Guidelines Update: Guidelines of the International Headache Society for controlled trials of preventive treatment of migraine in children and adolescents, 1st edition - An experience-based update.

BACKGROUND: Recent experience in designing and running clinical trials on new medications for the prevention of migraine in children and adolescents highlighted the need for revision of the 1st edition of the International Headache Society Guidelines for clinical trials of preventive treatment of migraine in children and adolescents which were published in 2019. METHODS: The authors of the 1st edition of the guidelines formed an informal focus group with aims of appraising the performance of the guidelines, clarifying any ambiguity and providing improvements, where needed, based on personal experience and expert analysis. RESULTS: This review and the following update were able to address issues related to the classification of migraine, the duration of migraine attacks, the age groups of children and adolescents, the use of electronic diaries, the assessment of outcome measures, the need for an interim analysis and the issues related to placebo response. CONCLUSIONS: This update provides necessary clarifications of the guidelines in order to enable better design and running of future clinical trials for the preventive treatment of migraine in children and adolescents.

Incidence and phenotypes of childhood-onset genetic epilepsies: a prospective population-based national cohort.

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.

Guidelines of the International Headache Society for controlled trials of preventive treatment of migraine in children and adolescents, 1st edition.

BACKGROUND: Because the results of clinical trials of investigational treatments influence regulatory policy, prescribing patterns, and use in clinical practice, high quality trials are an essential component of the evidence base for migraine. The International Headache Society has published guidelines for clinical trials in adults with migraine since 1991. With multiple issues specific to children and adolescents with migraine, as well as the emergence of novel trial designs and advances in pharmaceuticals, biologics, devices, and behavioural interventions, there is a need for guidance focusing on issues specific to the conduct of clinical trials in children and adolescents with migraine. OBJECTIVES: The objective of these guidelines is to provide a contemporary, standardized, and evidence-based approach to the design, conduct, and reporting of well-controlled clinical trials of preventive treatment of migraine in children and adolescents. METHODS: The development of these guidelines was based on guidelines previously published by the International Headache Society and regulatory bodies. The recommendations are evidence-based, where available. The process included consultations among various committees, roundtable discussions among stakeholders (lay people and the pharmaceutical industry), and open consultation with the IHS membership on the final draft. RESULTS: A series of recommendations addressing the major issues in clinical trials in children and adolescents with migraine is provided. Recommendations are supported by evidence-based practice and validated methodologies, where available. Supporting comments are provided to clarify ambiguities. CONCLUSIONS: These guidelines should be consulted and used in designing and conducting clinical trials of preventive treatments in children and adolescents with migraine.

Experts' opinion about the primary headache diagnostic criteria of the ICHD-3rd edition beta in children and adolescents.

BACKGROUND: The 2013 International Classification of Headache Disorders-3 (ICHD-3) was published in a beta version to allow the clinicians to confirm the validity of the criteria or to suggest improvements based on field studies. The aim of this work was to review the Primary Headache Disorders Section of ICHD-3 beta data on children and adolescents (age 0-18 years), and to suggest changes, additions, and amendments. METHODS: Several experts in childhood headache across the world applied different aspects of ICHD-3 beta in their normal clinical practice. Based on their personal experience and the literature available on pediatric headache, they made observations and proposed suggestions for the primary headache disorders section of ICHD-3 beta data on children and adolescents. RESULTS: Some headache disorders in children have specific features which are different from those seen in adults and which should be acknowledged and considered. Some features in children were found to be age-dependent: clinical characteristics, risks factors and etiologies have a strong bio psycho-social basis in children and adolescents making primary headache disorders in children distinct from those in adults. CONCLUSIONS: Several recommendations are presented in order to make ICHD-3 more appropriate for use with children.

Experts' opinion about the pediatric secondary headaches diagnostic criteria of the ICHD-3 beta.

BACKGROUND: The 2013 International Classification of Headache Disorders-3 was published in a beta version to allow clinicians to confirm the validity of the criteria or suggest improvements based on field studies. The aim of this work was to review the Secondary Headache Disorders and Cranial Neuralgias and Other Headache Disorders sections of ICHD-3 beta data on children and adolescents (age 0-18 years) and to suggest changes, additions, and amendments. METHODS: Several experts in childhood headache across the world applied different aspects of ICHD-3 beta in their normal clinical practice. Based on their personal experience and the available literature on pediatric headache, they made observations and proposed suggestions for the mentioned headache disorders on children and adolescents. RESULTS: Some headache disorders in children have specific features, which are different from adults that should be acknowledged and considered. Some features in children were found to be age-dependent: clinical characteristics, risks factors and etiologies have a strong bio psychosocial basis in children and adolescents making primary headache disorders in children distinct from those in adults. CONCLUSIONS: Several recommendations are presented in order to make ICHD-3 more appropriate for use in children.

Primary headaches in children under the age of 7 years.

Recurrent headache is increasingly recognised in young children. Migraine and tension-type headache feature commonly amongst the primary headache disorders seen at this age. Headaches at this age are more likely than in older patients to be 'unclassifiable', possibly a reflection of the difficulties in obtaining a detailed headache history from a young child. Together with recent epidemiological data this review highlights the more prevalent primary headache types with advice on making a focussed headache assessment and guidance on management in this age group.

Migraine in children and adolescents: Assessment and diagnosis.

Migraine is a complex, multifactorial brain disorder, and its presentation, complications, and response to treatment often follow the biopsychosocial model. Therefore, assessment and management include the wider aspects of the child's life within the family, at school, with peers, and in relation to his/her neurologic and emotional development. The diagnosis of headache disorders in children relies heavily on taking a careful clinical history, carrying out an appropriate physical and neurologic examination and a skilled interpretation of the findings. This chapter discusses the peculiarities of migraine in children, the differences in presentation from that in adults, and the skills that are needed in assessing the children and adolescents with headache. There is also a brief review of the epidemiology of headache and migraine in children and adolescents and an introduction of the principles of a comprehensive clinical assessment of the impact of migraine on child's quality of life. Several important elements of the clinical history and the physical and neurologic examination will be illustrated to help in the early detection of red flags that may necessitate further assessment and/or investigations. At the end of the assessment, the clinicians will be able to employ the International Classification of headache Disorders and make the correct diagnosis.

Management of migraine in children and adolescents.

Successful management of migraine in childhood and adolescence starts with making the correct diagnosis, assessing the impact of migraine on the child/adolescent's quality of life including impact on education, family life, and social activities. Understanding the child's and family's concerns and reasons for seeking medical advice is an important starting point in the management plan. Pharmacological treatment should go hand-in-hand with appropriate advice on maintaining a healthy life style, avoidance of triggers and aggravating factors, and exploring comorbid disorders that may influence response to treatment. Compared to those available for adult patients, pharmacologic treatment options for migraine in children and adolescents are relatively untested and limited at the present time. Therefore, an individual management plan on the appropriate use of medications, including the limitations of acute treatment and prevention of migraine, should be agreed and well understood by the patient, his/her carers, and school teachers, in order to achieve best results. Treatment of acute migraine episodes should be given as early as possible after onset of headache using an appropriate dose to child's age and weight and in the correct formulation and route of administration. Preventive treatment should be given regularly in a dose titrated to achieve maximum benefit with least adverse effect for at least 6-8 weeks before a judgment is made on its efficacy. Regular monitoring of treatment response can be facilitated by prospective headache diaries and follow-up.

Headache and Psychological Comorbidities: An Appraisal of the Evidence.

BACKGROUND: It has been observed that there is a higher-than-expected risk of anxiety and depression in children with chronic headache and also an increased risk for the persistence of headache in patients with anxiety and depression. OBJECTIVES: This review aims to identify and assess the relationships between primary headache disorders and comorbid emotional and psychological disorders. METHODS: A targeted review of the literature was carried out. RESULTS: The associations between the disorders are more pronounced in clinic patients, who may represent the severe end of the headache spectrum, but less clear in patients who were identified in population-based studies and who may represent the "average" child with headache or the "average" child with psychological disorders. CONCLUSIONS: Understanding this bidirectional association of comorbid disorders is of great importance to offering a holistic biopsychosocial approach to the management of headache disorders in children and adolescents and in addressing the risks for and the co-existence of psychological comorbidities.

Predicting quality of life outcomes in children with migraine.

INTRODUCTION: Several studies have shown that the response of children with migraine to medications is suboptimum and inferior to the response reported in adults, despite the similar pathogenesis and biological mechanisms. The poor response may be related to the significant differences that make assessment and treatment of children with migraine more challenging than in adults. AREAS COVERED: The purpose of this review is to discuss the whole process of assessment of children with migraine, the necessary skills for eliciting the clinical features, making the correct diagnosis and exploring lifestyle issues, co-morbid conditions (psychological and physical) and social influences on disease presentations. Also, to establish and address peculiarities of migraine in children that would enable clinicians to advise on lifestyle modifications, co-morbid conditions and the correct choice of treatment options including non-pharmacologic therapies and medications. EXPERT OPINION: The choice of treatment should be based on an assessment of each individual child taking into account, age, gender, pubertal status, body weight, comorbid disorders and family history. Also considering the profile of migraine episodes, frequency, duration, associated symptoms and effects of nausea and vomiting. Using the appropriate medications in appropriate dosage, formulation and route and timing of administration may improve adherence to treatment and outcome.

Headache in Children and Adolescents: A Focus on Uncommon Headache Disorders.

Migraine and tension-type headache are common in children and adolescents, but several other headache disorders may pose a great challenge in diagnosis and management to families and attending clinicians. In this review, we highlight several of these disorders, which need appropriate assessment to make the right diagnosis and appropriate investigations where necessary. Timely recognition and implementation of appropriate management strategies can improve the health of children with some disorders, and is vital in achieving improvement in the quality of life.

The childhood migraine syndrome.

Migraine is a complex genetic brain disorder with an intricate pathogenesis and polymorphous clinical presentations, particularly in children. In this Perspective, we describe the different phenotypes of migraine in children, including conditions that have been referred to in the International Classification of Headache Disorders as "syndromes that may be related to migraine''. Evidence is presented for the integration of abdominal migraine, cyclical vomiting syndrome, benign paroxysmal vertigo, benign paroxysmal torticollis and infantile colic into the unified diagnosis of 'childhood migraine syndrome' on the basis of clinical and epidemiological characteristics, and shared inheritance. In our opinion, such integration will guide clinicians from specialities other than neurology to consider migraine in the assessment of children with these disorders, as well as stimulate research into the genetics, pathophysiology and clinical features of all disorders within the syndrome. A diagnosis of childhood migraine syndrome would also enable patients to benefit from inclusion in clinical trials of old and new migraine treatments, thus potentially increasing the number of treatment options available.

Prevalence of headache and migraine in children and adolescents: a systematic review of population-based studies.

AIM: the aim of this study was to review systematically the prevalence of headache and migraine in children and adolescents and to study the influence of sex, age, and region of residence on the epidemiology. METHOD: we systematically searched the literature in electronic databases to cover the period between 1 January 1990 and 31 December 2007. We assessed and included population-based studies on epidemiology of headache and migraine in children and adolescents if they fulfilled the following criteria: (1) reporting on unselected childhood population; (2) reliable methods of data collection using a questionnaire or face-to-face interviews; (3) using the International Headache Society's (IHS) criteria (1988 or 2004) for the diagnosis of migraine; and (4) provision of sufficient and explicit data for analysis. We used Excel, Stata, and Confidence Interval Analysis software. RESULTS: we identified and analysed 50 population-based studies reporting the prevalence of headache and/or migraine in children and adolescents (<20y). The estimated prevalence of headache over periods between 1 month and lifetime in children and adolescents is 58.4% (95% confidence interval [CI] 58.1-58.8). Females are more likely to have headache than males (odds ratio [OR] 1.53, 95% CI 1.48-1.6). The prevalence of migraine over periods between 6 months and lifetime is 7.7% (95% CI 7.6-7.8). Females are more likely than males to have migraine (OR 1.67, 95% CI 1.60-1.75). Regional differences in prevalence of migraine, though statistically significant, may not be of clinical significance. The change in the IHS's criteria for the diagnosis of migraine was not associated with any significant change in the prevalence of migraine. INTERPRETATION: this study confirms the global high prevalence of headache and migraine in children and adolescents. Sex, age, and regional differences are evident.

Chronic daily headache in children and adolescents: a multi-faceted syndrome.

Chronic daily headache (CDH) is a multi-faceted, often complex pain syndrome in children and adolescents. Chronic daily headache may be primary or secondary. Chronic migraine and chronic tension-type are the most frequent subtypes. Chronic daily headache is co-morbid with adverse life events, anxiety and depressive disorders, possibly with other psychiatric disorders, other pain syndromes and sleep disorders; these conditions contribute to initiating and maintaining CDH. Hence, early management of episodic headache and treatment of associated conditions are crucial to prevention. There is evidence for the benefit of psychological therapies, principally relaxation and cognitive behavioral, and promising information on acupuncture for CDH. Data on drug treatment are based primarily on open label studies. The controversies surrounding CDH are discussed and proposals for improvement presented. The multifaceted nature of CDH makes it a good candidate for a multi-axial classification system. Such an approach should facilitate biopsychosocial management and enhance consistency in clinical research.

Neuronal antibody prevalence in children with seizures under 3 years: A prospective national cohort.

OBJECTIVE: To report the prevalence of anti-neuronal antibodies in a prospective whole-nation cohort of children presenting with seizures before their third birthday. METHODS: This 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 <3 years of age in Scotland who had undergone EEG. RESULTS: Two 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. CONCLUSIONS: Autoimmune encephalitis is very rare in early childhood. However serum neuronal antibodies are identified in 6.4% of children presenting with seizures at <3 years of age. Antibody testing should not be a routine clinical test in early childhood-onset epilepsy because, in the absence of other features of autoimmune encephalitis, antibody positivity is of doubtful clinical significance. Antibody testing should be reserved for patients with additional features of encephalitis.

Tension-type headache in children: the Cinderella of headache disorders!

Tension-type headache (TTH) may be as common a headache disorder as migraine in children and adolescents. TTH has a neurobiological basis with genetic and environmental factors making variable contributions to the different sub-types. The diagnostic criteria for TTH in the second edition of the "International Classification of Headache Disorders" appear to be applicable to children. Anxiety and mood disorders may be co-morbid with frequent episodic and chronic TTH. Psychosocial stressors play an important role in precipitating and maintaining TTH. Hence, a biopsychosocial approach should be adopted for care. Standardized histories and examinations together with prospective headache diaries are the foundations for good management; attention to 'red flags' will help identify secondary causes that present with headache similar to TT. There are no randomized controlled drug trials for the treatment of TTH. Relaxation and cognitive behavioral therapies are effective. TTH in children and adolescents warrants greater recognition from the clinician and scientist. Studies focusing on TTH are overdue.

Fractures and bone health monitoring in boys with Duchenne muscular dystrophy managed within the Scottish Muscle Network.

There are limited reports of radiologically confirmed fractures and bone health monitoring in with Duchenne muscular dystrophy. We performed a retrospective study of 91 boys, with a median age of 11.0 years, who are currently managed in Scotland with the aim to assess the frequency of radiologically confirmed fractures and report on bone health monitoring in relation to International Care Consensus Guidance. Of these boys, 59 (65%) were receiving glucocorticoid (GC) therapy and 23 (25%) had received previous treatment. Of those currently on GC, 37 (63%) had an assessment of bone mineral density and none had routine imaging for vertebral fractures during the study period. Of the 91 boys, 44 (48%) had sustained at least one symptomatic radiographically confirmed fracture. The probability of sustaining a first symptomatic fracture was 50% by 12.8 years old (95%CI: 12.1, 13.6). The most common sites for non-vertebral fracture were the femur and tibia. In this review of boys with DMD, almost half had sustained at least one radiologically confirmed symptomatic fracture. There is a need for standardized bone health monitoring in DMD that includes routine imaging of the spine to identify vertebral fractures, given the persistence of insult to the skeleton in these boys.