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We aimed to evaluate the percentage of posterior circulation arterial ischaemic stroke (PCAIS) caused by craniovertebral junction (CVJ) anomalies and describe their clinical course. Children admitted to a tertiary care paediatric hospital with PCAIS between July 2017 and December 2020 were assessed retrospectively for disease aetiology. We reviewed the clinical, radiological, and surgical details of children with evidence of CVJ anomalies. Fourteen (24.1%) of 58 children admitted with arterial ischaemic stroke had posterior circulation involvement. The mean age of patients presenting with posterior circulation stroke was 6 years 6 months (range 3 months–15 years), 11 were male. Six of 14 cases with PCAIS were due to CVJ anomaly, their ages ranged from 4 months to 15 years (two age ranges were noted, 4 months–4 years and 11–15 years), four were male. Two children had atlantoaxial dislocation with basilar invagination, two had Bow Hunter syndrome with Chiari malformation type 1 (one with completed stroke), one had Chiari malformation type 1 alone, and one presented with Farber disease with proatlas segmentation anomaly in CVJ. The time lag to stroke and CVJ diagnosis ranged from 2 weeks to 24 months. A dynamic angiogram was required to evaluate biomechanical changes on scans with inconclusive findings on standard stroke imaging. CVJ anomalies are an important treatable cause of paediatric posterior circulation stroke. Cervical spine x‐ray in flexion and extension should be done in all patients with posterior circulation stroke beyond the acute period. In cryptogenic aetiology, provocative angiography with guarded neck rotation should be considered to evaluate possible dynamic vertebral artery compression. What this paper adds: Craniovertebral junction anomalies are an important cause of posterior circulation stroke in children.Evidence of flat occiput, short neck, and short stature in children with posterior circulation stroke should be assessed.Dynamic imaging helps identify dynamic vertebral artery compression. [ABSTRACT FROM AUTHOR]

Paediatric movement disorders (PMDs) comprise a large group of disorders (tics, myoclonus, tremor, dystonia, chorea, Parkinsonism, ataxia), often with mixed phenotypes. Determination of the underlying aetiology can be difficult given the broad differential diagnosis and the complexity of the genotype–phenotype relationships. This can make the diagnostic process time‐consuming and difficult. In this overview, we present a diagnostic approach for PMDs, with emphasis on genetic causes. This approach can serve as a framework to lead the clinician through the diagnostic process in eight consecutive steps, including recognition of the different movement disorders, identification of a clinical syndrome, consideration of acquired causes, genetic testing including next‐generation sequencing, post‐sequencing phenotyping, and interpretation of test results. The aim of this approach is to increase the recognition and diagnostic yield in PMDs. What this paper adds: An up‐to‐date description and diagnostic framework for testing of paediatric movement disorders is presented.The framework helps to determine which patients will benefit from next‐generation sequencing. What this paper adds: An up‐to‐date description and diagnostic framework for testing of paediatric movement disorders is presented.The framework helps to determine which patients will benefit from next‐generation sequencing. [ABSTRACT FROM AUTHOR]

Copyright of Developmental Medicine & Child Neurology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Developmental Medicine & Child Neurology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Developmental Medicine & Child Neurology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Epilepsy of infancy with migrating focal seizures (EIMFS), one of the most severe developmental and epileptic encephalopathy syndromes, is characterized by seizures that migrate from one hemisphere to the other. EIMFS is genetically heterogeneous with 33 genes. We report five patients with EIMFS caused by recessive BRAT1 variants, identified via next generation sequencing. Recessive pathogenic variants in BRAT1 cause the rigidity and multifocal seizure syndrome, lethal neonatal with hypertonia, microcephaly, and intractable multifocal seizures. The epileptology of BRAT1 encephalopathy has not been well described. All five patients were profoundly impaired with seizure onset in the first week of life and focal seizure migration between hemispheres. We show that BRAT1 is an important recessive cause of EIMFS with onset in the first week of life, profound impairment, and early death. Early recognition of this genetic aetiology will inform management and reproductive counselling. [ABSTRACT FROM AUTHOR]

As yet, there is no aetiology-based intervention for autistic spectrum disorders (ASD); despite this, parents and professionals still need to make informed decisions regarding treatment options for children with ASD. This paper seeks to evaluate widely used interventions according to specific research criteria. Interventions presented are grouped into psychoeducational/behavioural approaches, psychopharmacological interventions, and the less traditional or complementary approaches. The conclusions are less than favourable: while some interventions do have empirical support, others have been proven to have no positive effects, and furthermore, there are no robust data favouring one approach over the others. Nevertheless, several criteria for choosing between treatment options are briefly discussed. [ABSTRACT FROM AUTHOR]

Aim: To agree wording of level descriptors for a measure of functional outcome of children's eating and drinking. Method: An online, modified Delphi method was used to gather feedback on current level descriptor wording and generate rewording suggestions. Thirty speech and language therapists, working in a variety of settings and geographical locations, were invited to be part of the Delphi expert panel. Content analysis was used to evaluate participants' comments and develop consensus level descriptors. Consensus for acceptable wording was set at 80% agreement. Face validity was assessed using 5‐point Likert scales. Results: Nineteen expert speech and language therapists (median experience 18 years) completed round one; 15 out of 19 completed round two. Level descriptor rating reached 80% agreement in two rounds. Additionally, 93% of participants agreed the scale would accurately capture change in their setting, with 87% likely to use the scale in practice. Interpretation: This study has produced agreed wording for a functional measure of eating and drinking activity suitable for use with paediatrics feeding disorders, regardless of disease aetiology, presentation, age, or setting. Potential for widespread use is supported. Further evaluation of the tool's reliability and validity is required. [ABSTRACT FROM AUTHOR]

This paper discusses some of the issues that, once resolved, may help child neurologists and pediatric neuroepidemiologists in their mutual understanding and collaborative efforts. Emphasis is placed on the all-too-frequent assumption that evidence-based medicine only covers the application of results from randomized double-blind trials in practice. A considerable proportion of child neurology concerns clinical diagnosis and etiological inference. Therefore, evidence-based child neurology might benefit not only from the therapeutic, but also from the diagnostic and etiological components of epidemiology. [ABSTRACT FROM AUTHOR]

Aim: To identify additional genes associated with infantile spasms using a cohort with defined infantile spasms. Method: Whole‐exome sequencing (WES) was performed on 21 consented individuals with infantile spasms and their unaffected parents (a trio‐based study). Clinical history and imaging were reviewed. Potentially deleterious exonic variants were identified and segregated. To refine potential candidates, variants were further prioritized on the basis of evidence for relevance to disease phenotype or known associations with infantile spasms, epilepsy, or neurological disease. Results: Likely pathogenic de novo variants were identified in NR2F1, GNB1, NEUROD2, GABRA2, and NDUFAF5. Suggestive dominant and recessive candidate variants were identified in PEMT, DYNC1I1, ASXL1, RALGAPB, and STRADA; further confirmation is required to support their relevance to disease etiology. Interpretation: This study supports the utility of WES in uncovering the genetic etiology in undiagnosed individuals with infantile spasms with an overall yield of five out of 21. High‐priority candidates were identified in an additional five individuals. WES provides additional support for previously described disease‐associated genes and expands their already broad mutational and phenotypic spectrum. [ABSTRACT FROM AUTHOR]

The aim of this study was to show the role of magnetic resonance imaging ( MRI) in elucidating the aetiology, or at least pathogenesis, of cerebral palsy ( CP). A systematic review of studies using MRI in children with CP was performed according to pathogenetic patterns characterizing different timing periods of occurence of the lesions, and with respect to gestational age (term vs preterm) and CP subtypes. Out of the studies published since 1990 in English, six met all the inclusion criteria; they involved children with spastic and dyskinetic CP. Abnormal MRI was reported in 334 out of 388 (86%) patients and gave clues to pathogenesis in 83%. Fourteen studies met only part of the inclusion criteria and abnormal MRIs were reported even more frequently in these (91%; 930/1022). Periventricular white matter lesions were most frequent (56%) followed by cortical and deep grey matter lesions (18%); brain maldevelopments were rather rare, described in 9%. Brain maldevelopments and grey matter lesions were more often seen in term than in preterm-born children with CP (brain maldevelopments: 16% vs 2.5%; grey matter lesions: 33% vs 3.5%); periventricular white matter lesions occurred significantly more often in preterm than in term-born children (90% vs 20%). CP is mainly characterized by brain lesions which can be identified by MRI in around 75% of preterm infants; brain maldevelopments occur in around 10%. [ABSTRACT FROM AUTHOR]

This commentary is on the original article by Elze et al. on pages 145–153 of this issue. [ABSTRACT FROM AUTHOR]

Aim: To describe cerebral palsy (CP) surveillance programmes and identify similarities and differences in governance and funding, aims and scope, definition, inclusion/exclusion criteria, ascertainment and data collection, to enhance the potential for research collaboration.Method: Representatives from 38 CP surveillance programmes were invited to participate in an online survey and submit their data collection forms. Descriptive statistics were used to summarize information submitted.Results: Twenty-seven surveillance programmes participated (25 functioning registers, two closed owing to lack of funding). Their aims spanned five domains: resource for CP research, surveillance, aetiology/prevention, service planning, and information provision (in descending order of frequency). Published definitions guided decision making for the definition of CP and case eligibility for most programmes. Consent, case identification, and data collection methods varied widely. Ten key data items were collected by all programmes and a further seven by at least 80% of programmes. All programmes reported an interest in research collaboration.Interpretation: Despite variability in methodologies, similarities exist across programmes in terms of their aims, definitions, and data collected. These findings will facilitate harmonization of data and collaborative research efforts, which are so necessary on account of the heterogeneity and relatively low prevalence of CP. [ABSTRACT FROM AUTHOR]

In comparison to hypotonia, hypertonia is less commonly expressed in the neonatal period. The scientific literature on the causes of neonatal hypertonia is scant, with no suggested diagnostic algorithm easily available to clinicians. Aetiologies include conditions affecting the central nervous system and spine, and rare peripheral neuromuscular disorders leading to hypertonia. Aetiology onset may be antepartum, peripartum with either transient hypertonia or persistent hypertonia which may appear later, or from a postnatal event/disease. This review discusses neonatal hypertonia and a diagnostic approach to neonatal hypertonia is suggested. [ABSTRACT FROM AUTHOR]

Neonatal encephalopathy, a clinical syndrome affecting term-born and late preterm newborn infants, increases the risk of perinatal death and long-term neurological morbidity, especially cerebral palsy. With the advent of therapeutic hypothermia, a treatment designed for hypoxic or ischaemic injury, associated mortality and morbidity rates have decreased. Unfortunately, only about one in eight neonates (95% confidence interval) who meet eligibility criteria for therapeutic cooling apparently benefit from the treatment. Studies of infants in representative populations indicate that neonatal encephalopathy is a potential result of a variety of antecedents and that asphyxial complications at birth account for only a small percentage of neonatal encephalopathy. In contrast, clinical case series suggest that a large proportion of neonatal encephalopathy is hypoxic or ischaemic, and trials of therapeutic hypothermia are specifically designed to include only infants exposed to hypoxia or ischaemia. This review addresses the differences, definitional and methodological, between infants studied and investigations undertaken, in population studies compared with cooling trials. It raises the question if there may be subgroups of infants with a clinical diagnosis of hypoxic-ischaemic encephalopathy (HIE) in whom the pathobiology of neonatal neurological depression is not fundamentally hypoxic or ischaemic and, therefore, for whom cooling may not be beneficial. In addition, it suggests approaches to future trials of cooling plus adjuvant therapy that may contribute to further improvement of care for these vulnerable neonates. [ABSTRACT FROM AUTHOR]

Aim To explore the appropriateness of using the interval-scale version of the Gross Motor Function Measure ( GMFM-66) in paediatric acquired brain injury ( ABI), and to characterize GMFM-66 recovery trajectories and factors that affect them. Method An observational study of gross motor recovery trajectories during rehabilitation at a single specialist paediatric in-patient rehabilitation centre using repeated GMFM-66 observations. The cohort comprised children rehabilitating after severe ABI of various causes. Results A total of 287 GMFM observations were made on 74 children (45 males, 29 females; age-at-injury range 0.3-17.3y, median age 11.3y, interquartile range 6.6-15.0y). Differences in item-difficulty estimates between this sample and the cerebral palsy population in which the GMFM-66 was initially developed are not detectable at this sample size. Changes in GMFM over time show lag-exponential forms. Children sustaining hypoxic-ischaemic injuries made the slowest and least complete recoveries. Older children made faster gross motor recoveries after controlling for aetiology. The time at which gross motor ability began to rise coincided approximately with admission to the rehabilitation facility. Interpretation Aetiology is strongly associated with gross motor recovery after ABI. Younger age at injury was associated with slower recovery. Comparable item-difficulty scores in this sample and in the cerebral palsy population suggest comparable sequences of gross motor ability reacquisition. [ABSTRACT FROM AUTHOR]

Aim The aim of this study was to assess the associations between dysmorphic features and neurological, mental, psychomotor, and behavioural development in order to improve our understanding of aetiological pathways leading to minor developmental problems. Method In our cross-sectional study, 272 generally healthy 2-year-olds (143 males, 129 females; median gestational age 39 weeks, [range 30-43wks]), born after a parental history of subfertility either with or without fertility treatment, were examined. Dysmorphic features were classified as abnormalities (clinically relevant or not), minor anomalies, or common variants according to Merks' classification system. Hempel's neurological assessment resulted in a neurological optimality score ( NOS) and fluency score. Mental and psychomotor development were assessed with the Dutch version of the Bayley Scales of Infant Development and behavioural development with the Achenbach Child Behaviour Checklist. Results Of the different types of dysmorphic feature, clinically relevant abnormalities were most strongly associated with a lower NOS (difference −2.53, 95% confidence interval [ CI] −4.23 to −0.83) and fluency score (difference −0.62, 95% CI −1.1 to −0.15). The presence of one or more abnormalities (clinically relevant or not) or one or more common variants was significantly associated with a lower NOS, and the presence of three or more minor anomalies was associated with lower fluency scores. Dysmorphic features were not associated with mental, psychomotor, or behavioural development. Interpretation As dysmorphic features originate during the first trimester of pregnancy, the association between dysmorphic features and minor alterations in neurodevelopment may suggest an early ontogenetic origin of subtle neurological deviations. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder ( ASD) is a heterogeneous neurodevelopmental disorder of multifactorial origin. Today, ASD is generally not curable, although it is treatable to a varying degree to prevent worse outcomes. Some reports indicate the possibility of major improvements or even recovery in ASD. However, these studies are based on scientific shortcomings, and the lack of a clear definition of 'cure' in ASD further compromises interpretation of research findings. The development of animal models and decreasing costs of genome sequencing provide new options for treatment research and individualized medicine in ASD. This article briefly reviews several issues related to the question whether there is recovery from ASD, starting with a short overview of the presumed aetiologies. [ABSTRACT FROM AUTHOR]

AIM: The aim of this study was to assess the diagnostic approach to microcephaly in childhood and to identify the prevalence of the various underlying causes/disease entities. METHOD: We conducted a retrospective study on a cohort of 680 children with microcephaly (399 males, 281 females; mean age at presentation 7-8mo, range 1mo-5y) from patients presenting to Charité - University Medicine Berlin (n=474) and University Hospital Dresden (n=206). Patient discharge letters were searched electronically to identify cases of microcephaly, and then the medical records of these patients were used to analyze parameters for distribution. RESULTS: The putative aetiology for microcephaly was ascertained in 59% of all patients, leaving 41% without a definite diagnosis. In the cohort of pathogenetically defined microcephaly, genetic causes were identified in about half of the patients, perinatal brain damage accounted for 45%, and postnatal brain damage for 3% of the cases. Microcephaly was associated with intellectual impairment in 65% of participants, epilepsy was diagnosed in 43%, and ophthalmological disorders were found in 30%. Brain magnetic resonance imaging revealed abnormalities in 76% of participants. INTERPRETATION: Microcephaly remains a poorly defined condition, and a uniform diagnostic approach is urgently needed. A definite aetiological diagnosis is important in order to predict the prognosis and offer genetic counselling. Identifying gene mutations as causes of microcephaly increases our knowledge of brain development and the clinical spectrum of microcephaly. We therefore propose a standardized initial diagnostic approach to microcephaly. [ABSTRACT FROM AUTHOR]

Selective motor control (SMC) impairment involves movement patterns dominated by flexor or extensor synergies that interfere with functional movements in children with cerebral palsy ( CP). Emerging evidence on neural correlates of impaired SMC has important implications for etiology and for the treatment for children with CP. Early evidence on the microstructure of brain white matter assessed with diffusion tensor imaging in adult patients after stroke suggests that the rubrospinal tract may compensate for injury to the corticospinal tract. Furthermore, the observed changes on diffusion tensor imaging corresponded to the degree of SMC impairment. The rubrospinal tract may provide imperfect compensation in response to corticospinal tract injury, resulting in diminished SMC. Cortical mapping evidence in stroke patients indicates that loss of SMC is also associated with increased overlap of joint representation in the sensorimotor cortices. The severity of SMC impairment can be assessed with the recently developed Selective Control Assessment of the Lower Extremity, a validated observation-based measure designed for children with spastic CP. Recent advances in neuroimaging and assessment of SMC provide an opportunity to better understand the etiology and impact of impaired SMC, which may ultimately guide strategic treatment for children with CP. [ABSTRACT FROM AUTHOR]

Aims The objective of this study was to describe a cohort of infants with basal ganglia stroke associated with mineralization in the lenticulostriate arteries and their clinical outcomes. Method Subcortical strokes occurring in infants during the study period were categorized as arterial ischaemic, venous, or haemorrhagic. A cohort of infants with basal ganglia infarcts and associated mineralization of lenticulostriate arteries were identified. This group was analysed for possible aetiological factors, clinical course, and recurrence rate of the stroke. Results Of 23 infants with basal ganglia arterial ischaemic stroke, 22 (16 males, six females; mean age 11mo [±SD 4.8mo]) were found to have lenticulostriate artery mineralization. Twenty infants presented with hemiparesis and two presented with recurrent episodes of hemidystonia. Eighteen infants had a history of minor trauma before onset of stroke. No other predisposing factors were identified in this cohort. There were no demonstrable causes for vascular and soft tissue calcification. The mean follow-up was 11 months, during which five infants experienced stroke recurrence. Of the 17 infants who did not experience a recurrent stroke, eight exhibited complete neurological recovery, and nine had mild residual hemiparesis. Interpretation Acute basal ganglia stroke after minor trauma associated with mineralization of lenticulostriate arteries in infants is a distinct clinicoradiological entity. Investigations for prothrombotic states and vasculopathies are normal. Although neurological outcomes in most children are good, trauma is a risk factor for recurrence of stroke. [ABSTRACT FROM AUTHOR]

This commentary is on the original article by Smith et al on pages 264–270 of this issue. [ABSTRACT FROM AUTHOR]

Aim The aim of this study was to examine the impact of dystonia aetiology and duration, contracture, and age at deep brain stimulation ( DBS) surgery on outcome in a cohort of children with medically refractory, disabling primary, secondary-static, or secondary-progressive dystonias, including neurodegeneration with brain iron accumulation ( NBIA). Method Dystonia severity was assessed using the Burke- Fahn- Marsden Dystonia Rating Scale ( BFMDRS) motor score at baseline and 6 and 12 months postoperatively in a cohort of 70 consecutive children undergoing DBS between June 2005 and July 2011. Results Two children (3%) received unilateral DBS for hemidystonia and were excluded and five (7%) developed infections requiring part- DBS removal within 6 months, leaving 63 children (90%) undergoing bilateral DBS for follow-up (34 males, 29 females; mean age at surgery for the whole group 10y 4mo, SD 4y 2mo, range 1-14y). Seventeen children were classified with primary dystonia: mean age 12 years 11 months, SD 4 years 6 months range 4 years 6 months to 17 years 3 months; 28 as having secondary-static dystonia: mean age 10 years 2 months, SD 4 years 9 months (range 3y 3mo-20y); five as having secondary-progressive dystonia: mean age 8 years 11 months, SD 3 years 9 months (range 5y 5mo-13y 1mo); and 13 as having NBIA dystonia: mean age 10 years 2 months, SD 3 years 11 months (range 1-14y). Children with primary dystonias demonstrated greater improvements in BFMDRS motor score than those in the other aetiological categories ( Kruskal- Wallis test, p<0.001), which correlated negatively with dystonia duration and more strongly still against the ratio of dystonia duration normalized to age at surgery ( DD/ AS ratio) at 1 year (Spearman's rank correlation coefficient 0.4752 and −0.599 respectively). A similar significant negative correlation was found in the secondary-static dystonia group between outcome at 1 year and DD/ AS ratio (−0.461). Poorer outcome in secondary dystonia coincided with the absence of a period of normal motor development in comparison with the primary dystonia group. A significant improvement in BFMDRS motor score was seen in the NBIA group at 6, but not 12 months ( Wilcoxon signed rank test p=0.028, p=0.85 respectively). No reduction in efficacy was seen in children with a musculoskeletal deformity at the time of surgery. Conclusion Response to pallidal DBS in the treatment of dystonia declines with the proportion of life lived with dystonia in primary and secondary dystonia. Other intrinsic factors reduce the median magnitude of reduction in secondary dystonia after DBS. DBS should be offered early, preferably within 5 years of onset, to maximize benefits and reduce the childhood experience of dystonia, including musculoskeletal deformity. Other multidimensional assessments are required to understand how DBS improves the lives of children with dystonia. [ABSTRACT FROM AUTHOR]

Aim Having previously shown that comorbidity is a major determinant of neurological sequelae in hypoglycaemia, our aim was to describe the neuroimaging patterns of brain damage in different hypoglycaemic situations and to elucidate the factors that determine lesion topography. Method We reviewed 50 patients (31 females, 19 males) with symptomatic hypoglycaemia (<2.8mmol/L) occurring between 1 day and 5 years of age (median 4d) who had undergone magnetic resonance imaging (MRI; at least axial T2-weighted, sagittal T1-weighted, and coronal fluid-attenuated inversion recovery [FLAIR]-weighted imaging). MRI was performed during the follow-up examination at least 1 month after the occurrence of symptomatic hypoglycaemia, i.e. between 1 month and 5 years of age (median 3mo). Hypoglycaemia resulted from three inborn errors of metabolism: congenital hyperinsulinism (33 patients), fatty acid β-oxidation disorders (13 patients), or glycogen storage disease type I (four patients). We selected the patients with clear MRI abnormalities and analysed their topography according to aetiology and age at occurrence of the lesion. Results The topography of the brain lesions depended on age: from the neonatal period to 6 months of age, lesions predominantly involved the posterior white matter; between 6 and 22 months the basal ganglia, and after 22 months the parietotemporal cortex ( p=0.04). Interpretation The relationship between brain lesions and age could reflect the maturation sequence of the brain. [ABSTRACT FROM AUTHOR]

Aim To determine risk factors for neurological sequelae following hypoglycemia. Method We analysed the neurological outcome in 164 patients (mean age 10y 10mo, SD 5.9) following hypoglycemia due to three diseases with various metabolic contexts, different ages at onset, and combinations with comorbidity (fever/infection, hypoxia/ischemia): glycogen storage disease type I (GSDI) (21 patients, mean age at first hypoglycemic episode 3.8mo, SD 3.5); fatty acid β-oxidation defects (FAOD) (29 patients, mean age at first hypoglycemic episode 14.8mo, SD 12.6); and hyperinsulinism (HIns) (114 patients, mean age at first hypoglycemic episode 2.3mo, SD 4.7). Results Risk factors of poor neurological outcome were aetiology ( p<0.006), comorbidity ( p<0.001), and prolonged convulsions ( p<0.001). Ordinal logistic regression showed that comorbidity ( p<0.001) and status epilepticus ( p=0.002) were the main determinants of sequelae. Asymptomatic hypoglycemia did not lead to sequelae, whatever the aetiology. Age was not correlated to sequelae, whatever the aetiology. The highest prevalence of hypoglycemic sequelae was found in FAOD and HIns combined with comorbidity, the lowest in GSDI ( p<0.001) in which hypoglycemia is often asymptomatic, associated with increased plasma lactate, and rarely combined with comorbidity. Interpretation Hypoglycemia is severely deleterious for the brain in the context of fever/infection and/or hypoxia/ischemia, and status epilepticus. The metabolic context providing alternative fuels may improve neurological outcome. [ABSTRACT FROM AUTHOR]

Aim The aim of the study was to describe seizure outcome following surgery for focal extratemporal epilepsy and identify factors associated with prolonged postsurgical freedom from seizures. Method In this retrospective cohort study, children with drug-resistant focal extratemporal epilepsy were treated surgically and followed up in a single tertiary care centre between 1997 and 2008. Results Eighty children were identified for inclusion in the study (42 males, 38 females; median age 9y 1mo, range 3mo-18y 7mo). The aetiology was identified as focal cortical dysplasia ( n=37), low-grade tumour ( n=22), tuberous sclerosis ( n=9), or non-specific ( n=12). Children were followed for a median of 3 years 1 month (range 8mo-10y 7mo) after surgery. Overall, at last follow-up, 50% of the children had been completely seizure free since surgery (Engel class Ia); of these 40 individuals, 15 had discontinued all antiepileptic drugs. Several presurgical factors were associated with a favourable outcome. However, after controlling for confounding factors, aetiology appeared to be the only determinant of long-term seizure outcome as non-specific lesion pathology was associated with seizure recurrence (hazard ratio 10.43; 95% confidence interval 3.26-33.39). Interpretation In 50% of cases, children with surgically treated drug-resistant extratemporal epilepsies have an excellent long-term outcome. The aetiology of the epileptogenic lesion appears to be the only significant determinant of surgical outcome in this population of children. It is difficult to correctly identify non-specific pathology on presurgical magnetic resonance imaging. [ABSTRACT FROM AUTHOR]

Aim Cerebral visual impairment (CVI) is a disorder caused by damage to the retrogeniculate visual pathways. Cerebral palsy (CP) and CVI share a common origin: 60 to 70% of children with CP also have CVI. We set out to describe visual dysfunction in children with CP. A further aim was to establish whether different types of CP are associated with different patterns of visual involvement. Methods A total of 129 patients (54 females, 75 males; mean age 4y 6mo, SD 3y 5mo; range 3mo-15y) with CP (51 with diplegia, 61 with tetraplegia, and 17 with hemiplegia; 62 [48%] of participants were able to walk) and CVI enrolled at the Centre of Child Neuro-ophthalmology (at the Department of Child Neurology and Psychiatry, IRCCS 'C. Mondino Institute of Neurology', University of Pavia) underwent an assessment protocol including neurological examination, developmental and/or cognitive assessment, neuro-ophthalmological evaluation including ophthalmological assessment, evaluation of visual acuity, contrast sensitivity, optokinetic nystagmus, visual field and stereopsis, and neuroradiological investigations. Results Visual dysfunction in diplegia was characterized mainly by refractive errors (75% of patients), strabismus (90%), abnormal saccadic movements (86%), and reduced visual acuity (82%). The participants with hemiplegia showed strabismus (71%) and refractive errors (88%); oculomotor involvement was less frequent (59%). This group had the largest percentage of patients with altered visual field (64%). Children with tetraplegia showed a severe neuro-ophthalmological profile, characterized by ocular abnormalities (98%), oculomotor dysfunction (100%), and reduced visual acuity (98%). Interpretation Neuro-ophthalmological disorders are one of the main symptoms in CP. Each clinical type of CP is associated with a distinct neuro-ophthalmological profile. Early and careful neuro-ophthalmological assessment of children with CP is essential for an accurate diagnosis and for personalized rehabilitation. [ABSTRACT FROM AUTHOR]

Aims We have identified an excess of children with cerebral palsy (CP) born to women who received antibiotic treatment for spontaneous preterm labour (SPL). This nested study investigated the profile of impairment among children with CP in the ORACLE Children Study (OCS), and contrasted outcomes with those in 4Child, a population CP registry. Method The study group comprised 167 children aged from 7 to 10 years (100 males, 67 females) with CP from the OCS, who were subdivided into a preterm rupture of membranes (PROM) group (87 children) and an SPL group (80 children). The OCS sought follow-up information regarding the health and behaviour of surviving children at 7 years of age in the UK using a parent-report postal questionnaire. Families provided further information to define wider aspects of function and were offered a physiotherapy assessment. Results The prevalence of CP was higher among children in the OCS than among those in 4Child (standardized morbidity ratios: SPL group, 3.12 [95% confidence interval CI 2.47-3.87); PROM group: 1.56 (CI 1.24-1.92)]. The proportion of children with CP born after 32 weeks of gestation was higher in in the SPL group (73%) than in the PROM group (30%); the prevalence of CP was higher in the SPL group than in the PROM group or 4Child. Children with CP in the OCS tended to have similar distributions of neuroimpairment as children in 4Child, but motor impairment and associated vision and hearing problems were found to be less severe. Interpretation The pattern of CP in both the PROM and the SPL groups was similar, but functional outcomes were milder, compared with children with CP in the general population. However, in these groups the risk of CP was increased independently of gestational age. This is consistent with findings that ongoing inflammatory damage can cause CP. [ABSTRACT FROM AUTHOR]

Aim 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. Method 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). Results 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. Interpretation 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. [ABSTRACT FROM AUTHOR]

Mitochondrial respiratory chain diseases represent one of the most common inherited neurometabolic disorders of childhood, affecting a minimum of 1 in 7500 live births. The marked clinical, biochemical, and genetic heterogeneity means that accurate genetic counselling relies heavily upon the identification of the underlying causative mutation in the individual and determination of carrier status in the parents. Isolated complex I deficiency is the most common respiratory chain defect observed in children, resulting in organ-specific or multisystem disease, but most often presenting as Leigh syndrome, for which mitochondrial DNA mutations are important causes. Several recurrent, pathogenic point mutations in the MTND3 gene - including m.10191T>C ( p.Ser45Pro) - have been previously identified. In this short clinical review we evaluate the case reports of the m.10191T>C mutation causing complex I-deficient Leigh syndrome described in the literature, in addition to two new ones diagnosed in our laboratory. Both of these appear to have arisen de novo without transmission of the mutation from mother to offspring, illustrating the importance not only of fully characterizing the mitochondrial genome as part of the investigation of children with complex I-deficient Leigh syndrome but also of assessing maternal samples to provide crucial genetic advice for families. [ABSTRACT FROM AUTHOR]

Aim The functional polymorphism Val158Met in the catechol- O-methyltransferase ( COMT) gene was analysed to determine its association with maternal stress and childhood total difficulties. Method Data were collected at birth from a group of infants who were born small for gestational age and a group who were born at an appropriate size for gestational age and had been enrolled in the Auckland Birthweight Collaborative Study. Children were followed up at the ages of 1 year, 3 years 6 months, 7 years, and 11 years. At the age of 11 years, DNA samples were collected from 546 children (270 females, 276 males): 227 children born small for gestational age and 319 children born at an appropriate size for gestational age. The main independent variable was perceived maternal stress at birth and at 7 and 11 years of age, assessed using the total difficulties scale of the Strength and Difficulties Questionnaire. IQ was assessed at the age of 7 years. Results Met/Met homozygotes were at a significantly increased risk of behavioural and emotional problems at the ages of 7 ( p=0.002) and 11 years ( p=0.003), relative to either heterozygous or homozygous carriers of the Val158Met polymorphism, but only when they were exposed to maternal stress in utero. Met/Met homozygotes had, on average, IQ scores that were four points higher than those of Val/Val homozygotes ( p=0.010). Interpretation These findings emphasize the potential long-term consequences of prenatal stress for genetically susceptible individuals during neurodevelopment in utero. Our findings add to the general understanding of the aetiology and developmental nature of childhood emotional and behavioural problems. [ABSTRACT FROM AUTHOR]

The article presents recommendations on clinical practice guidelines (CPG) for developmental coordination disorder (DCD) by the European Academy of Childhood Disability (EACD). The goals of the CPG-DCD include determining key questions on aetiology, diagnosis and intervention, raising priority practice questions and advising on the best evidence-based practice. The article states that healthcare professionals handling children with confirmed or suspected DCD may use the CPG.

Severe myoclonic epilepsy of infancy (SMEI) is a complex form of epilepsy that was first described in France in 1978. Because the myoclonic component of this epilepsy is not always present and because some variability has been observed in the symptomatology, the name was changed to Dravet syndrome in 1989. The genetic aetiology of this epilepsy was discovered in 2001, and since then numerous studies have contributed to a better knowledge of the disease. Around 70% of affected patients are carriers of a mutation on the alpha subunit of the SCN1A gene. An accurate analysis of the clinical features leads to the distinction between typical and atypical forms, both with the same unfavourable prognosis and the same genetic background. However, many studies are being conducted in order to establish correlations between phenotypes and genotypes, and to understand the factors underlying the cognitive impairment of the affected patients. [ABSTRACT FROM AUTHOR]

To study the aetiology of intellectual disability in patients presenting to hospital and the diagnostic yield of a standardized examination. Over a 1-year period, the first three children presenting to the paediatric outpatients department (OPD) on 2 selected weekdays with developmental delay, suspected intellectual disability, or school failure were enrolled for study if they satisfied standard definitions of global developmental delay (GDD), or intellectual disability as tested by scales for Indian children: Developmental Assessment for Indian Infants, Binet Karnat Test, and the Vineland Social Maturity Scale (Malin's Adaptation). Detailed history, and physical and neurological examinations were recorded. An algorithmic approach to investigations was followed. Also, neuroimaging, thyroid function, electroencephalograph, karyotyping, and studies for fragile-X syndrome were conducted. Aetiological diagnosis was considered established only if clinical features were supported by investigations. Clinical features associated with a successful aetiological diagnosis were computed. A total of 122 children were enrolled in a cross-sectional analytic study (mean age 43.5mo [SD 40.66]; 84 males, 38 females). Of these, a definite aetiology could be assigned in 66 children (54.1%); 17 prenatal, 38 perinatal/neonatal, and 11 postneonatal. Factors associated with reaching a definite diagnosis included younger age at presentation, presence of seizures, microcephaly, adverse neonatal events, and abnormal motor signs. Clinical history and examination gave important clues to the aetiology in 89 (72.9%) patients. Neuroimaging was abnormal in 91 out of 114 children, with aetiological findings in 48 children. Perinatal/neonatal causes predominate as the cause of GDD or intellectual disability in India. The study highlights that a large majority of cases seen here were preventable. [ABSTRACT FROM AUTHOR]

Aim The effects of sensorineural hearing loss (SNHL) are often complicated by additional disabilities, but the epidemiology of associated disorders is not clearly defined. The aim of this study was to evaluate the frequency and type of additional neurodevelopmental disabilities in a sample of children with SNHL and to investigate the relation between these additional disabilities and the aetiology of deafness. Method One hundred children with severe/profound SNHL (60 males, 40 females; mean age 5y 7mo, SD 3y 6mo, range 8mo–16y) were investigated using a diagnostic protocol including neurodevelopmental, genetic, neurometabolic, and brain magnetic resonance imaging (MRI) assessment. Results Forty-eight per cent of the sample exhibited one or more additional disabilities, with cognitive, behavioural–emotional, and motor disorders being the most frequent. The risk of additional disabilities varied according to the type of aetiology. Thirty-seven out of 80 individuals with available MRIs showed signal abnormalities, in particular brain malformations (46%) and white matter abnormalities (54%). Frequency and type of disability were associated with aetiology ( p=0.015) and MRI data ( p<0.001). Interpretation A multidimensional evaluation, including aetiological, neurodevelopmental, and MRI investigation, is needed for planning therapeutic intervention, such as cochlear implantation in children with severe to profound hearing impairment. The aetiology of deafness is a relevant risk indicator for the presence of an associated disorder. [ABSTRACT FROM AUTHOR]

Aim It has been suggested that high levels of prenatal testosterone exposure are implied in the aetiology of attention-deficit–hyperactivity disorder (ADHD). This study examined the association between the ratio of the length of the second and fourth digits (2D:4D ratio), a marker of fetal testosterone exposure, and the presence of ADHD-related cognitive and behavioural problems in children with ADHD and in typically developing comparison individuals. Method A clinically referred group of 64 children who fulfilled DSM-IV-TR criteria for ADHD (47 males, 17 females; mean age 8y 8mo, SD 1y 8mo, range 7–12y) and 46 comparison children (25 males, 21 females; mean age 9y 2mo; SD 1y 10mo, range 7–12y) were included in the study. The length of the second and fourth digits was measured by two independent raters. The Child Behaviour Checklist (CBCL) and the Test of Everyday Attention for Children (TEA-Ch) were used to assess behavioural problems and different aspects of attention. Results No group differences in 2D:4D ratio were observed between children with (combined, inattentive, or hyperactive-impulsive subtype of) ADHD and comparison children. The ratio did not show the postulated relation with cognitive and behavioural aspects of ADHD. Interpretation These findings challenge the hypothesis that fetal testosterone exposure plays a prominent role in the aetiology of ADHD. [ABSTRACT FROM AUTHOR]

A de novo 4.1-megabase microdeletion of chromosome 1p34.2p34.3 has been identified by array-based comparative genomic hybridization in a young male with severely delayed development, microcephaly, pronounced hypotonia, and facial dysmorphism. The deleted region encompasses 48 genes, among them the glucose transporter 1 ( SLC2A1 or GLUT1) gene. The deletion of the GLUT1 gene was in line with the abnormal ratio of cerebrospinal fluid (CSF) glucose to blood glucose, indicative of GLUT1 deficiency syndrome (MIM #606777). GLUT1 deficiency syndrome is characterized by therapy-resistant infantile seizures, developmental delay, acquired microcephaly, spasticity, ataxia, and a low concentration of glucose in the CSF. It is known that a ketogenic diet can lead to better control of seizures. This case study shows that identifying a microdeletion as the cause of learning disability is not only important for genetic counselling but might also lead to therapeutic intervention. [ABSTRACT FROM AUTHOR]

This supplement deals with the definition and classification of cerebral palsy (CP). The disease was predominantly studied in relation to pathology and aetiology of the impairment. But it was during the 19th century that the discussion on the definition of CP was first recorded in medical literature. A lecture of English orthopaedic surgeon William Little in 1843 has elucidated the seminal work describing CP. In the 1940s and 1950s, Myer Perlstein, an American neurologist, recounted methods for classifying CP children.

Diagnosing ischaemic stroke and determining its cause is difficult in children. Both are important for selection of treatment and prediction of outcome. This study explored the diagnostic changes that lead to a delay in the correct diagnosis of paediatric stroke. Case histories of 45 children with ischaemic stroke (31 males, 14 females; median age 6y; age range 2mo–16y) were retrospectively reviewed. The initial clinical diagnosis, based on the interpretation of presenting symptoms, was compared with the final aetiological stroke diagnosis after completion and review of diagnostic work-up. The type of diagnostic change, consequent time delay until correct diagnosis, reasons for change of diagnosis, and alterations to management were evaluated. Twenty-four diagnostic changes were identified; 19 in ‘primary stroke diagnosis’ (symptoms initially not attributed to stroke), and five in ‘aetiological diagnosis’ (incorrect initial determination of type or cause of stroke). The median interval between initial and final diagnosis was 7 days (3h–2y). The change in diagnosis led to therapeutic alterations in 17 patients. Risk factors for childhood stroke differ from those in adults. Stroke is frequently not recognized as the cause of the child's symptoms, and the correct determination of stroke aetiology takes time. We recommend that children with stroke be evaluated in a centre with expertize, using standardized diagnostic protocols and careful follow-up. [ABSTRACT FROM AUTHOR]

Children with autism have a relatively shorter index finger (2D) compared with their ring finger (4D). It is often presumed that the 2D:4D ratio is associated with fetal testosterone levels and that high fetal testosterone levels could play a role in the aetiology of autism. It is unknown whether this effect is specific to autism. In this study, 2D:4D ratios of 144 males aged 6 to 14 years (mean age 9y 1mo [SD 1y 11mo]) with psychiatric disorders were compared with those of 96 males aged 6 to 13 years from the general population (mean age 9y 1mo [SD 1y 10mo]). Psychiatric disorders were divided into autism/Asperger syndrome (n=24), pervasive developmental disorder–not otherwise specified (PDD–NOS; n=26), attention-deficit–hyperactivity disorder (ADHD)/oppositional defiant disorder (ODD; n=68), and anxiety disorders (n=26). Males with autism/Asperger syndrome (p<0.05) and ADHD/ODD (p<0.05) had significantly lower (though not significantly; p=0.52) ratios than males with an anxiety disorder, and males with autism/Asperger syndrome had lower ratios than those in the comparison group. These results indicated that higher fetal testosterone levels may play a role, not only in the origin of autism, but also in the aetiology of PDD–NOS and of ADHD/ODD. Males with anxiety disorders might have been exposed to lower prenatal testosterone levels. [ABSTRACT FROM AUTHOR]

Hydrocephalus in children has many aetiologies, and can cause multiple ophthalmic and visual disorders. This study sets out to detect and quantify visual and visuoperceptual dysfunction in children who have received surgical treatment for hydrocephalus with and without myelomeningocele, and to relate the results to the associated diagnoses and results from a comparison group. Seventy-five school-aged children (41 males, 34 females) with surgically-treated hydrocephalus and 140 comparison children (76 males, 64 females) matched for age and sex underwent comprehensive ophthalmologic examination. Median age at examination was 9 years and 4 months (range 7y 4mo–12y 10mo). Visual function deficits were identified in 83% (62/75) of the children with hydrocephalus. Visual impairment (binocular visual acuity <0.3) was found in 15% (11/73; comparison group 0%) but in none with myelomeningocele. Strabismus was found in 69% (51/74; comparison group 4% [5/140], p<0.001), and refractive errors were found in 67% (47/70; comparison group 20% [28/140], p<0.001). Cognitive visual dysfunction was identified in 59% (38/64; comparison group 3% [4/140], p<0.001). These disorders were identified in various combinations and comprised impaired ability to plan movement through depth (e.g. going down a stair), impaired simultaneous perception, impaired perception of movement, impaired orientation, and (least frequently) impaired recognition. In this study, children with hydrocephalus associated with myelomeningocele were least commonly affected. Visual disorders were most frequent in those with epilepsy, cerebral palsy, and/or cognitive disability. [ABSTRACT FROM AUTHOR]

Idiopathic brachial neuritis (idiopathic neuralgic amyotrophy) in children is a well-recognized but rare condition. Although the precise aetiology is unknown, its usual occurrence after an infection suggests an immunological process. There is no specific test for brachial neuritis, and the diagnosis is one of exclusion with supportive evidence from nerve conduction studies, electromyography (EMG), and, in adults, changes in affected muscles on magnetic resonance imaging. Young children are often unable to tolerate EMG. [ABSTRACT FROM AUTHOR]

This commentary is on the original article by Trønnes et al. on pages 779–785 of this issue. [ABSTRACT FROM AUTHOR]

Aim In this observational study, we adopted a systematic approach to the radiological phenotyping of disorders associated with intracranial calcification, with the aim of determining if characteristic patterns could be defined as an aid to the future diagnosis of known conditions and the identification of new disorders. Method A cranial imaging-based scoring system was devised using both computed tomography and magnetic resonance imaging data. Patients were grouped into diagnostic categories where a definitive molecular diagnosis was known, or where the clinical and radiological features suggested a specific diagnosis. For patients in whom the diagnosis was unknown, subgroups were defined according to shared radiological features. Results Data on 244 scans from 119 patients were analysed. A specific diagnosis was available for 59 patients (31males, 28 females; median age 50mo, range 1wk to 54y). These were as follows (number of patients in brackets): Aicardi-Goutières syndrome (33), cerebroretinal microangiopathy with calcification and cysts (10), band-like calcification with simplified gyration and polymicrogyria (6), COL4A1-related disease (3), Degos disease (2), Krabbe disease (2), Alexander disease (1), mitochondrial disease (1), and tetrasomy 15 (1). In 60 patients the aetiology was unknown. Within this group, subsets demonstrating shared characteristics suggestive of a specific calcification phenotype could be identified. Interpretation This study confirms the value of a systematic approach to radiological phenotyping of disorders associated with intracranial calcification. [ABSTRACT FROM AUTHOR]

The author comments on a study which described the etiological yield and profile of a consecutive series of children with intellectual disability or global developmental delay (GDD) seen in the pediatric outpatient department (POD) and pediatric neurology clinics in India. He believes that the study offers considerable opportunities for prevention, including improved access to obstetric and neonatal care, along with routine pediatric immunizations against bacterial pathogens.