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Summary Background Acute flaccid myelitis (AFM) is characterised by rapid onset of limb weakness with spinal cord grey-matter abnormalities on MRI scan. We aimed to assess whether detection of enterovirus in respiratory or other specimens can help predict prognosis in children with AFM. Methods In this nationwide, longitudinal study, we evaluated the significance of detection of enterovirus in any sample in predicting outcomes in a cohort of Canadian children younger than 18 years presenting with AFM to tertiary paediatric hospitals in Canada in 2014 and 2018. All patients fulfilled the 2015 US Centers for Disease Control and Prevention case definition for definite AFM or probable AFM. Clinical data, laboratory findings, treatment, and neuroimaging results were collected (follow up period up to 5 years). We assessed neurological function and motor outcomes using Kurtzke's Expanded Disability Status Scale (EDSS) and a Weakest Limb Score. Findings 58 children with AFM (median age 5·1 years, IQR 3·8–8·3) were identified across five of Canada's ten provinces and three territories. 25 (43%) children had enterovirus detected in at least one specimen: 16 (64%) with EV-D68, two (8%) with EV-A71, two (8%) with coxsackievirus, 10 (40%) with untyped enterovirus. Children who were enterovirus positive were more likely than those that were negative to have had quadriparesis (12 [48%] of 25 vs four [13%] of 30; p=0·028), bulbar weakness (11 [44%] of 25 vs two [7%] of 30; p=0·028), bowel or bladder dysfunction (14 [56%] of 25 vs seven [23%] of 30; p=0·040), cardiovascular instability (nine [36%] of 25 vs one [3%] of 30; p=0·028), and were more likely to require intensive care unit admission (13 [52%] of 25 vs 5 [17%] of 30; p=0·028). On MRI, most children who were enterovirus positive showed brainstem pontine lesions (14 [61%] of 23), while other MRI parameters did not correlate with enterovirus status. Median EDSS of enterovirus positive (EV+) and enterovirus negative (EV–) groups was significantly different at all timepoints: baseline (EDSS 8·5, IQR 4·1–9·5 vs EDSS 4·0, IQR 3·0–6·0; p=0·0067), 3 months (EDSS 4·0, IQR 3·0–7·4 vs EDSS 3·0, IQR 1·5–4·3; p=0·0067), 6 months (EDSS 3·5, IQR 3·0–7·0 vs EDSS 3·0, IQR 1·0–4·0; p=0·029), and 12 months (EDSS 3·0, IQR 3·0–6·9 vs EDSS 2·5 IQR 0·3–3·0; p=0·0067). Kaplan-Meier survival analysis of a subgroup of patients showed significantly poorer motor recovery among children who tested positive for enterovirus than for those who tested negative (p=0·037). Interpretation Detection of enterovirus in specimens from non-sterile sites at presentation correlated with more severe acute motor weakness, worse overall outcomes and poorer trajectory for motor recovery. These results have implications for rehabilitation planning as well as counselling of families of children with these disorders. The findings of this study support the need for early testing for enterovirus in non-CNS sites in all cases of AFM. Funding None.

Genetically determined leukoencephalopathies comprise a group of rare inherited white matter disorders. The majority are progressive diseases resulting in early death. We performed a cross-sectional pilot study including 55 parents from 36 families to assess the level of stress experienced by parents of patients with genetically determined leukoencephalopathies, aged 1 month to 12 years. Thirty-four mothers and 21 fathers completed the Parenting Stress Index–4th Edition. One demographic questionnaire was completed per family. Detailed clinical data was gathered on all patients. Statistical analysis was performed with total stress percentile score as the primary outcome. Mothers and fathers had significantly higher stress levels compared with the normative sample; 20% of parents had high levels of stress whereas 11% had clinically significant levels of stress. Mothers and fathers had comparable total stress percentile scores. We identified pediatric behavioral difficulties and gross motor function to be factors influencing stress in mothers. Our study is the first to examine parental stress in this population and highlights the need for parental support early in the disease course. In this pilot study, we demonstrated that using the Parenting Stress Index–4th Edition to assess stress levels in parents of patients with genetically determined leukoencephalopathies is feasible, leads to valuable and actionable results, and should be used in larger, prospective studies.

Purpose: Haploinsufficiency of USP7, located at chromosome 16p13.2, has recently been reported in seven individuals with neurodevelopmental phenotypes, including developmental delay/intellectual disability (DD/ID), autism spectrum disorder (ASD), seizures, and hypogonadism. Further, USP7 was identified to critically incorporate into the MAGEL2-USP7-TRIM27 (MUST), such that pathogenic variants in USP7 lead to altered endosomal F-actin polymerization and dysregulated protein recycling. Methods: We report 16 newly identified individuals with heterozygous USP7 variants, identified by genome or exome sequencing or by chromosome microarray analysis. Clinical features were evaluated by review of medical records. Additional clinical information was obtained on the seven previously reported individuals to fully elucidate the phenotypic expression associated with USP7 haploinsufficiency. Results: The clinical manifestations of these 23 individuals suggest a syndrome characterized by DD/ID, hypotonia, eye anomalies,feeding difficulties, GERD, behavioral anomalies, and ASD, and more specific phenotypes of speech delays including a nonverbal phenotype and abnormal brain magnetic resonance image findings including white matter changes based on neuroradiologic examination. Conclusion: The consistency of clinical features among all individuals presented regardless of de novo USP7 variant type supports haploinsufficiency as a mechanism for pathogenesis and refines the clinical impact faced by affected individuals and caregivers.

Purpose: Pathogenic variants in ARID1B are one of the most frequent causes of intellectual disability (ID) as determined by large-scale exome sequencing studies. Most studies published thus far describe clinically diagnosed Coffin-Siris patients (ARID1BCSS) and it is unclear whether these data are representative for patients identified through sequencing of unbiased ID cohorts (ARID1B-ID). We therefore sought to determine genotypic and phenotypic differences between ARID1B-ID and ARID1B-CSS. In parallel, we investigated the effect of different methods of phenotype reporting. Methods: Clinicians entered clinical data in an extensive webbased survey. Results: 79 ARID1B-CSS and 64 ARID1B-ID patients were included. CSS-associated dysmorphic features, such as thick eyebrows, long eyelashes, thick alae nasi, long and/or broad philtrum, small nails and small or absent fifth distal phalanx and hypertrichosis, were observed significantly more often (p < 0.001) in ARID1B-CSS patients. No other significant differences were identified. Conclusion: There are only minor differences between ARID1BID and ARID1B-CSS patients. ARID1B-related disorders seem to consist of a spectrum, and patients should be managed similarly. We demonstrated that data collection methods without an explicit option to report the absence of a feature (such as most Human Phenotype Ontology-based methods) tended to underestimate gene-related features., We are grateful for the assistance of Pepijn Cox in setting up the website www.arid1bgene.com. This study has made use of data generated by the Human Disease Genes website series, www.humandiseasegenes.com. This work was financially supported by grants from the Netherlands Organisation for Health Research and Development (917-86-319 to B.B.A.d.V., 912-12-109 to B.B.A.d.V.)

The GTPBP2 gene encodes a guanosine triphosphate (GTP)-binding protein of unknown function. Biallelic loss-of-function variants in the GTPBP2 gene have been previously reported in association with a neuro-ectodermal clinical presentation in six individuals from four unrelated families. Here, we provide detailed descriptions of three additional individuals from two unrelated families in the context of the previous literature. Both families carry nonsense variants in GTPBP2: homozygous p.(Arg470*) and compound heterozygous p.(Arg432*)/p.(Arg131*). Key features of this clinically recognizable condition include prenatal onset microcephaly, tone abnormalities, and movement disorders, epilepsy, dysmorphic features, retinal dysfunction, ectodermal dysplasia, and brain iron accumulation. Our findings suggest that some aspects of the clinical presentation appear to be age-related; brain iron accumulation may appear only after childhood, and the ectodermal findings and peripheral neuropathy are most prominent in older individuals. In addition, we present prenatal and neonatal findings as well as the first Caucasian and black African families with GTPBP2 biallelic variants. The individuals described herein provide valuable additional phenotypic information about this rare, novel, and progressive neuroectodermal condition.

To determine the physical literacy, defined as the capability for a physically active lifestyle, of children with medical conditions compared with healthy peers, this multicenter cross-sectional study recruited children with medical conditions from cardiology, neurology (including concussion), rheumatology, mental health, respirology, oncology, hematology, and rehabilitation (including cerebral palsy) clinics. Participants aged 8–12 years (N = 130; mean age: 10.0 ± 1.44 years; 44% female) were randomly matched to 3 healthy peers from a normative database, based on age, gender, and month of testing. Total physical literacy was assessed by the Canadian Assessment of Physical Literacy, a validated assessment of physical literacy measuring physical competence, daily behaviour, knowledge/understanding, and motivation/confidence. Total physical literacy mean scores (/100) did not differ (t(498) = –0.67; p = 0.44) between participants (61.0 ± 14.2) and matched healthy peers (62.0 ± 10.7). Children with medical conditions had lower mean physical competence scores (/30; –6.5 [–7.44 to –5.51]; p < 0.001) but higher mean motivation/confidence scores (/30; 2.6 [1.67 to 3.63]; p < 0.001). Mean daily behaviour and knowledge/understanding scores did not differ from matches (/30; 1.8 [0.26 to 3.33]; p = 0.02;/10; –0.04 [–0.38 to 0.30]; p = 0.81; respectively). Children with medical conditions are motivated to be physically active but demonstrate impaired movement skills and fitness, suggesting the need for targeted interventions to improve their physical competence. Novelty: Physical literacy in children with diverse chronic medical conditions is similar to healthy peers. Children with medical conditions have lower physical competence than healthy peers, but higher motivation and confidence. Physical competence (motor skill, fitness) interventions, rather than motivation or education, are needed for these youth.

Context 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date. Objective To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy. Design An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated. Setting This was a multicenter retrospective study using information collected from 3 predominant centers. Patients A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included. Main Outcome Measures Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts. Results The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients. Conclusions Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder., Canadian Institutes of Health Research [201610PJT-377869, MOP-G2-341146-159133-BRIDG]; Fondation Les Amis d'Elliot; Leuco-Action; Fondation Lueur d'Espoir pour Ayden; Fondation le Tout pour Loo; Reseau de Medecine Genetique Appliquee of the Fonds de Recherche du Quebec-Sante; Compute Canada; Fonds de Recherche du Quebec en Sante (FRQS) Doctoral Scholarship; Fondation du Grand defi Pierre Lavoie Doctoral Scholarship; McGill Faculty of Medicine F. S.B. Miller Fellowship; Research Institute of the McGill University Health Centre Desjardins Studentship in Child Health Research; Directorate of Higher Education Overseas Scholarship-Dikti Scholarship, Ministry of National Education, Republic of Indonesia; CIHR [201603PJT-148695]; BC Children's Hospital Foundation through its intramural Investigator Grant Award Program (IGAP); National Institute for Neurological Disorders and Stroke [R01NS082094]; Jakob Kamens Chair in Translational Neurotherapeutics; Fonds de Recherche du Quebec-Sante (FRQS); Canadian Institutes of Health Research; European Reference Network for Rare Neurological Disorders (ERN-RND) [739510], This study was supported by grants from the Canadian Institutes of Health Research (201610PJT-377869, MOP-G2-341146-159133-BRIDG), Fondation Les Amis d'Elliot, Leuco-Action, Fondation Lueur d'Espoir pour Ayden, Fondation le Tout pour Loo, and Reseau de Medecine Genetique Appliquee of the Fonds de Recherche du Quebec-Sante to G. Bernard. This research was enabled in part by support provided by Compute Canada (www.computecanada.ca).S.Perrier is supported by the Fonds de Recherche du Quebec en Sante (FRQS) Doctoral Scholarship, the Fondation du Grand defi Pierre Lavoie Doctoral Scholarship, the McGill Faculty of Medicine F. S.B. Miller Fellowship, and the Research Institute of the McGill University Health Centre Desjardins Studentship in Child Health Research. F. K.C. is a recipient of the Directorate of Higher Education Overseas Scholarship-Dikti Scholarship, Ministry of National Education, Republic of Indonesia. W.T. G. received funding from the CIHR (201603PJT-148695) and is supported by the BC Children's Hospital Foundation through its intramural Investigator Grant Award Program (IGAP). B.L. F. was supported by the National Institute for Neurological Disorders and Stroke (R01NS082094). A.V. receives funding from the Jakob Kamens Chair in Translational Neurotherapeutics. G. Bernard has received a Research Scholar Junior 1 award from the Fonds de Recherche du Quebec-Sante (FRQS) (2012-2016) and the New Investigator Salary Award from the Canadian Institutes of Health Research (2017-2022). I.K.M., M. Synofzik, D. Tonduti, B.P.v.d.W., M.S. V.d.K., and N.I.W. are members of the European Reference Network for Rare Neurological Disorders (ERN-RND), project ID 739510.

Background: Acute flaccid myelitis (AFM) is characterized by rapid onset of limb weakness with spinal cord grey matter abnormalities on magnetic resonance imaging (MRI). It is unclear whether detection of enterovirus (EV) in respiratory or other specimens can help predict prognosis in children with AFM. Methods: In this nationwide longitudinal study, we evaluated the significance of peripheral detection of EV in predicting outcomes in a cohort of Canadian children presenting with AFM in 2014 and 2018. Clinical data, laboratory findings, treatment, and neuroimaging were collected (follow up period up to five years). We assessed neurologic function and motor outcomes using Kurtzke’s Expanded Disability Status Scale (EDSS) and a “weakest limb score” (WLS). Findings: 58 children with AFM (median 5⋅1 years [IQR 3⋅8-8⋅3]) were identified across five provinces. Twenty-two (39%) children had detectable EV in at least one specimen: EV-D68 in 14 (64%), EV-A71 in two (9%), coxsackievirus, and untyped EV in eight (36%). Children with EV detected were more likely to have had quadriparesis (55% vs. 12%, p=0⋅005), bulbar weakness (50% vs 6%, p=0⋅004), bowel/bladder dysfunction (59% vs 24%, p=0⋅033), cardiovascular instability (36% vs 6%, p=0⋅032), and were more likely to require intensive care unit admission (59% vs. 15%, p 0⋅005). On MRI, most children with EV positivity showed brainstem pontine lesions (59%), while other MRI parameters did not correlate with EV status. EDSS of EV+ and EV- groups was significantly different at baseline (median 8⋅5 [interquartile range, IQR 4-9⋅5] vs. 4⋅8 [IQR 3⋅4-7⋅1], p=0⋅012) and 12 months (median 3 [IQR 3-7] vs. 3 [IQR 2-3], p=0⋅036). Kaplan-Meier survival analysis of a subgroup of patients showed significantly poorer motor recovery among children with detected EV than those tested negative (p=0⋅032). Interpretation: Detection of EV in specimens from non-sterile sites at presentation correlated with more severe acute motor weakness, worse overall outcomes and poorer trajectory for motor recovery. Funding Statement: None. Declaration of Interests: EAY reports grants from Canadian Network of MS Clinics during the conduct of the study; grants from Biogen, grants from NMSS, grants from CMSC, grants from 18 MSSC/MS Foundation, grants from OIRM, grants from SCN, grants from SickKids Foundation, personal fees from ACI, personal fees from US FDA, grants from CBMH, grants from TEVA, grants from Guthy Jackson Foundation, personal fees from Juno, outside the submitted work. All other authors have no conflict of interest to disclose. Ethics Approval Statement: This study was approved by the research ethics board/committee of all above-listed participating institutions. Informed consents were obtained according to individual institutional requirements.

We describe the presenting features and long-term outcome of an unusual cluster of pediatric acute flaccid paralysis cases that occurred in Canada during the 2014 enterovirus D68 outbreak. Children (n = 25; median age 7.8 years) presenting to Canadian centers between July 1 and October 31, 2014, and who met diagnostic criteria for acute flaccid paralysis were evaluated retrospectively. The predominant presenting features included prodromal respiratory illness (n = 22), cerebrospinal fluid lymphocytic pleocytosis (n = 18), pain in neck/back (n = 14) and extremities (n = 10), bowel/bladder dysfunction (n = 9), focal central gray matter lesions found in all regions of the spinal cord within the cohort (n = 16), brain stem lesions (n = 8), and bulbar symptoms (n = 5). Enterovirus D68 was detectable in nasopharyngeal specimens (n = 7) but not in cerebrospinal fluid. Acute therapies (corticosteroids, intravenous immunoglobulins, plasmapheresis) were well tolerated with few side effects. Fourteen of 16 patients who were followed beyond 12 months post onset had neurologic deficits but showed ongoing clinical improvement and motor recovery.

Major advances have been made in the clinical and radiologic characterization of children presenting with the different forms of an acquired inflammatory demyelinating syndrome (ADS) such as acute disseminating encephalomyelitis, neuromyelitis optica spectrum disorders, and clinically isolated syndromes. Nevertheless, a proportion of cases that present with similar symptoms are due to a broad spectrum of other inflammatory disorders affecting the white matter, primary CNS tumors, or neurometabolic diseases. The clinician therefore has to be aware of the different forms of ADS, the risk factors for a chronic-relapsing course, and features that indicate an alternative diagnosis. The goal of this article is therefore to provide an outline of a pathway for evaluating pediatric patients with a presumed inflammatory demyelinating disorder and discussing the spectrum of the more common differential diagnoses.

Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is a rare hypomyelinating leukodystrophy characterized by infantile or childhood onset of motor developmental delay, progressive rigidity and spasticity, with hypomyelination and progressive atrophy of the basal ganglia and cerebellum due to a genetic mutation of the TUBB4A gene. It has only been recognized since 2002 and the full spectrum of the disorder is still being delineated. Here, we review a case report of a severely affected girl with a thorough neuropathological evaluation demonstrating novel clinical and pathological findings. Clinically, our patient demonstrated visual dysfunction and hypodontia in addition to the typical phenotype. Morphologically, more severe and widespread changes in the white matter were observed, including to the optic tracts; in gray structures such as the caudate nucleus, thalamus, globus pallidus, and substantia nigra; as well as an area of focal cortical dysplasia. Overall this case offers further insight into the broad range of clinical and neuropathological findings that may be associated with H-ABC and related TUBB4A gene mutations.

Summary Background MRI and laboratory features have been incorporated into international diagnostic criteria for multiple sclerosis. We assessed the pattern of MRI lesions and contributions of cerebrospinal fluid (CSF) and serum antibody findings that best identifies children with multiple sclerosis, and the applicability of international diagnostic criteria in the paediatric context. Methods In this prospective cohort study, detailed clinical assessments, serum and CSF studies, and MRI scans were done in youth (aged 0·46–17·87 years) with incidental acquired demyelinating syndrome. Participants were examined prospectively to identify relapsing disease. All MRI scans were assessed using a validated scoring method. A random forest classifier identified imaging and laboratory features that best predicted a multiple sclerosis or monophasic outcome. Performance of the 2001, 2010, and 2017 international McDonald criteria for the diagnosis of multiple sclerosis, the 2016 MRI in multiple sclerosis (MAGNIMS) criteria, and our 2011 proposed (Verhey) criteria were determined; performance was adjudicated with generalised linear models. Findings Between Sept 1, 2004, and June 30, 2017, we included 324 participants with median follow-up of 72 months (range 6–150), 71 (22%) participants with multiple sclerosis, 237 (73%) with monophasic acquired demyelinating syndrome, 14 (4%) with relapsing non-multiple sclerosis, and two (1%) with alternative diagnoses. We scored 2391 brain, 444 spinal, and 67 dedicated orbital MRI scans. One or more T1 hypointense lesions plus one or more periventricular lesions (Verhey criteria) best predicted multiple sclerosis outcome. Performance of the 2017 McDonald criteria was comparable to the 2010 McDonald criteria and was easier to adjudicate. The ability of CSF oligoclonal bands to substitute for the requirement for both enhancing and non-enhancing lesions in the 2017 McDonald criteria improved its performance compared with the 2010 criteria. Myelin oligodendrocyte testing at baseline did not improve performance of the 2017 McDonald criteria. Interpretation The 2017 McDonald criteria for the diagnosis of multiple sclerosis, as applied at the time of incident attack, perform well in identifying children and youth with multiple sclerosis, indicating that the same diagnostic criteria for multiple sclerosis apply across the age span. The presence of so-called black holes on MRI and periventricular lesions at baseline (Verhey criteria) also effectively distinguish children with multiple sclerosis from children with monophasic demyelination. The presence of CSF oligoclonal bands improve diagnostic accuracy. Myelin oligodendrocyte glycoprotein antibodies identify children with acute disseminated encephalomyelitis, and those with relapsing non-multiple sclerosis, most of whom do not meet 2017 McDonald criteria at onset. Funding The Multiple Sclerosis Scientific Research Foundation and The Children's Hospital of Philadelphia.

BACKGROUND: Few prospective studies have systematically evaluated the extent of recovery from incident acquired demyelinating syndromes (ADS) of the central nervous system in children. METHODS: In a national cohort study of pediatric ADS, severity of the incident attack and extent of recovery by 12 months were evaluated. Annual evaluations were used to determine current diagnoses (monophasic ADS or multiple sclerosis [MS]) and new deficits. RESULTS: Of 283 children, 244 (86%) required hospitalization for a median (interquartile range [IQR]) of 6 (3–10) days, and 184 had moderate or severe deficits; 41 children were profoundly encephalopathic, 129 were unable to ambulate independently, and 59 with optic neuritis (ON) had moderately or severely impaired vision. Those with transverse myelitis (TM) and patients with monophasic disease were more likely to have moderate or severe deficits at onset. Twenty-seven children (10%) did not experience full neurologic recovery from their incident attack; 12 have severe residual deficits. Monophasic illness, TM, and moderate or severe deficits at onset were associated with poor recovery. After a median (IQR) follow-up of 5.06 (3.41–6.97) years, 59 children (21%) were diagnosed with MS; all recovered fully from their incident ADS attacks, although 6 subsequently acquired irreversible deficits after a median (IQR) observation period of 5.93 (4.01–7.02) years. CONCLUSIONS: ADS is a serious illness, with 86% of affected Canadian children requiring hospitalization. More than 90% of children recovered physically from their ADS event, including those children experiencing onset of MS. However, permanent visual or spinal cord impairment occurred in some children with ON or TM.

Unique clinical presentations and magnetic resonance imaging patterns can help differentiate the various adult presentations of leukodystrophies and leukoencephalopathies. White-matter disorders are genetically based disorders affecting the central nervous system white matter, with or without peripheral nervous system involvement. These disorders predominantly affect patients in the pediatric population; however, a number of classic leukodystrophies can present in adulthood. Disease progression can be of variable onset with a broad range of symptoms, usually progressing from cognitive dysfunction. Recognition of specific disorders can have important implications for treatment, involvement of multidisciplinary services, and important conversations surrounding social issues the families may face. The focus of this chapter is to highlight the adult presentations of the classic childhood-onset leukodystrophies as well as to describe leukodystrophies which predominantly present in adulthood.

Background We attempted to characterize the health-related quality of life in patients with genetically determined leukoencephalopathies as it relates to the severity of clinical features and the presence or absence of a precise molecular diagnosis. Methods Health-related quality of life was assessed using the Pediatric Quality of Life Inventory model (Pediatric Quality of Life Inventory 4.0 Self- and Proxy-reports) on 59 patients diagnosed with genetically determined leukoencephalopathies. In total, 38 male and 21 female patients ranging from one to 32 years of age (mean nine years), as well as their parents, completed the Pediatric Quality of Life Inventory health-related quality of life measures. In addition, participants completed detailed standardized clinical assessments or questionnaires. The correlation between health-related quality of life results and the severity of the clinical features, as well as the presence or absence of a molecular diagnosis, were analyzed. Results Patients with more severe clinical features showed statistically significant lower total Pediatric Quality of Life Inventory scores. More specifically, lower health-related quality of life was noted in children with sialorrhea, gastrostomy, and dystonia and in children who use a wheelchair. Conclusions Patients with more severe clinical features experience a lower quality of life. Our study further highlights the importance of addressing both physical and psychosocial issues and discussing perception of quality of life with both parents and children. A larger multicenter prospective study will be needed to further define the burden of these diseases and to identify modifiable factors.

Background Champlain BASE™ (Building Access to Specialists through eConsultation) is a web-based asynchronous electronic communication service that allows primary-care- practitioners (PCPs) to submit “elective” clinical questions to a specialist. For adults, PCPs have reported improved access and timeliness to specialist advice, averted face-to-face specialist referrals in up to 40% of cases and high provider satisfaction. Objective To determine whether the expansion of eConsult to a pediatric setting would result in similar measures of improved healthcare system process and high provider acceptance reported in adults. Design Prospective observational cohort study. Setting Single Canadian tertiary-care academic pediatric hospital (June 2014–16) servicing 1.2 million people. Participants 1. PCPs already using eConsult. 2.Volunteer pediatric specialists provided services in addition to their regular workload. 3.Pediatric patients (< 18 years-old) referred for none-acute care conditions. Main outcomes and measures Specialty service utilization and access, impact on PCP course-of-action and referral-patterns and survey-based provider satisfaction data were collected. Results 1064 eConsult requests from 367 PCPs were answered by 23 pediatric specialists representing 14 specialty-services. The top three specialties represented were: General Pediatrics 393 cases (36.9%), Orthopedics 162 (15.2%) and Psychiatry 123 (11.6%). Median specialist response time was 0.9 days (range 93.3%) of PCPs rated eConsult as very good/excellent value for both patients and themselves. All specialist survey-respondents indicated eConsult should be a continued service. Conclusions and relevance Similar to adults, eConsult improves PCP access and timeliness to elective pediatric specialist advice and influences their care decisions, while reporting high end-user satisfaction. Further study is warranted to assess impact on resource utilization and clinical outcomes.

Hypomyelinating leukodystrophies are a heterogeneous group of disorders. Simons et al. identify four patients with brain hypomyelination and a remarkably benign clinical presentation, all with the same dominant missense mutation in TMEM106B encoding a protein involved in lysosomal trafficking. The findings emphasize the essential role that lysosomes play in myelination.See Zhou and Rademakers (doi:10.1093/brain/awx318) for a scientific commentary on this article. Hypomyelinating leukodystrophies are a heterogeneous group of disorders with a clinical presentation that often includes early-onset nystagmus, ataxia and spasticity and a wide range of severity. Using next-generation sequencing techniques and GeneMatcher, we identified four unrelated patients with brain hypomyelination, all with the same recurrent dominant mutation, c.754G > A p.(Asp252Asn), in TMEM106B. The mutation was confirmed as de novo in three of the cases, and the mildly affected father of the fourth affected individual was confirmed as mosaic for this variant. The protein encoded by TMEM106B is poorly characterized but is reported to have a role in regulation of lysosomal trafficking. Polymorphisms in TMEM106B are thought to modify disease onset in frontotemporal dementia, but its relation to myelination is not understood. Clinical presentation in three of the four patients is remarkably benign compared to other hypomyelinating disorders, with congenital nystagmus and mild motor delay. These findings add TMEM106B to the growing list of genes causing hypomyelinating disorders and emphasize the essential role lysosomes play in myelination

To date, none of the formative clinical drug trials in multiple sclerosis (MS) have included children. Just as in other fields in pediatrics, current prescribed therapies are off-label and are based on the results of adult studies. Emerging oral, injectable and intravenous immunotherapies appear to be more efficacious, but simultaneously have more worrisome side effects. In order to optimize therapy for children with MS, these therapies must be evaluated in robust clinical trials with a focus on monitoring for potential toxicities both in the short and long term. Many challenges exist in conducting clinical trials in children, including smaller patient populations. International collaboration and mandated pediatric investigation plans will facilitate the process of conducting these valuable clinical trials, which may lend to a better understanding of MS overall.

Isolated 7p22.3p22.2 deletions are rarely described with only two reports in the literature. Most other reported cases either involve a much larger region of the 7p arm or have an additional copy number variation. Here, we report five patients with overlapping microdeletions at 7p22.3p22.2. The patients presented with variable developmental delays, exhibiting relative weaknesses in expressive language skills and relative strengths in gross, and fine motor skills. The most consistent facial features seen in these patients included a broad nasal root, a prominent forehead a prominent glabella and arched eyebrows. Additional variable features amongst the patients included microcephaly, metopic ridging or craniosynostosis, cleft palate, cardiac defects, and mild hypotonia. Although the patients’ deletions varied in size, there was a 0.47 Mb region of overlap which contained 7 OMIM genes: EIP3B, CHST12, LFNG, BRAT1, TTYH3, AMZ1, and GNA12. We propose that monosomy of this region represents a novel microdeletion syndrome. We recommend that individuals with 7p22.3p22.2 deletions should receive a developmental assessment and a thorough cardiac exam, with consideration of an echocardiogram, as part of their initial evaluation.

A 3-year-old boy is admitted to a hospital after a two-day history of a mild upper respiratory tract illness. He presented with confusion, irritability, and slurred speech. As the day progressed, he developed difficulty swallowing.

Under the umbrella of pediatric-acquired demyelinating syndromes, there is a multitude of disorders, including optic neuritis, transverse myelitis, acute disseminated encephalomyelitis (ADEM), multiple sclerosis (MS), and neuromyelitis optica spectrum disorders (NMOSD). Due to overlapping clinical and magnetic resonance imaging (MRI) features, it can be challenging to provide an accurate diagnosis. In view of therapeutic and prognostic implications, an early and reliable diagnosis is however of utmost importance. Recent studies of myelin oligodendrocyte glycoprotein (MOG) identify MOG, as a promising target for antibody-mediated demyelination and a biomarker for a relatively benign and non-MS disease course. We describe the clinical and MRI presentation of five children presenting with an acute, severe central nervous system inflammatory disease involving the brain and spinal cord, all of whom were positive for MOG-IgG antibody. Encephalopathy was uncommon at presentation and all had quick resolution of symptoms with intravenous steroid and intravenous immunoglobulin (IVIG) treatment. All patients recovered well, and have been treated with IVIG to potentially prevent relapses.

BACKGROUND: Pediatric multiple sclerosis (MS), once considered a rare childhood illness, has been increasingly identified as an important childhood acquired neurologic disease requiring early recognition and intervention. SUMMARY: We present a comprehensive review of the current terminology of acquired central nervous system demyelination in children, pertinent investigations, including magnetic resonance imaging and cerebrospinal fluid cerebrospinal fluid studies, and an approach to the differential diagnosis of pediatric onset MS. In addition, the recent studies exploring the epidemiology and pathobiology will be discussed. Finally, we present an algorithm for the treatment of episodes of demyelination along with chronic immunomodulatory therapeutic options in this patient population. CONCLUSIONS: Although some similarities exist to adult onset MS, MS onset during childhood and adolescence presents unique diagnostic challenges and requires specialized multidisciplinary care for optimal management. National and international collaborative studies are underway to aid in the understanding of the early and ongoing pathogenesis of MS.

BACKGROUND. Specific language impairment is a primary developmental language disorder in which language is impaired disproportionately to other developmental domains. Electroencephalography is often conducted in the medical investigation of a child with specific language impairment; however, at present, there is uncertainty regarding necessary testing using electroencephalography.METHODS. The cases of 111 children with the diagnosis of specific language impairment over a 10-year interval, who also underwent electroencephalography, were systematically reviewed in a retrospective manner. Children with a history of previous afebrile seizures, acquired language delay, or documented language regression, developmental delay, hearing loss, coexisting autistic features, and known central nervous system disorders were excluded.RESULTS. The majority (76%) of the children were boys. Thirty-five (31.5%) children had abnormal electroencephalography results, including 7 (6.3%) children with epileptiform activity. This is higher than the prevalence rate of epileptiform activity in a historical cohort of 3726 (3.54%) children but not statistically significant. The epileptiform activity was deemed active in only 3 of 7 patients and was not related to the specific type of language delay observed.CONCLUSIONS. Although abnormal electroencephalographic activity is seen frequently in children with specific language impairment, epileptiform activity is rare and without apparent impact on clinical care. Awake electroencephalography does not seem to be useful in the routine diagnostic evaluation of young children with specific language impairment, although further investigations of both wake and sleep electroencephalography in this homogenous population must be conducted before definitive recommendations can be made.

The role of brain biopsy is well established in patients with neoplastic lesions, with a diagnostic yield approaching 95%. The diagnostic yield of brain biopsy in adults with neurological decline varies from 20% to 43%. Only a few studies have examined the diagnostic yield of brain biopsy in children with idiopathic neurological decline. A retrospective analysis was conducted on all open and closed pediatric brain biopsies performed between January 1988 and May 2003. Biopsies were performed for diagnostic purposes in patients showing a progressively deteriorating neurologic course in whom less-invasive modalities such as neuroimaging, electroencephalography (EEG), and molecular genetic studies were either negative or inconclusive. Immunocompromised patients were included. Patients were excluded if the preoperative diagnosis was a neoplasm or if the patient was undergoing a resection as part of a work-up for intractable epilepsy. Each patient underwent numerous investigations before brain biopsy. The utility of each biopsy was analyzed. Sixty-six children had brain biopsies performed for diagnostic purposes during the study period. Patient ages ranged from 2 months to 16 years and 9 months at the time of biopsy. The diagnostic yield was 48.5% overall, with a yield of 68.8% between 1996 and 2003. Of the total, 26 (39.4%) biopsies were both diagnostic and useful. Patients most frequently presented with seizures (56.1%) and encephalopathy (33%). The most frequently diagnosed disease was vasculitis (18.2%). A total of 71.9% of patients with diagnostic biopsies improved with appropriate treatment. Brain biopsy in children had a diagnostic yield of 48.5% in our series. A specific diagnosis may help in management and outcome, especially with a diagnosis of vasculitis.

Objective To determine the frequency and clinical-radiological associations of antibodies to myelin oligodendrocyte glycoprotein (MOG) and aquaporin-4 (AQP4) in children presenting with neuromyelitis optica (NMO) and limited forms. Methods Children with a first event of NMO, recurrent (RON), bilateral ON (BON), longitudinally extensive transverse myelitis (LETM) or brainstem syndrome (BS) with a clinical follow-up of more than 12 months were enrolled. Serum samples were tested for MOG- and AQP4-antibodies using live cell-based assays. Results 45 children with NMO (n=12), LETM (n=14), BON (n=6), RON (n=12) and BS (n=1) were included. 25/45 (56%) children had MOG-antibodies at initial presentation (7 NMO, 4 BON, 8 ON, 6 LETM). 5/45 (11%) children showed AQP4-antibodies (3 NMO, 1 LETM, 1 BS) and 15/45 (33%) were seronegative for both antibodies (2 NMO, 2 BON, 4 RON, 7 LETM). No differences were found in the age at presentation, sex ratio, frequency of oligoclonal bands or median EDSS at last follow-up between the three groups. Children with MOG-antibodies more frequently (1) had a monophasic course (p=0.018) after one year, (2) presented with simultaneous ON and LETM (p=0.004) and (3) were less likely to receive immunosuppressive therapies (p=0.0002). MRI in MOG-antibody positive patients (4) less frequently demonstrated periependymal lesions (p=0.001), (5) more often were unspecific (p=0.004) and (6) resolved more frequently (p=0.016). Conclusions 67% of all children presenting with NMO or limited forms tested positive for MOG- or AQP4-antibodies. MOG-antibody positivity was associated with distinct features. We therefore recommend to measure both antibodies in children with demyelinating syndromes.

β-propeller protein-associated neurodegeneration (BPAN) is a recently identified X-linked dominant form of neurodegeneration with brain iron accumulation caused by mutations in the WDR45 gene. BPAN commonly presents as global developmental delay in childhood with rapid onset of parkinsonism and dementia in early adulthood and associated pathognomonic changes seen on brain MRI. In this case report, we present a pediatric patient with mild cognitive delay and pathognomonic MRI changes indicative of BPAN preceding neurologic deterioration who is found to have a novel de novo mutation in the WDR45 gene.

Spinal cord infarction is extremely rare in childhood and can result from a wide range of causes. Fibrocartilaginous embolism can give rise to spinal stroke and mimic non-vascular disease such as acute transverse myelitis.We report two children who suffered an asymmetrical spinal cord infarction due to fibrocartilaginous embolism. The clinical presentation, radiological findings, and pathophysiology of fibrocartilaginous embolism are described. Each patient demonstrated marked clinical improvement after receiving extensive physical therapy and rehabilitation. One child demonstrated complete clinical recovery. The other had persistent asymmetrical foot weakness and distal sensory deficits.We outline the key clinical and radiographic features that enable spinal cord infarction to be differentiated from transverse myelitis. Prognosis depends on many factors such as extent and type of injury, level of the cord affected, and age at the time of spinal cord infarction.

Purpose: Computerized artificial neural networks are analogous to biological neuronal systems. Since they may be trained to recognize the relevance of complex patterns in data, neural networks may be useful for decision making in the multifactorial management of ureteropelvic junction obstruction. We determine the ability of a customized neural network to predict sonographic outcome after pyeloplasty in children with ureteropelvic junction obstruction.Materials and Methods: A data set was constructed with 242 demographic, clinical, radiological and surgical elements. We analyzed the available retrospective data in 100 consecutive children who underwent unilateral pyeloplasty for ureteropelvic junction obstruction chosen from all 144 surgically treated for ureteropelvic junction obstruction between 1993 and 1995. One radiologist reviewed all film data and provided a final sonographic outcome designation in each case. We wrote a set of computer programs to construct a neural network. A composite 4-l...

Introduction The literature on complementary and alternative medicine (CAM) is expanding. One of the most common conditions for which CAM is studied in the pediatric population is migraine. Nutraceuticals are a form of CAM that is being used for pediatric migraine prophylaxis. Methods A literature search was carried out in order to identify both observational studies and randomized controlled trials on the use of nutraceuticals for the prophylaxis of pediatric migraine. Adult studies on included nutraceuticals were also reviewed. Review Thirty studies were reviewed on six different nutraceuticals: butterbur, riboflavin, ginkgolide B, magnesium, coenzyme Q10 and polyunsaturated fatty acids. Conclusion Overall, the quality of the evidence for the use of nutraceuticals in pediatric migraine prophylaxis is poor. Further research needs to be done in order to study the efficacy of nutraceuticals for the prophylaxis of pediatric migraine.

The Canadian Multiple Sclerosis Working Group (CMSWG) developed practical recommendations in 2004 to assist clinicians in optimizing the use of disease-modifying therapies (DMT) in patients with relapsing multiple sclerosis. The CMSWG convened to review how disease activity is assessed, propose a more current approach for assessing suboptimal response, and to suggest a scheme for switching or escalating treatment. Practical criteria for relapses, Expanded Disability Status Scale (EDSS) progression and MRI were developed to classify the clinical level of concern as Low, Medium and High. The group concluded that a change in treatment may be considered in any RRMS patient if there is a high level of concern in any one domain (relapses, progression or MRI), a medium level of concern in any two domains, or a low level of concern in all three domains. These recommendations for assessing treatment response should assist clinicians in making more rational choices in their management of relapsing MS patients.

The objective of this study was to determine the major comorbidities in patients with spastic quadriplegic (SQ) cerebral palsy (CP) and their possible clinical associations. Medical records of patients with SQ CP from a pediatric neurology practice over a 14-year period were retrospectively and systematically reviewed. Variables examined included demographics, prenatal, perinatal, and postnatal risk factors. Comorbidities documented included those involving hearing, vision, feeding status, and epilepsy. Binomial logistic regression analyses were applied to identify clinical associations of the comorbidities. Ninety-two children were included in this study of whom 39 were born preterm. Mean age of presentation was 2 months (SD 3.5) and males comprised 60% of the group. A total of 57% had a Gross Motor Function Classification Score (GMFCS) of Level IV or V. The four documented comorbidities occurred at a high frequency: 66 out of 83 children (80%) had a visual impairment with 13 (21%) having a substantial impairment; 37 out of 86 children (40%) had a hearing deficit; 43 out of 92 children (47%) had epilepsy; and 29 (33%) required assisted feeding. A GMFCS Level of IV or V and documented microcephaly was associated with the need for assisted feeding (odds ratio [OR] 8.1; 95% confidence interval [CI] 2.1-29.8, p=0.002 and OR 4.9, 95% CI 1.7-14.8, p=0.004 respectively). Epilepsy was associated with the occurrence of neonatal encephalopathy (OR 2.3, 95% CI 1.0-55; p=0.05), microcephaly (OR 4.9, 95% CI 1.6-14.8; p=0.004), periventricular leukomalacia (OR 7.4, 95% CI 1.6-35.0; p=0.012), and perinatal asphyxia (OR 3.6, 95% CI 1.5-8.9; p=0.005). There is a high frequency of comorbidity in the setting of SQ CP which can impact on quality of life and burdens of care. Few clinical associations of this burden appear, thus necessitating systematic programmatic follow-up of these children to facilitate early identification and intervention.

The etiologic profile and possible predictors of etiology in children with spastic quadriplegia were assessed in a consecutive cohort of children with this motor impairment. Medical records from a single pediatric neurology practice over a 14-year interval were retrospectively and systematically reviewed. Variables comprised possible demographic, prenatal, perinatal, and postnatal risk factors. Of the 99 patients included in the study, 39 were premature (37 weeks gestation). The overall etiologic yield was 83%. The top three diagnoses were hypoxic-ischemic perinatal asphyxia (33%), periventricular leukomalacia (15%), and central nervous system infections (11%). In premature children, the most common diagnoses were periventricular leukomalacia (33%), perinatal asphyxia (26%), and central nervous system infections (15%). In term-born children, the most frequent diagnoses were perinatal asphyxia (37%), metabolic disease (12%), and structural malformation or infection (9% each). Factors predicting the identification of an etiology included male sex (P = 0.05), low birth weight (P = 0.003), prematurity (P = 0.01), perinatal complications (P = 0.002), and neonatal encephalopathy (P = 0.006). The etiologic yield in patients with spastic quadriplegia was 83%, with differing underlying etiologies depending on gestational age. These results should help guide physicians in investigating possible underlying etiologies in patients with spastic quadriplegia.

Pediatric acquired demyelinating syndromes have overlapping clinical and imaging features, but management and prognosis vary. We describe four children between the ages of 3 and 10 presenting with inflammatory brain disease - one with polyfocal neurological symptoms, one with severe bilateral optic neuritis and two with transverse myelitis, all without encephalopathy. All brain MRIs had extensive involvement of both deep grey and subcortical white matter. Three patients had longitudinally extensive spinal cord lesions. Clinical and radiological findings did not meet criteria for multiple sclerosis, acute disseminated encephalomyelitis, or neuromyelitis optica (NMO). NMO IgG testing was negative. All patients had resolution of clinical and imaging findings after treatment with steroids and IVIg. We found, elevated levels of anti-myelin oligodendrocyte glycoprotein antibodies in all four patients. Three of the children receive monthly IVIg infusions. Two of the patients relapsed once within 18 months of their initial attack and have since remained relapse free for 32 months and 43 months, respectively. The third patient (transverse myelitis) has not had any relapses since her initial attack 15 months ago. It appears that children with this syndrome may have more favourable outcomes when compared to other CNS relapsing inflammatory conditions.