29 patients (21 females, eight males). All patients showed severe developmental delay, especially in males. Involuntary movements were observed in 15 patients. No antiepileptic drugs (AEDs) achieved seizure freedom by monotherapy. AEDs achieving ≥ 50% reduction in seizure frequency were sodium valproate in two patients, vigabatrin in one, and lamotrigine in one. Seizure aggravation was observed during the use of lamotrigine, potassium bromide, and levetiracetam. Adrenocorticotrophic hormone (ACTH) was the most effective treatment. The ketogenic diet (KD), corpus callosotomy and vagus nerve stimulation did not improve seizure frequency in most patients, but KD was remarkably effective in one. The degree of brain atrophy on magnetic resonance imaging (MRI) reflected disease severity. Compared with females, males had lower levels of attained motor development and more severe cerebral atrophy on MRI. CONCLUSION: Our patients showed more severe global developmental delay than those in previous studies and had intractable epilepsy, likely because previous studies had lower numbers of males. Further studies are needed to investigate appropriate therapy for CDD, such as AED polytherapy or combination treatment involving ACTH, KD, and AEDs.

The phenotypic spectrum of X-linked, infantile onset ALG13-related developmental and epileptic encephalopathy.

OBJECTIVE: Asparagine-linked glycosylation 13 (ALG13) deficiencies have been repeatedly described in the literature with the clinical phenotype of a developmental and epileptic encephalopathy (DEE). Most cases were females carrying the recurrent ALG13 de novo variant, p.(Asn107Ser), with normal transferrin electrophoresis. METHODS: We delineate the phenotypic spectrum of 38 individuals, 37 girls and one boy, 16 of them novel and 22 published, with the most common pathogenic ALG13 variant p.(Asn107Ser) and additionally report the phenotype of three individuals carrying other likely pathogenic ALG13 variants. RESULTS: The phenotypic spectrum often comprised pharmacoresistant epilepsy with epileptic spasms, mostly with onset within the first 6 months of life and with spasm persistence in one-half of the cases. Tonic seizures were the most prevalent additional seizure type. Electroencephalography showed hypsarrhythmia and at a later stage of the disease in one-third of all cases paroxysms of fast activity with electrodecrement. ALG13-related DEE was usually associated with severe to profound developmental delay; ambulation was acquired by one-third of the cases, whereas purposeful hand use was sparse or completely absent. Hand stereotypies and dyskinetic movements including dystonia or choreoathetosis were relatively frequent. Verbal communication skills were absent or poor, and eye contact and pursuit were often impaired. SIGNIFICANCE: X-linked ALG13-related DEE usually manifests as West syndrome with severe to profound developmental delay. It is predominantly caused by the recurrent de novo missense variant p.(Asn107Ser). Comprehensive functional studies will be able to prove or disprove an association with congenital disorder of glycosylation.