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Clinical practice guidelines (CPGs) are statements that provide evidence-based recommendations aimed at optimizing patient care. However, many other documents are often published as "guidelines" when they are not; these documents, although also important in clinical practice, are usually not systematically produced following rigorous processes linking the evidence to the recommendations. Specifically, the International League Against Epilepsy (ILAE) guideline development toolkit aims to ensure that high-quality CPGs are developed to fill knowledge gaps and optimize the management of epilepsy. In addition to adhering to key methodological processes, guideline developers need to consider that effective CPGs should lead to improvements in clinical processes of care and health care outcomes. This requires monitoring the effectiveness of epilepsy-related CPGs and interventions to remove the barriers to epilepsy CPG implementation. This article provides an overview of what distinguishes quality CPGs from other documents and discusses their benefits and limitations. We summarize the recently revised ILAE CPG development process and elaborate on the barriers and facilitators to guideline dissemination, implementation, and adaptation.

BackgroundIntrathecal baclofen (ITB) is a useful treatment for hypertonia where non-invasive treatments have been ineffective or poorly tolerated. There is an absence of national guidance on selection criteria and a lack of literature regarding patient characteristics and treatment details for children and young people (CYP) receiving ITB therapy in the UK and Ireland. We aimed to gather patient and treatment characteristics for CYP receiving ITB in the UK and Ireland.MethodsAn electronic survey was sent to all paediatric ITB centres in the UK and Ireland. Anonymised data were returned between December 2019 and April 2020. CYP >16 years and those awaiting ITB pump removal were excluded from the dataset.Results176 CYP were identified as receiving ITB therapy across the UK and Ireland. The majority of CYP with ITB pumps were non-ambulant (93%) with a diagnosis of cerebral palsy (79%). Median age of ITB insertion was 9 years; median current age was 14 years. 79% of CYP had significant spasticity, 55% had significant dystonia. The most commonly used ITB dosing modes were continuous (73%) and flexible (23%).ConclusionsITB pumps were most frequently used for non-ambulant CYP with cerebral palsy and existence of spasticity and/or dystonia in the UK and Ireland. Most CYP were receiving a continuous dose of ITB. There is significant variation in the number of paediatric ITB pumps across UK and Ireland. There is a need for development of nationally accepted paediatric referral criteria and clinical standards for ITB use.

Following media attention on children with refractory epilepsies reportedly deriving benefit from cannabis-based medicinal products (CBMPs), the UK government changed the law in 2018 so that CBMPs could be legally prescribed. Subsequently, a pure cannabidiol (CBD) product has been licensed for two epilepsy syndromes. However, despite pressure from campaign groups and allied politicians, almost no children have received unlicensed CBMPs under the UK NHS. This review explores the science behind CBMPs in paediatric epilepsies and highlights the areas that warrant further research. It identifies a lack of level I evidence for efficacy and safety as, currently, the major obstacle to prescribing. Unlicensed medicines are often used in paediatrics but almost all are used 'off-label', with supporting evidence of efficacy and safety derived either from other age-groups or from disease conditions. CBMPs, except for pure CBD, are unique in that they are currently both unlicensed and fall outside the 'off-label' category. The review acknowledges the treatment gap in refractory epilepsies and the potential use of CBMPs. However, it argues against exceptionally circumventing the usual standard of evidence required by regulatory prescribing authorities and warns against allowing vulnerable children to become the 'trojan horse' for deregulation of the commercial cannabis market.

Purpose To validate a patient-reported-experience-measure, PREM, of the NHS paediatric epilepsy service. Methods Section 1 of the PREM recorded demographic and clinical characteristics, and Section 2 collected information about the users’ experience with the service. Section 2 included eighteen statements around three constructs: communication and provision of information to service users, interpersonal skills of staff, and clinic visits and accessibility to the services. Face validity, construct validity, internal reliability, and internal consistency were used to examine the robustness of these statements. The PREM was completed by parents/carers and also children/young people. Results PREMs were received from 145 of the 192 audit units; 2335 completed forms were returned; the attitude statements were completed by 750 children/young people and 1550 parents/carers. Face validity of the PREM was good. Construct validity was indecisive; confirmatory factor analysis of the hypothesised construct was weak. Exploratory factor analysis identified a four factor solution for the parent/carers dataset and a five factor solution for the children/young people’s dataset. Internal reliability was good for the parent/carers dataset but less good for the children/young people. Internal consistency was moderately good for both datasets. Conclusions These findings indicate that the PREM is likely to be a valid tool with the potential to elicit a wide variety of reliable views from parents/carers of children with epilepsy. The construct validity for the PREM should be reassessed with confirmatory factor analysis in a new dataset. More work needs to be undertaken with children/young people to design statements that capture their specific needs.

Epilepsies of early childhood are frequently resistant to therapy and often associated with cognitive and behavioural comorbidity. Aetiology focused precision medicine, notably gene-based therapies, may prevent seizures and comorbidities. Epidemiological data utilizing modern diagnostic techniques including whole genome sequencing and neuroimaging can inform diagnostic strategies and therapeutic trials. We present a 3-year, multicentre prospective cohort study, involving all children under 3 years of age in Scotland presenting with epilepsies. We used two independent sources for case identification: clinical reporting and EEG record review. Capture-recapture methodology was then used to improve the accuracy of incidence estimates. Socio-demographic and clinical details were obtained at presentation, and 24 months later. Children were extensively investigated for aetiology. Whole genome sequencing was offered for all patients with drug-resistant epilepsy for whom no aetiology could yet be identified. Multivariate logistic regression modelling was used to determine associations between clinical features, aetiology, and outcome. Three hundred and ninety children were recruited over 3 years. The adjusted incidence of epilepsies presenting in the first 3 years of life was 239 per 100 000 live births [95% confidence interval (CI) 216–263]. There was a socio-economic gradient to incidence, with a significantly higher incidence in the most deprived quintile (301 per 100 000 live births, 95% CI 251–357) compared with the least deprived quintile (182 per 100 000 live births, 95% CI 139–233), χ2 odds ratio = 1.7 (95% CI 1.3–2.2). The relationship between deprivation and incidence was only observed in the group without identified aetiology, suggesting that populations living in higher deprivation areas have greater multifactorial risk for epilepsy. Aetiology was determined in 54% of children, and epilepsy syndrome was classified in 54%. Thirty-one per cent had an identified genetic cause for their epilepsy. We present novel data on the aetiological spectrum of the most commonly presenting epilepsies of early childhood. Twenty-four months after presentation, 36% of children had drug-resistant epilepsy (DRE), and 49% had global developmental delay (GDD). Identification of an aetiology was the strongest determinant of both DRE and GDD. Aetiology was determined in 82% of those with DRE, and 75% of those with GDD. In young children with epilepsy, genetic testing should be prioritized as it has the highest yield of any investigation and is most likely to inform precision therapy and prognosis. Epilepsies in early childhood are 30% more common than previously reported. Epilepsies of undetermined aetiology present more frequently in deprived communities. This likely reflects increased multifactorial risk within these populations., In a prospective study involving all children presenting with epilepsy aged under 3 years in Scotland, Symonds et al. show that epilepsies of undetermined aetiology present more frequently in socially disadvantaged groups. Aetiology is the strongest predictor of outcome, and genetic testing should be prioritized.

ObjectiveTo report the prevalence of anti-neuronal antibodies in a prospective whole-nation cohort of children presenting with seizures before their third birthday.MethodsThis was a prospective population-based national cohort study involving all children presenting with new-onset epilepsy or complex febrile seizures before their third birthday over a 3-year period. Patients with previously identified structural, metabolic, or infectious cause for seizures were excluded. Serum samples were obtained at first presentation and tested for 7 neuronal antibodies using live cell-based assays. Clinical data were collected with structured proformas at recruitment and 24 months after presentation. In addition, patients with seizures and clinically suspected autoimmune encephalitis were independently identified by a review of the case records of all children ResultsTwo hundred ninety-eight patients were identified and recruited and underwent autoantibody testing. Antibody positivity was identified in 18 of 298 (6.0%). The antibodies identified were GABA receptor B (n = 8, 2.7%), contactin-associated protein 2 (n = 4, 1.3%), glycine receptor (n = 3, 1.0%), leucine-rich glioma inactivated 1 (n = 2, 0.7%), NMDA receptor (n = 1, 0.3%), and GABA receptor A (n = 1, 0.3%). None of these patients had a clinical picture of autoimmune encephalitis. Seizure classification and clinical phenotype did not correlate with antibody positivity.ConclusionsAutoimmune encephalitis is very rare in early childhood. However serum neuronal antibodies are identified in 6.4% of children presenting with seizures at

See Scheffer (doi:10.1093/brain/awz208) for a scientific commentary on this article. In a prospective population-based cohort study, Symonds et al. perform high-throughput genetic testing in children presenting with seizures before 3 years of age, and provide incidence estimates for the most common single-gene epilepsies. One quarter of cases are found to have a genetic cause, and 80% of the genetic diagnoses are found to have potential treatment implications., Epilepsy is common in early childhood. In this age group it is associated with high rates of therapy-resistance, and with cognitive, motor, and behavioural comorbidity. A large number of genes, with wide ranging functions, are implicated in its aetiology, especially in those with therapy-resistant seizures. Identifying the more common single-gene epilepsies will aid in targeting resources, the prioritization of diagnostic testing and development of precision therapy. Previous studies of genetic testing in epilepsy have not been prospective and population-based. Therefore, the population-incidence of common genetic epilepsies remains unknown. The objective of this study was to describe the incidence and phenotypic spectrum of the most common single-gene epilepsies in young children, and to calculate what proportion are amenable to precision therapy. This was a prospective national epidemiological cohort study. All children presenting with epilepsy before 36 months of age were eligible. Children presenting with recurrent prolonged (>10 min) febrile seizures; febrile or afebrile status epilepticus (>30 min); or with clusters of two or more febrile or afebrile seizures within a 24-h period were also eligible. Participants were recruited from all 20 regional paediatric departments and four tertiary children’s hospitals in Scotland over a 3-year period. DNA samples were tested on a custom-designed 104-gene epilepsy panel. Detailed clinical information was systematically gathered at initial presentation and during follow-up. Clinical and genetic data were reviewed by a multidisciplinary team of clinicians and genetic scientists. The pathogenic significance of the genetic variants was assessed in accordance with the guidelines of UK Association of Clinical Genetic Science (ACGS). Of the 343 patients who met inclusion criteria, 333 completed genetic testing, and 80/333 (24%) had a diagnostic genetic finding. The overall estimated annual incidence of single-gene epilepsies in this well-defined population was 1 per 2120 live births (47.2/100 000; 95% confidence interval 36.9–57.5). PRRT2 was the most common single-gene epilepsy with an incidence of 1 per 9970 live births (10.0/100 000; 95% confidence interval 5.26–14.8) followed by SCN1A: 1 per 12 200 (8.26/100 000; 95% confidence interval 3.93–12.6); KCNQ2: 1 per 17 000 (5.89/100 000; 95% confidence interval 2.24–9.56) and SLC2A1: 1 per 24 300 (4.13/100 000; 95% confidence interval 1.07–7.19). Presentation before the age of 6 months, and presentation with afebrile focal seizures were significantly associated with genetic diagnosis. Single-gene disorders accounted for a quarter of the seizure disorders in this cohort. Genetic testing is recommended to identify children who may benefit from precision treatment and should be mainstream practice in early childhood onset epilepsy.

To provide quality care for children with epilepsy there is a continuing need to synthesize clinical research into forms that reflect best clinical practice. The design of evidence-based guidelines allows the gathering of this information together. This review discusses the components needed to analyze published data and produce recommendations for clinical management. Guideline implementation should be seen as an essential component that is integrated into guideline development. Robust clinical practice guidelines can also form the basis of defining quality standards that in turn should allow the development and measurement of clinical outcomes that lead to direct improvements in patient care.

Aim To measure the adherence to antiepileptic drugs (AED) in a population cohort of children with epilepsy and to study the relationship between adherence and a series of clinical variables. Method A population-based study of children (90%) across a year of treatment. Twenty-five percent of children had an Adherence Index of less than 50%. Adherence declined with increasing age. There was no significant correlation between adherence and other clinical characteristics studied (sex, duration of epilepsy, other comorbid health problems, other regular medications, and seizure frequency). Interpretation Our data shows adherence to AED treatment is poor in children with epilepsy.

Purpose To survey patient and carer experience for children and young people with epilepsy across the United Kingdom. Methods We used a Patient Reported Experience Measure methodology to explore perceived satisfaction with their epilepsy service. A survey collected anonymised proxy data on demography and illness severity, and perceptions of interaction with clinicians, ease of access to the service and the quality and quantity of epilepsy information provided. The questionnaire was completed by the child’s or young person’s carer or by the young person. Results Survey questionnaires were distributed across all of the 192 paediatric units providing epilepsy care for children in the UK. 145 units (75%) submitted data and there were 2335 responses. 90% of young people and 86% of carers were satisfied with the care they had received. Using multi-level logistic regression modelling, those factors most strongly affecting satisfaction were determined. While many proxies of illness severity adversely affected satisfaction, comorbidity did not. A dedicated clinic setting, perceived adequate information and guidance on restrictions on their child, if any, all improved satisfaction. However, the significantly strongest factor influencing satisfaction was “ease of access” to the service. Conclusions These data demonstrate the feasibility of collecting large population sizes to allow a better understanding of the needs of children and young people accessing an epilepsy service. They allow the identification of factors most closely linked to patient satisfaction and provide potentially valuable information on how to improve the quality of care of children and young people with epilepsy.

Clinical practice guidelines (CPGs) contain evidence-based recommendations to guide clinical care, policy development, and quality of care improvement. A recent systematic review of epilepsy guidelines identified considerable variability in the quality of available guidelines. Although excellent frameworks for CPG development exist, processes are not followed uniformly internationally, and resources to develop CPGs may be limited in certain settings. An International League Against Epilepsy (ILAE) working group was charged with proposing methodology to guide the development of future epilepsy-specific CPGs. A comprehensive literature search (1985-2014) identified articles related to CPG development and handbooks. Guideline handbooks were included if they were publicly available, and if their methodology had been used to develop CPGs. The working group's expertise also informed the creation of methodologies and processes to develop future CPGs for the ILAE. Five handbooks from North America (American Academy of Neurology), Europe (Scottish Intercollegiate Guidelines Network & National Institute for Health and Care Excellence), Australia (National Health and Medical Research Council), World Health Organization (WHO), and additional references were identified to produce evidence-based, consensus-driven methodology for development of epilepsy-specific CPGs. Key components of CPG development include the following: identifying the topic and defining the scope; establishing a working group; identifying and evaluating the evidence; formulating recommendations and determining strength of recommendations; obtaining peer reviews; dissemination, implementation, and auditing; and updating and retiring the CPG. A practical handbook and toolkit was developed. The resulting CPG development toolkit should facilitate the development of high-quality ILAE CPGs to improve the care of persons with epilepsy.

There has been considerable evolution in epilepsy healthcare for children over the last decade in the United Kingdom. There has been no single explanation for this. The development of national clinical guidelines, locally delivered but nationally designed educational programmes, nation-wide clinical audit, clinical networks and development of designated services have all had complimentary roles in enabling the implementation of national recommendations for the development of epilepsy care. These models may be applicable to other healthcare settings outside the UK.

Multifocal motor neuropathy is an acquired pure motor neuropathy seen principally in adults and usually responds to treatment with intravenous immunoglobulin. We report a 12 year old boy with marked distal weakness in both upper and lower limbs with no proximal involvement. These clinical features appear to be distinct from more common inflammatory childhood neuropathies and are in keeping with a diagnosis of Multifocal Motor Neuropathy. Confirming the diagnosis, serial nerve conduction studies showed a pattern of pure motor conduction block with normal sensory potentials. To our knowledge this is only the second case report of this condition occurring in childhood.

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is an inherited neuromuscular condition resulting from recessive mutations in the immunoglobulin mu-binding protein (IGHMBP2) gene. Affected individuals characteristically present in infancy with progressive distal weakness and respiratory distress secondary to diaphragmatic weakness. Considerable clinical heterogeneity has been described both in its presentation and phenotype in childhood; however little data pertaining to phenotype in adulthood have been reported to date. This report describes a 21 year old woman with genetically confirmed SMARD1 who has stable muscle weakness, normal cognitive abilities and is able to lead a socially integrated lifestyle, using mechanical ventilation only overnight. This report adds new evidence for clinical variability throughout the course of SMARD1.

The NKX2-1 (TTF-1 or TITF-1) gene on chromosome 14q13 codes for the thyroid transcription factor 1 (TTF-1). It is expressed in the developing brain, lung, and thyroid. Defects have been associated with chorea, hypothyroidism, and lung disease, comprising the “brain-thyroid-lung syndrome.” We describe here 3 cases of novel missense mutation (c.626G>C; p.Arg209Pro) in NKX2-1 in 2 generations of a nonconsanguinous family. Firstly 2 sons were affected by childhood-onset hypothyroidism and a movement disorder characterized by ataxia in the early years followed by the emergence of a superimposed chorea. The mutation was also found in the granddaughter, when she presented with the same clinical features. We hypothesize that the mutation arose as a result of gonadal mosaicism, as the mutation was not detected in leucocyte DNA from either grandparent. The features are consistent with a diagnosis of Brain-thyroid-lung syndrome, which previously could have been classified as benign hereditary chorea with hypothyroidism.

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is an uncommon, idiopathic partial epilepsy characterized by clusters of motor seizures occurring in sleep. We describe a mutation of the beta2 subunit of the nicotinic acetylcholine receptor, effecting a V287M substitution within the M2 domain. The mutation, in an evolutionary conserved region of CHRNB2, is associated with ADNFLE in a Scottish family. Functional receptors with the V287M mutation are highly expressed in Xenopus oocytes and characterized by an approximately 10-fold increase in acetylcholine sensitivity. CHRNB2 is a new gene for idiopathic epilepsy, the second acetylcholine receptor subunit implicated in ADNFLE.

Background Aicardi syndrome (AS) is a rare neurodevelopmental disorder characterized by the triad of corpus callosum agenesis, chorioretinal lacunae, and infantile spasms. Most patients with AS also have intractable epilepsy, moderate to severe learning disability, and a reduced life expectancy. An X-linked dominant inheritance caused by de novo mutations pattern, lethal in males, is postulated, but the gene has not yet been isolated. There are three case reports of 47 XXY males with classic features of AS who all had severe developmental disability. Case report We report a case of a 3.5-year old 47 XXY male with the classic triad of Aicardi syndrome but with good seizure control and mild learning disability.

We present a case of vertical gaze palsy in a 13-year-old girl caused by underlying infective endocarditis, secondary to an infected navel piercing. This case illustrates that infective endocarditis does not always present with classic signs. J Pediatr Ophthalmol Strabismus 2006;43:41-43. AUTHORS The authors are from Ninewells Hospital, Dundee, Scotland. Originally submitted March 30, 2004. Accepted for publication November 19, 2004. Address reprint requests to Dr. Andrew Ferguson, Department of Ophthalmology, Ninewells Hospital, Dundee DD1 9SY, Scotland. Presented in part at the Annual Meeting of the Scottish Ophthalmological Club; October 3, 2003; Erskine, Scotland.

To describe the frequency and causes of death in children with epilepsy, ascertain the contribution of seizure disorder to cause of death, and compare with rates of sudden unexplained death in children without epilepsy.This study was a retrospective review of clinical and death certificate records. It examined two UK population-based samples of deaths in children with epilepsy from 1 month to 18 years, together comprising the largest reported series of deaths in children with epilepsy (n=265).In approximately two-thirds, the death was not due to the seizure disorder. Rates of unexplained death were similar in the two samples at 7.3% and 9.7%: all were in children with symptomatic or presumed symptomatic epilepsy. There were no unexplained deaths in the children with idiopathic epilepsy. Four per cent of the deaths were of children experiencing acute symptomatic seizures as part of their final illness. The risk of unexpected, unexplained death in children with idiopathic epilepsy is not more than 65 per 100,000 child-years.Epilepsy is associated with an increased risk of death in childhood but this risk is almost entirely confined to those with an associated neurodevelopmental disorder. The risk of unexpected, unexplained death in children with idiopathic epilepsy is extremely small.

It is important to determine the reproducibility of objective measures of gait in children with motor disorders in order that the effect of interventions to improve gait can be monitored. Data for walking velocity and vertical ground reaction force expressed as a percentage of body weight were collected from 15 normal children and 11 with spastic cerebral palsy. Five recordings were obtained for each foot of each child on 3 consecutive days, and calculations of variability made for each set of five recordings. Children with cerebral palsy had slower walking velocities and greater ground reaction force values, and both these parameters had low intraindividual variation for both normal children and those with cerebral palsy (coefficients of variation < 12.5%). This good reproducibility applied to intrasubject and intraday variability; no learning effect was seen over 3 days' recordings. There was no significant difference in variability whether the first three recordings or all five were used. These techniques of gait measurement in children have good reproducibility and a potential role in the objective assessment of medical and surgical interventions.

OBJECTIVE: To describe the clinical phenotype of paroxysmal extreme pain disorder (previously called familial rectal pain syndrome), an autosomal dominant condition recently shown to be a sodium channelopathy involving SCN9A. METHODS: An international consortium of clinicians, scientists, and affected families was formed. Clinical details of all accessible families worldwide were collected, including age at onset, features of attacks, problems between attacks, investigational results, treatments tried, and evolution over time. A validated pain questionnaire was completed by 14 affected individuals. RESULTS: Seventy-seven individuals from 15 families were identified. The onset of the disorder is in the neonatal period or infancy and persists throughout life. Autonomic manifestations predominate initially, with skin flushing in all and harlequin color change and tonic attacks in most. Dramatic syncopes with bradycardia and sometimes asystole are common. Later, the disorder is characterized by attacks of excruciating deep burning pain often in the rectal, ocular, or jaw areas, but also diffuse. Attacks are triggered by factors such as defecation, cold wind, eating, and emotion. Carbamazepine is effective in almost all who try it, but the response is often incomplete. CONCLUSIONS: Paroxysmal extreme pain disorder is a highly distinctive sodium channelopathy with incompletely carbamazepine-sensitive bouts of pain and sympathetic nervous system dysfunction. It is most likely to be misdiagnosed as epilepsy and, particularly in infancy, as hyperekplexia and reflex anoxic seizures.

Occasionally, but more often than has been reported, true epileptic seizures are triggered by non-epileptic syncopes. This combination of syncope and epileptic seizure has been called an anoxic-epileptic seizure. A few examples of such anoxic-epileptic seizures, including the induction of status epilepticus, have been reported in books and medical journals, but no video-recordings have been published. We show here home video recordings of the first three known examples of the transition from the triggering syncope and anoxic seizure, to the subsequent epileptic seizure. In the first two children, a neurally-mediated syncope, probably mediated by prolonged expiratory apnoea (so-called breath-holding spells), induces a long, clonic epileptic seizure with some features of myoclonic absence. In the third example, a compulsive Valsalva in an older autistic child provokes a vibratory tonic epileptic seizure. In addition, we show two further video clips of the most usual type of epileptic seizure induced by syncopes in very young children. In one, the video recording begins after the end of the triggering syncope and shows a rhythmic clonic seizure that includes repetitive vocalizations. The final recoding is of a spontaneous epileptic seizure with features of myoclonic absence: this child had both epilepsy and identical episodes induced by syncopes, that is, anoxic- epileptic seizures. Not only paediatricians and paediatric neurologists, but also adult neurologists and epileptologists in general, should be aware of the important clinical scenario of true epileptic seizures induced by syncopes. This phenomenon is not considered in any international classification. (Published with videosequences)

A 3-week-old infant with meningococcal meningitis is described whose clinical course was complicated by paraparesis and urinary retention. This rare complication of meningococcal meningitis has not previously been reported in the neonatal age group.