Applicability of the International League Against Epilepsy (ILAE) 2022 diagnostic criteria for epilepsy syndromes in children: A retrospective review of 1550 children with epilepsy.

OBJECTIVE: Recently, the ILAE Nosology and Definitions Task Force defined diagnostic criteria for epilepsy syndromes. There is paucity of data on the use of these new diagnostic criteria in children with epilepsy, and how these criteria may lead to changes from previous practice. METHODS: This was a retrospective chart review of data of children attending the epilepsy clinic in a tertiary care children's hospital from January 2011 to January 2023. The clinical details such as age at onset, types of seizures, co-morbidities, and results of EEG, MRI and genetic testing were reviewed. Epilepsy syndrome diagnosis was made as per the ILAE 2022 criteria, and compared with the previous syndrome diagnosis as per records. RESULTS: Data from 1550 children (63 % boys) with epilepsy were analysed, and 55.4 % children were classified to have epilepsy syndromes as per the new ILAE 2022 diagnostic criteria. Application of the new 2022 ILAE diagnostic criteria was associated with a change in name alone in 676 (77.8 %) children. Hundred (11.5 %) children were newly classified under an epilepsy syndrome who had previously remained unclassified. Eleven (1.3 %) children who were previously classified into an epilepsy syndrome could not be classified using the new diagnostic criteria. Eight (0.9 %) were shifted to a new syndromic category. Overall, change in diagnosis occurred in 13.7 (11.5 + 1.3 + 0.9)%. No change in epilepsy syndrome classification/nomenclature occurred in 74 (8.5 %) children. SIGNIFICANCE: The new diagnostic criteria led to an overall change in diagnosis in 13.7 % of children with epilepsy. These criteria will hopefully lead to uniformity in diagnosis of epilepsy syndromes across diverse settings.

Epileptic spasms in clusters without hypsarrhythmia in infancy and childhood: A single age-dependent type of epilepsy or well-defined epileptic syndrome?

OBJECTIVE: In this study, we present the electroclinical features and outcomes of 92 patients with epileptic spasms (ES) in clusters without modified or classical hypsarrhythmia that started in either in infancy or in childhood; we compared both groups in terms of electroclinical features, etiology, treatment, evolution, and outcome. METHODS: Between June 2000 and July 2022, 92 patients met the electroclinical diagnostic criteria of ES in clusters without hypsarrhythmia. Patients with ES associated with other epileptic encephalopathies including West Syndrome, as well as those with the specific etiology of ES and developmental and epileptic encephalopathy associated with CDKL5 were excluded. RESULTS: The patients were divided into two groups based on the age at ES onset: those with ES onset before (Group 1) and those with ES onset after 2 years of age (Group 2). The features of ES and the type of associated seizures before and after ES onset, as well as the interictal and ictal EEG and electromyography findings were similar in both groups. The etiologies were mainly structural (40.2%), genetic (11.9%), and unknown (44.6%) in majority of the patients in both groups. Thirty-one patients were seizure-free, while in the remaining patients the seizures continued. Nine patients (9.8%) with unilateral structural lesions underwent surgery with good results. The neurological abnormalities and developmental findings prior to ES onset depended on the underlying etiology. CONCLUSION: Our series of patients may represent a well-defined epileptic syndrome or type of epilepsy with onset in infancy or childhood characterized by ES in clusters without hypsarrhythmia associated with focal and generalized seizures and EEG paroxysms without neurological deterioration.

Providing quality care for people with CDKL5 deficiency disorder: A European expert panel opinion on the patient journey.

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a developmental and epileptic encephalopathy caused by variants in the CDKL5 gene. The disorder is characterized by intractable early-onset seizures, severe neurodevelopmental delay, hypotonia, motor disabilities, cerebral (cortical) visual impairment and microcephaly. With no disease-modifying therapies available for CDD, treatment is symptomatic with an initial focus on seizure control. Another unmet need in the management of people with CDD is the lack of evidence to aid standardized care and guideline development. To address this gap, experts in CDD and representatives from patient advocacy groups from Denmark, Finland, France, Germany, Italy, Poland, Spain, and the United Kingdom convened to form an Expert Working Group. The aim was to provide an expert opinion consensus on how to ensure quality care in routine clinical practice within the European setting, including in settings with limited experience or resources for multidisciplinary care of CDD and other developmental and epileptic encephalopathies. By means of one-to-one interviews around the current treatment landscape in CDD, insights from the Expert Working Group were collated and developed into a Europe-specific patient journey for individuals with CDD, which was later validated by the group. Further discussions followed to gain consensus of opinions on challenges and potential solutions for achieving quality care in this setting. The panel recognized the benefit of early genetic testing, a holistic personalized approach to seizure control (taking into consideration various factors such as concomitant medications and comorbidities), and age- and comorbidity-dependent multidisciplinary care for optimizing patient outcomes and quality of life. However, their insights and experiences also highlighted much disparity in management approaches and resources across different European countries. Development of standardized European recommendations is required to align realistic diagnostic criteria, treatment goals, and management approaches that can be adapted for different settings. PLAIN LANGUAGE SUMMARY: Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a rare condition caused by a genetic mutation with a broad range of symptoms apparent from early childhood, including epileptic seizures that do not respond to medication and severe delays in development. Due to the lack of guidance on managing CDD, international experts and patient advocates discussed best practices in the care of people with CDD in Europe. The panel agreed that early testing, a personalized approach to managing seizures, and access to care from different disciplines are beneficial. Development of guidelines to ensure that care is standardized would also be valuable.

Diagnosis of Lennox-Gastaut syndrome and strategies for early recognition.

INTRODUCTION: Lennox Gastaut syndrome (LGS) as an electroclinical diagnosis has been utilized as a clinical entity for more than 70 years. However, with the recognition of other distinct electroclinical epilepsy syndromes, no consistent single etiology, and the variability of criteria used in clinical trials, the clinical utility of such a diagnosis has been questioned. Recently, the International League Against Epilepsy for the first time defined diagnostic criteria for epilepsy syndromes, thereby allowing consistent language and inclusion criteria to be utilized. AREAS COVERED: Recent diagnostic criteria for syndrome diagnosis are explored as defined by the International League Against Epilepsy, with further literature reviewed to highlight relevant features, and differential diagnosis explored. EXPERT OPINION: Developmental and Epileptic Encephalopathy (DEE) is an overall term that may be descriptive of many different epilepsies, most of early onset, whether electroclinically or etiologically defined, of which LGS is one. Although we have moved forward in defining an increasing number of etiologically specific syndromes, this to date remains a minority of the DEEs. Although there is progress with precision medicine targeted at specific causes, the term LGS still remains useful as a diagnosis in defining treatment options, as well as overall prognosis.

Pediatric epilepsy syndromes with associated developmental impairment.

In 2022, the International League Against Epilepsy revised their classification of epilepsy syndromes for clinicians to better understand the relationships between different epilepsy syndromes, their underlying causes, and their associated developmental and behavioral features. This review highlights portions of the current classification with an emphasis on epilepsy syndromes that readily present with developmental challenges and provides a unique framework, based on electroencephalography, to easily identify and understand these syndromes. Included in this review are a helpful categorization scheme with visual aid, descriptions of updated epilepsy syndromes, figures of relevant identifiers of syndrome and information regarding future directions toward treatment and research. Covered syndromes include developmental and epileptic encephalopathy, Dravet syndrome, Rasmussen syndrome, and infantile epileptic spasm syndrome, among others. WHAT THIS PAPER ADDS: The revised epilepsy syndrome classification by the International League Against Epilepsy aims to improve the outcomes for children with epilepsy. The electroencephalography features of epilepsy syndromes are grouped based on a categorization model. This model allows clinicians to understand overlapping phenotypes and aid with both identification and diagnosis.

The development, content and response process validation of a caregiver-reported severity measure for CDKL5 deficiency disorder.

BACKGROUND: CDKL5 Deficiency Disorder (CDD) is a severe X-linked developmental and epileptic encephalopathy. Existing developmental outcome measures have floor effects and cannot capture incremental changes in symptoms. We modified the caregiver portion of a CDD clinical severity assessment (CCSA) and assessed content and response-process validity. METHODS: We conducted cognitive interviews with 15 parent caregivers of 1-39-year-old children with CDD. Caregivers discussed their understanding and concerns regarding appropriateness of both questions and answer options. Item wording and questionnaire structure were adjusted iteratively to ensure questions were understood as intended. RESULTS: The CCSA was refined during three rounds of cognitive interviews into two measures: (1) the CDD Developmental Questionnaire - Caregiver (CDQ-Caregiver) focused on developmental skills, and (2) the CDD Clinical Severity Assessment - Caregiver (CCSA-Caregiver) focused on symptom severity. Branching logic was used to ensure questions were age and skill appropriate. Initial pilot data (n = 11) suggested no floor effects. CONCLUSIONS: This study modified the caregiver portion of the initial CCSA and provided evidence for its content and response process validity.

ILAE Genetic Literacy Series: Self-limited familial epilepsy syndromes with onset in neonatal age and infancy.

The self-limited (familial) epilepsies with onset in neonates or infants, formerly called benign familial neonatal and/or infantile epilepsies, are autosomal dominant disorders characterized by neonatal- or infantile-onset focal motor seizures and the absence of neurodevelopmental complications. Seizures tend to remit during infancy or early childhood and are therefore called "self-limited". A positive family history for epilepsy usually suggests the genetic etiology, but incomplete penetrance and de novo inheritance occur. Here, we review the phenotypic spectrum and the genetic architecture of self-limited (familial) epilepsies with onset in neonates or infants. Using an illustrative case study, we describe important clues in recognition of these syndromes, diagnostic steps including genetic testing, management, and genetic counseling.

Bridging the Gap: Tailoring an Approach to Treatment in Febrile Infection-Related Epilepsy Syndrome.

Cytokine profiling before immunotherapy is increasingly prevalent in febrile infection-related epilepsy syndrome (FIRES). In this case, an 18-year-old man presented with first-onset seizure after a nonspecific febrile illness. He developed super-refractory status epilepticus requiring multiple antiseizure medications and general anesthetic infusions. He was treated with pulsed methylprednisolone and plasma exchange and started on ketogenic diet. Contrast-enhanced MRI brain revealed postictal changes. EEG findings showed multifocal ictal runs and generalized periodic epileptiform discharges. CSF analysis, autoantibody testing, and malignancy screening were unremarkable. Genetic testing revealed variants of uncertain significance in the CNKSR2 and OPN1LW genes. Initial serum and CSF cytokine analyses performed on days 6 and 21 revealed that interleukin (IL)-6, IL-1RA, monocyte chemoattractant protein-1, macrophage inflammatory protein 1ß, and interferon γ were elevated predominantly in the CNS, a profile consistent with cytokine release syndrome. Tofacitinib was initially trialed on day 30 of admission. There was no clinical improvement, and IL-6 continued to rise. Tocilizumab was given on day 51 with significant clinical and electrographic response. Anakinra was subsequently trialed from days 99 to 103 because clinical ictal activity re-emerged on weaning anesthetics but stopped because of poor response. Serial cytokine profiles showed improvement after 7 doses of tocilizumab. There was corresponding improved seizure control. This case illustrates how personalized immunomonitoring may be helpful in cases of FIRES, where proinflammatory cytokines are postulated to act in epileptogenesis. There is an emerging role for cytokine profiling and close collaboration with immunologists for the treatment of FIRES. The use of tocilizumab may be considered in patients with FIRES with upregulated IL-6.

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.

Analysis of electrocardiograms in individuals with CDKL5 deficiency disorder.

CDKL5 deficiency disorder (CDD) is an epileptic encephalopathy associated with medically refractory epilepsy. We sought to determine whether prolonged corrected QT interval (QTc) or other cardiac conduction abnormalities were seen in CDD in a clinical cohort. A cohort of individuals with CDD was evaluated in the Children's Hospital Colorado's International Foundation for CDKL5 Research designated Center of Excellence clinic with routine electrocardiograms obtained as part of routine clinical care. Retrospective review of electrocardiograms was completed. ECGs from 44 individuals (7 male, 37 female, age range 0-34.5 years) with pathogenic mutations and findings consistent with CDD were evaluated. Multiple ECGs were available from the 44 individuals obtained from 1996 to 2020. Prolonged QTc was found in two individuals (4.5%) and either resolved or was not confirmed on Holter monitor; no additional interventions were performed. A total of 11 individuals had echocardiograms for a variety of indications including unexplained tachycardia and ECG abnormalities; all were normal. Two individuals in the cohort died during the study with no abnormal findings on ECG. The incidence of prolonged QTc or other significant actionable cardiac abnormalities was rare in a cohort of individuals with CDD though was higher than the prevalence seen within the general population. Further studies in a larger, confirmatory cohort over a longer period are needed.

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.

Quality of life beyond diagnosis in intellectual disability - Latent profiling.

OBJECTIVE: To compare quality of life (QOL) across diagnoses associated with intellectual disability, construct QOL profiles and evaluate membership by diagnostic group, function and comorbidities. METHOD: Primary caregivers of 526 children with intellectual disability (age 5-18 years) and a diagnosis of cerebral palsy, autism spectrum disorder, Down syndrome, CDKL5 deficiency disorder or Rett syndrome completed the Quality of Life Inventory-Disability (QI-Disability) questionnaire. Latent profile analysis of the QI-Disability domain scores was conducted. RESULTS: The mean (SD) total QOL score was 67.8 (13.4), ranging from 60.3 (14.6) for CDD to 77.5 (11.7) for Down syndrome. Three classes describing domain scores were identified: Class 1 was characterised by higher domain scores overall but poorer negative emotions scores; Class 2 by average to high scores for most domains but low independence scores; and Class 3 was characterised by low positive emotions, social interaction, and leisure and the outdoors scores, and extremely low independence scores. The majority of individuals with autism spectrum disorder and Down syndrome belonged to Class 1 and the majority with CDKL5 deficiency disorder belonged to Class 3. Those with better functional abilities (verbal communication and independent walking were predominately members of Class 1 and those with frequent seizures were more often members of Class 2 and 3. CONCLUSION: The profiles illustrated variation in QOL across a diverse group of children. QOL evaluations illustrate areas where interventions could improve QOL and provide advice to families as to where efforts may be best directed.

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.

Initial Validation and Reliability of the CDKL5 Deficiency Disorder Hand Function Scale (CDD-Hand).

Pathogenic variants in the CDKL5 gene result in CDKL5 deficiency disorder (CDD), which is characterized by early-onset epilepsy, severe developmental delay, and often, cortical visual impairment. Validated clinical outcome measures are needed for future clinical trials to be successful. This study aimed to adapt the Rett Syndrome Hand Function Scale for CDKL5 deficiency disorder and evaluate its feasibility, acceptability, content validity, and reliability. Consultation with a cortical visual impairment experienced specialist and the Consumer Reference Group informed modifications to the instructions of the Rett Syndrome Hand Function Scale for children with CDKL5 deficiency disorder (CDD-Hand). Eighty-six families registered with the International CDKL5 Disorder Database provided video clips of their child's hand function and provided feedback about the measure. Video data were coded by 2 researchers to evaluate intra- and interrater reliability. This study provides initial evidence of validation and reliability. The scale appears to be suitable for a range of ages and functional abilities for CDKL5 deficiency disorder.

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.

The Lived Experience of Parents' Receiving the Diagnosis of CDKL5 Deficiency Disorder for Their Child.

CDKL5 deficiency disorder (CDD), a severe developmental and epileptic encephalopathy, is being diagnosed earlier with improved access to genetic testing, but this may also have unanticipated impacts on parents' experience receiving the diagnosis. This study explores the lived experience of parents receiving a diagnosis of CDD for their child using mixed methods. Thirty-seven semistructured interviews were conducted with parents of children with a diagnosis of CDD, which were coded and analyzed to identify themes. Grief was a nearly universal theme expressed among participants. Parents of younger children discussed grief in the context of receiving the diagnosis, whereas parents of older children indicated they were at different stages along the grieving journey when they received the diagnosis. Parents with less understanding of their child's prognosis (poorer prognostic awareness) connected their grief to receiving the diagnosis as this brought a clear understanding of the prognosis. Several themes suggested what providers did well to improve the diagnostic experience for parents, much of which aligns with existing literature around how to provide serious news. Additionally, parents identified long-term benefits of having a diagnosis for their child's medical problems. Although interview data were concordant with a survey of parents' diagnostic experience from a large international cohort, most participants in this study were relatively affluent, white mothers and further research is needed to better understand if other groups of parents have a different diagnostic experience. This study gives context of parental experience that providers should be aware of when conveying new genetic diagnoses to families.

[A case of febrile infection-related epilepsy syndrome requiring prolonged intensive care management: a trial of intravenous ketamine and intrathecal dexamethasone therapy].

A 16-year-old male was brought to the emergency room with fever and status epilepticus, and was diagnosed with febrile infection-related epilepsy syndrome (FIRES). Seizure control was not achieved and the patient developed multiple complications. Ketamine infusion therapy and intrathecal dexamethasone therapy were administered, in addition to other anti-seizure treatment and immunotherapy for super-refractory status epilepticus (SRSE). The patient was weaned from the ventilator on day 170 and was able to live at home, although he continued to experience monthly focal motor seizures and moderate motor impairment. This case suggests that more aggressive treatment might be an option in FIRES with prolonged SRSE.