Extended Phenotyping of Migraine in Children: A Cross-Sectional Study in a Specialist Children's Headache Clinic.

BACKGROUND: The pediatric migraine phenotype may exhibit differences to adults, leading to diagnostic challenges. We aimed to perform a cross-sectional systematic study to characterize the extended phenotype of pediatric migraine. METHODS: New migraine patients presenting to the Children's Headache Clinic were included (n = 105). Data were collected via a detailed symptom questionnaire at the first clinical encounter and were analyzed using descriptive statistics, Cohen kappa (k), Spearman correlation (ρ), and Poisson and binomial logistic regression models within SPSS. RESULTS: Patients were 65% female and aged five to 17 years (median 14, interquartile range [IQR] 11 to 15), with a mean disease duration of 4.7 years (S.D. 2.8). Monthly headache frequency was 1 to 30 days (median 30, IQR 12 to 30). Attack duration varied between 2 and 168 hours (median 12, IQR 5 to 72). The majority (81%) experienced bilateral headache. Premonitory symptoms (PS) were reported by 93% (range 0 to 7; mood change and tiredness most commonly), cranial autonomic symptoms (CAS) by 58% (range 0 to 6; pallor and lacrimation most commonly), and premonitory CAS by 23%. Vertigo (53%) and allodynia (16%) were present. The laterality of headache and CAS showed agreement (k = 0.5, P < 0.001). For every year of disease duration, 1.07 times more PS were reported (95% confidence interval [CI] 1.03 to 1.12, P < 0.001). The number of CAS (odds ratio 2.13, 95% CI 1.2 to 3.8, P = 0.01) significantly predicted allodynia. CONCLUSIONS: Children display a more enriched PS phenotype with disease chronicity. CAS and allodynia may be markers of central sensitization with shared neurobiological mechanisms in the absence of peripheral nociceptor activation.

Consensus recommendations for the assessment and management of idiopathic intracranial hypertension in children and young people.

BACKGROUND: Idiopathic intracranial hypertension (IIH) is a potentially disabling condition. There is a lack of evidence and national guidance on how to diagnose and treat paediatric IIH, leading to variation in clinical practice. We conducted a national Delphi consensus via the Children's Headache Network to propose a best-practice diagnostic and therapeutic pathway. METHODS: The Delphi process was selected as the most appropriate methodology for examining current opinion among experts in the UK. 104 questions were considered by 66 healthcare professionals, addressing important aspects of IIH care: assessment, diagnosis, treatment, follow-up and surveillance. General paediatricians, paediatric neurologists, ophthalmologists, opticians, neuroradiologists and neurosurgeons with a clinical interest or experience in IIH, were invited to take part. RESULTS: The Delphi process consisted of three rounds comprising 104 questions (round 1, 67; round 2, 24; round 3 (ophthalmological), 13) and was completed between March 2019 and August 2021. There were 54 and 65 responders in the first and second rounds, respectively. The Delphi was endorsed by the Royal College of Ophthalmologists, which engaged 59 ophthalmologists for round 3. CONCLUSIONS: This UK-based Delphi consensus process reached agreement for the management of paediatric IIH and has been endorsed by the Children's Headache Network and more broadly, the British Paediatric Neurology Association. It provides a basis for a pragmatic clinical approach. The recommendations will help to improve clinical care while minimising under and over diagnosis.

Bi-allelic variants in INTS11 are associated with a complex neurological disorder.

The Integrator complex is a multi-subunit protein complex that regulates the processing of nascent RNAs transcribed by RNA polymerase II (RNAPII), including small nuclear RNAs, enhancer RNAs, telomeric RNAs, viral RNAs, and protein-coding mRNAs. Integrator subunit 11 (INTS11) is the catalytic subunit that cleaves nascent RNAs, but, to date, mutations in this subunit have not been linked to human disease. Here, we describe 15 individuals from 10 unrelated families with bi-allelic variants in INTS11 who present with global developmental and language delay, intellectual disability, impaired motor development, and brain atrophy. Consistent with human observations, we find that the fly ortholog of INTS11, dIntS11, is essential and expressed in the central nervous systems in a subset of neurons and most glia in larval and adult stages. Using Drosophila as a model, we investigated the effect of seven variants. We found that two (p.Arg17Leu and p.His414Tyr) fail to rescue the lethality of null mutants, indicating that they are strong loss-of-function variants. Furthermore, we found that five variants (p.Gly55Ser, p.Leu138Phe, p.Lys396Glu, p.Val517Met, and p.Ile553Glu) rescue lethality but cause a shortened lifespan and bang sensitivity and affect locomotor activity, indicating that they are partial loss-of-function variants. Altogether, our results provide compelling evidence that integrity of the Integrator RNA endonuclease is critical for brain development.

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.

A recent surge of fulminant and early onset subacute sclerosing panencephalitis (SSPE) in the United Kingdom: An emergence in a time of measles.

BACKGROUND: Subacute Sclerosing Panencephalitis (SSPE) is a fatal progressive neurological disorder following measles infection. METHODS: Cases were collated from Paediatric Neurology centres in the UK over 24 months from 2017 to 2019 and represent all cases referred to the National Viral Reference Department (VRD). Diagnosis was established with detection of a raised measles index, demonstrating intrathecal measles antibody production. FINDINGS: Six children presented with SSPE over two years, with median age five years (range 2-7 years) and median latency period three years (range 2-6 years). The majority were exposed to measles during infancy. Atypical features were common, including visual impairment, focal and generalised tonic-clonic seizures, headache, vomiting and movement disorders. EEG demonstrated typical features in five cases, though not always at presentation. Initial MRI was normal in four cases, with two showing focal and widespread white matter changes. Antiviral and immunomodulatory treatment led to minimal or no improvement. All progressed to cognitive regression, seizures and neurological decline within six months. INTERPRETATION: These cases demonstrate the highest incidence of SSPE in the UK since 2000, all progressing to acute fulminant disease, following younger age of onset, short latency period and atypical presentations. Recent global surges in measles cases raise the importance of clinician awareness of SSPE as a potential diagnosis in children with neurological regression. Herd immunity remains the key protective mechanism for infants and groups that cannot be vaccinated. Health care providers, educators and governments must ensure resources continue to target effective education and access to immunisation programmes, the only means to combat this devastating and fatal condition.

Post-licensure observational safety study after meningococcal B vaccine 4CMenB (Bexsero) vaccination within the routine UK immunisation program.

The study investigated the safety of 4-component meningococcal serogroup B vaccination (4CMenB) in routine care. 4CMenB exposure and seizures, febrile seizures and Kawasaki disease were identified from The Health Improvement Network (THIN) database of UK electronic primary healthcare records, 2015-2018. A self-controlled case series analysis was completed. Anaphylaxis, Guillain-Barré syndrome and acute disseminated encephalomyelitis were secondary outcomes. A total of 107,231 children aged 1-18 months received ≥1 doses of 4CMenB vaccination. Most 4CMenB exposure (93%) was on the same day as other vaccines within a complete national immunisation program stage. With day 0 as day of vaccination, 43 seizures occurred in days 0-6 after 239,505 doses, and 23 febrile seizures occurred in days 0-6, and 4 Kawasaki disease cases in days 1-28 after 194,929 4CMenB doses. Adjusted incidence rate ratios including all 4CMenB exposures were 1.43 (95%CI: 1.02-2.02) for seizures and 1.72 (95%CI: 1.08-2.75) for febrile seizures. There were insufficient cases to model Kawasaki disease, and no cases of the secondary outcomes in risk periods when they may be associated with the vaccination. This study shows few cases of the outcomes after vaccination including 4CMenB with an increased risk of seizures and febrile seizures. It is not possible to attribute the finding to one specific vaccination as the majority of 4CMenB was given with other vaccinations. Trial registration: NA.

Diagnostic algorithm for children presenting with epilepsia partialis continua.

OBJECTIVE: To characterize a cohort of children with epilepsia partialis continua (EPC) and develop a diagnostic algorithm incorporating key differential diagnoses. METHODS: Children presenting with EPC to a tertiary pediatric neurology center between 2002 and 2019 were characterized. RESULTS: Fifty-four children fulfilled EPC criteria. Median age at onset was 7 years (range 0.6-15), with median follow-up of 4.3 years (range 0.2-16). The diagnosis was Rasmussen encephalitis (RE) in 30 of 54 (56%), a mitochondrial disorder in 12 of 54 (22.2%), and magnetic resonance imaging (MRI) lesion-positive focal epilepsy in 6 of 54 (11.1%). No diagnosis was made in 5 of 54 (9%). Children with mitochondrial disorders developed EPC earlier; each additional year at presentation reduced the odds of a mitochondrial diagnosis by 26% (P = .02). Preceding developmental concerns (odds ratio [OR] 22, P < .001), no seizures prior to EPC (OR 22, P < .001), bilateral slowing on electroencephalogram (EEG) (OR 26, P < .001), and increased cerebrospinal fluid (CSF) protein level (OR 16) predicted a mitochondrial disorder. Asymmetry or hemiatrophy was evident on MRI at presentation with EPC in 18 of 30 (60%) children with RE, and in the remainder at a median of 6 months (range 3-15) after EPC onset. The first diagnostic test is brain MRI. Hemiatrophy may permit a diagnosis of RE with unilateral clinical and EEG findings. For children in whom a diagnosis of RE cannot be made on first scan but the clinical and radiological presentation resembles RE, repeat imaging every 6 months is recommended to detect progressive unicortical hemiatrophy, and brain biopsy should be considered. Evidence of intrathecal inflammation (oligoclonal bands and raised neopterin) can be supportive. In children with bihemispheric EPC, rapid polymerase gamma testing is recommended and if negative, sequencing mtDNA and whole-exome sequencing on blood-derived DNA should be performed. SIGNIFICANCE: Children presenting with EPC due to a mitochondrial disorder show clinical features distinguishing them from RE and structural epilepsies. A diagnostic algorithm for children with EPC will allow targeted investigation and timely diagnosis.

Correction: The clinical spectrum and natural history of early-onset diseases due to DNA polymerase gamma mutations.

Since the online publication of the article, the authors have noted errors with Table 2; this has now been corrected in both the HTML and the PDF.

Treatment of disabling headache with greater occipital nerve injections in a large population of childhood and adolescent patients: a service evaluation.

BACKGROUND: Pediatric headache disorders can be extremely disabling, with marked reduction in the quality of life of children and their carers. Evidenced-based options for the treatment of primary headache disorders with preventive medication is limited and clinical outcomes are often unsatisfactory. Greater occipital nerve injections represent a rapid and well-tolerated therapeutic option, which is widely used in clinical practice in adults, and has previously shown a good outcome in a pediatric population. METHODS: This service evaluation reviewed greater occipital nerve injections performed unilaterally with 30 mg 1% lidocaine and 40 mg methylprednisolone, to treat disabling headache disorders in children and adolescents. RESULTS: We analyzed a total of 159 patients who received 380 injections. Of the population, 79% had chronic migraine, 14% new daily persistent headache, 4% a trigeminal autonomic cephalalgia, 3% secondary headache and one patient had chronic tension-type headache. An improvement after injection was seen in 66% (n = 105) of subjects, lasting on average 9 ± 4 weeks. Improvement was seen in 68% of patients with chronic migraine, 67% with a trigeminal autonomic cephalalgia and 59% with new daily persistent headache. Side effects were reported in 8% and were mild and transient. Older age, female gender, chronic migraine, increased number of past preventive use, medication overuse and developing side effects were all associated with an increased likelihood of positive treatment outcome. CONCLUSIONS: This large single centre service evaluation confirms that unilateral injection of the greater occipital nerve is a safe, rapid-onset and effective treatment strategy in disabling headache disorders in children, with a range of diagnoses and severity of the condition, and with minimal side effects.

The clinical spectrum and natural history of early-onset diseases due to DNA polymerase gamma mutations.

PurposeMutations in POLG, the most common single-gene cause of inherited mitochondrial disease, are diagnostically challenging owing to clinical heterogeneity and overlap between syndromes. We aimed to improve the clinical recognition of POLG-related disorders in the pediatric population.MethodsWe performed a multinational, phenotype: genotype study using patients from three centers, two Norwegian and one from the United Kingdom. Patients with age at onset <12 years and confirmed pathogenic biallelic POLG mutations were considered eligible.ResultsA total of 27 patients were identified with a median age at onset of 11 months (range 0.6-80.4). The majority presented with global developmental delay (n=24/24, 100%), hypotonia (n=22/23, 96%) and faltering growth (n=24/27, 89%). Epilepsy was common, but notably absent in patients with the myocerebrohepatopathy spectrum phenotype. We identified two novel POLG gene mutations.ConclusionOur data suggest that POLG-related disease should be suspected in any child presenting with diffuse neurological symptoms. Full POLG sequencing is recommended since targeted screening may miss mutations. Finally, we simplify the classification of POLG-related disease in children using epilepsy as the crucial defining element; we show that Alpers and myocerebrohepatopathy spectrum follow different outcomes and that they manifest different degrees of respiratory chain dysfunction.

Headache outcomes in children undergoing foramen magnum decompression for Chiari I malformation.

OBJECTIVE: A common symptom of Chiari I malformation (CIM) is headache, which is diagnosed using non-validated criteria from the International Headache Society (IHS). CIM-associated headaches should resolve following neurosurgical treatment of the malformation by foramen magnum decompression (FMD). We aimed to validate the IHS criteria and determine (1) the efficacy of FMD in treating headache and (2) whether duraplasty confers an advantage over simple bony decompression in the treatment of this symptom. METHODS: A retrospective review of CIM cases treated with FMD at Great Ormond Street Hospital from 1989 to 2014 was carried out. Clinical headache characteristics were compared against IHS criteria and correlated with outcome following FMD. RESULTS: Headache was a presenting symptom in 57/102 (55.9%) of patients. Of these, 42/57 (73.7%) could be classified as Chiari I-type headache. Following FMD, 42/57 (73.7%) of all presenting headaches showed a sustained improvement (>3 months) compared with 32/39 (82.1%) of Chiari I-type headaches. Duraplasty led to a sustained improvement in headache in 32/38 (84.2%) cases compared with 9/16 (56.3%) cases treated with bone-only decompression. CONCLUSIONS: Our data suggest that 80% of headaches classified as Chiari I-type will show a sustained improvement following FMD, and, as such, the IHS criteria are clinically useful in evaluating symptoms attributable to CIM. For all headaches associated with CIM, duraplasty may confer a benefit in terms of long-term improvement, compared with bone-only decompression.

Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia.

Histone lysine methylation, mediated by mixed-lineage leukemia (MLL) proteins, is now known to be critical in the regulation of gene expression, genomic stability, cell cycle and nuclear architecture. Despite MLL proteins being postulated as essential for normal development, little is known about the specific functions of the different MLL lysine methyltransferases. Here we report heterozygous variants in the gene KMT2B (also known as MLL4) in 27 unrelated individuals with a complex progressive childhood-onset dystonia, often associated with a typical facial appearance and characteristic brain magnetic resonance imaging findings. Over time, the majority of affected individuals developed prominent cervical, cranial and laryngeal dystonia. Marked clinical benefit, including the restoration of independent ambulation in some cases, was observed following deep brain stimulation (DBS). These findings highlight a clinically recognizable and potentially treatable form of genetic dystonia, demonstrating the crucial role of KMT2B in the physiological control of voluntary movement.

Mutations in SNORD118 cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts.

Although ribosomes are ubiquitous and essential for life, recent data indicate that monogenic causes of ribosomal dysfunction can confer a remarkable degree of specificity in terms of human disease phenotype. Box C/D small nucleolar RNAs (snoRNAs) are evolutionarily conserved non-protein-coding RNAs involved in ribosome biogenesis. Here we show that biallelic mutations in the gene SNORD118, encoding the box C/D snoRNA U8, cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts (LCC), presenting at any age from early childhood to late adulthood. These mutations affect U8 expression, processing and protein binding and thus implicate U8 as essential in cerebral vascular homeostasis.

Radiologic Improvement After Early Medical Intervention in Localised Facial Morphea.

We report the case of a young girl who presented with hemiparesis, seizures, and subtle features consistent with a linear form of facial morphea (en coup de sabre). She was treated with pulsed parenteral steroids and oral steroids and started on methotrexate. Magnetic resonance imaging results and neurologic problems improved after 6 months. Switching off inflammation early in the course of disease seemed to reverse some of the central nervous system changes. Assessment of children with unexplained hemiparesis and seizures should include careful examination of the face and scalp, looking for subtle signs of skin change and asymmetry. This is one of the few reported cases of neuroradiologic improvement after immunosuppressive treatment in a child with en coup de sabre.

EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy.

Vici syndrome is a progressive neurodevelopmental multisystem disorder due to recessive mutations in the key autophagy gene EPG5. We report genetic, clinical, neuroradiological, and neuropathological features of 50 children from 30 families, as well as the neuronal phenotype of EPG5 knock-down in Drosophila melanogaster. We identified 39 different EPG5 mutations, most of them truncating and predicted to result in reduced EPG5 protein. Most mutations were private, but three recurrent mutations (p.Met2242Cysfs*5, p.Arg417*, and p.Gln336Arg) indicated possible founder effects. Presentation was mainly neonatal, with marked hypotonia and feeding difficulties. In addition to the five principal features (callosal agenesis, cataracts, hypopigmentation, cardiomyopathy, and immune dysfunction), we identified three equally consistent features (profound developmental delay, progressive microcephaly, and failure to thrive). The manifestation of all eight of these features has a specificity of 97%, and a sensitivity of 89% for the presence of an EPG5 mutation and will allow informed decisions about genetic testing. Clinical progression was relentless and many children died in infancy. Survival analysis demonstrated a median survival time of 24 months (95% confidence interval 0-49 months), with only a 10th of patients surviving to 5 years of age. Survival outcomes were significantly better in patients with compound heterozygous mutations (P = 0.046), as well as in patients with the recurrent p.Gln336Arg mutation. Acquired microcephaly and regression of skills in long-term survivors suggests a neurodegenerative component superimposed on the principal neurodevelopmental defect. Two-thirds of patients had a severe seizure disorder, placing EPG5 within the rapidly expanding group of genes associated with early-onset epileptic encephalopathies. Consistent neuroradiological features comprised structural abnormalities, in particular callosal agenesis and pontine hypoplasia, delayed myelination and, less frequently, thalamic signal intensity changes evolving over time. Typical muscle biopsy features included fibre size variability, central/internal nuclei, abnormal glycogen storage, presence of autophagic vacuoles and secondary mitochondrial abnormalities. Nerve biopsy performed in one case revealed subtotal absence of myelinated axons. Post-mortem examinations in three patients confirmed neurodevelopmental and neurodegenerative features and multisystem involvement. Finally, downregulation of epg5 (CG14299) in Drosophila resulted in autophagic abnormalities and progressive neurodegeneration. We conclude that EPG5-related Vici syndrome defines a novel group of neurodevelopmental disorders that should be considered in patients with suggestive features in whom mitochondrial, glycogen, or lysosomal storage disorders have been excluded. Neurological progression over time indicates an intriguing link between neurodevelopment and neurodegeneration, also supported by neurodegenerative features in epg5-deficient Drosophila, and recent implication of other autophagy regulators in late-onset neurodegenerative disease.