Patient Delay, Lead Times, and Adherence to Diagnostic Guidelines in Children and Adolescents With Idiopathic Intracranial Hypertension.

AIMS: In a cohort of 45 children and adolescents diagnosed with idiopathic intracranial hypertension (IIH), our main aims were to investigate patient delay, lead time to final diagnosis, and adherence to current diagnostic guidelines. METHODS: This population-based, retrospective, single-center cohort study was performed at Uppsala University Children's Hospital, Sweden, a tertiary referral center for children and adolescents with rare and/or complicated neurologic disease. Patient data were retrieved from the local registries for patients filling the following criteria: age (0-17.99 yr), study period (2000-2020), and International Classification of Diseases code G93.2 (IIH). Medical records from pediatric, neuropediatric, ophthalmology, and neurosurgery departments were scrutinized. All included patients met the Friedman criteria. RESULTS: Fifty-one percent of the patients sought medical advice within 1 month of symptom debut, 23% were seen within 1 to three months, and 26% after three months. A final diagnosis of IIH was reached within 48 hours in 60%, within two weeks in 80%, and within four weeks in 89% of patients. Visual fields, color vision, and complete ancillary laboratory investigations to exclude secondary etiologies were performed in 62%, 47%, and 59% of patients, respectively. CONCLUSION: The clinical presentation of IIH in children and adolescents may range from acute fulminant symptoms, to a more insidious or even chronic presentation with long-term headache. Although a majority of patients received a correct and prompt diagnosis, lead time to final diagnosis and adherence to diagnostic care guidelines might be improved. A higher awareness and knowledge of the condition may achieve this.

Prospective registration of symptoms and times to diagnosis in children and adolescents with central nervous system tumors: A study of the Swedish Childhood Cancer Registry.

BACKGROUND: The elapsed time taken to diagnose tumors of the central nervous system in children and adolescents varies widely. The aim of the present study was to investigate such diagnostic time intervals at a national level in Sweden as they correlate with clinical features. METHODS: Data prospectively accumulated over a 4-year period in the Swedish Childhood Cancer Registry from patients aged 0-18 years were pooled, and diagnostic time intervals were analyzed considering tumor location, tumor type, patient age and sex, initial symptoms, and clinical timelines. All six pediatric oncology centers in Sweden contributed to collection of data. Time points for calculating the total diagnostic interval (TDI) defined as the time from symptom onset to diagnosis were reported in 257 of 319 patients (81%). RESULTS: The time from symptom onset to the first healthcare consultation, median 2.6 weeks, did not vary significantly between patients categorized according to tumor type or location. The median TDI was 8.3 weeks for the 4-year study period. Patients with optic pathway glioma (TDI 26.6 weeks), those with tumors of the spinal cord (TDI 25.9 weeks), and those with midline tumors (TDI 24.6 weeks) had the longest lead times. Additionally, older age, too few initial symptoms, and seeking initial redress outside an emergency ward were factors associated with a longer time to diagnosis. CONCLUSION: This study identified several factors associated with delayed diagnosis of central nervous system tumors among Swedish children and adolescents. These novel data ought to help direct future efforts toward clinical improvement.

Left-handedness should not be overrated as a risk factor for postoperative speech impairment in children after posterior fossa tumour surgery: a prospective European multicentre study.

PURPOSE: Cerebellar mutism syndrome (CMS) is a severe neurological complication of posterior fossa tumour surgery in children, and postoperative speech impairment (POSI) is the main component. Left-handedness was previously suggested as a strong risk factor for POSI. The aim of this study was to investigate the relationship between handedness and the risk of POSI. METHODS: We prospectively included children (aged < 18 years) undergoing surgery for posterior fossa tumours in 26 European centres. Handedness was assessed pre-operatively and postoperative speech status was categorised as either POSI (mutism or reduced speech) or habitual speech, based on the postoperative clinical assessment. Logistic regression was used in the risk factor analysis of POSI as a dichotomous outcome. RESULTS: Of the 500 children included, 37 (7%) were excluded from the present analysis due to enrolment at a reoperation; another 213 (43%) due to missing data about surgery (n = 37) and/or handedness (n = 146) and/or postoperative speech status (n = 53). Out of the remaining 250 (50%) patients, 20 (8%) were left-handed and 230 (92%) were right-handed. POSI was observed equally frequently regardless of handedness (5/20 [25%] in left-handed, 61/230 [27%] in right-handed, OR: 1.08 [95% CI: 0.40-3.44], p = 0.882), also when adjusted for tumour histology, location and age. CONCLUSION: We found no difference in the risk of POSI associated with handedness. Our data do not support the hypothesis that handedness should be of clinical relevance in the risk assessment of CMS.

Novel pathogenic ALG2 mutation causing congenital myasthenic syndrome: A case report.

ALG2 mutations are extremely rare causes of congenital myasthenic syndromes (CMS). The clinical phenotype and treatment response is therefore not well described. We present the case of a baby who immediately after birth presented with pronounced truncal hypotonia, proximal muscle weakness and feeding difficulties. Single fibre electromyography showed neuromuscular transmission failure and salbutamol and ephedrine treatment improved both muscle weakness and neuromuscular transmission. Genetic analysis revealed a likely pathogenic variant c.1040del, p.(Gly347Valfs*27) in exon 2 and a variant of uncertain significance, c.239G>A, p.(Gly80Asp) in exon 1 of the ALG2 gene. Western blot in whole cell lysates of HEK293 cells transfected with p.Gly80Asp, or p.Gly347Valfs*27 expression constructs indicated that p.Gly347Valfs*27 is likely a null allele and p.Gly80Asp is pathogenic through marked reduction of ALG2 expression. This case highlights the utility of functional studies in clarifying variants of unknown significance, in suspected cases of CMS.

Acute disseminated encephalomyelitis with delayed onset and feasibility of the Miethke shunt and sensor reservoir system: a case report.

Acute disseminated encephalomyelitis (ADEM) is an immune-mediated demyelinating central nervous system disorder with predilection for early childhood. Delayed onset of ADEM is rare, and herein we present a previously healthy 5-year-old boy, with an unusual clinical course of ADEM with high intracranial pressure (ICP) and acute visual loss that was at first diagnosed as idiopathic intracranial hypertension without papilledema (IIHWOP). The boy underwent acute neurosurgical intervention with ventriculoperitoneal (VP) shunt using Miethke valve and sensor reservoir system and received high-dose steroid treatment with symptom relieve within days. This is the first case report using this system in such a young child, and we find it feasible and valuable also in younger children when VP shunt with ICP measurement is indicated.

Genotype-phenotype correlations in recessive titinopathies.

PURPOSE: High throughput sequencing analysis has facilitated the rapid analysis of the entire titin (TTN) coding sequence. This has resulted in the identification of a growing number of recessive titinopathy patients. The aim of this study was to (1) characterize the causative genetic variants and clinical features of the largest cohort of recessive titinopathy patients reported to date and (2) to evaluate genotype-phenotype correlations in this cohort. METHODS: We analyzed clinical and genetic data in a cohort of patients with biallelic pathogenic or likely pathogenic TTN variants. The cohort included both previously reported cases (100 patients from 81 unrelated families) and unreported cases (23 patients from 20 unrelated families). RESULTS: Overall, 132 causative variants were identified in cohort members. More than half of the cases had hypotonia at birth or muscle weakness and a delayed motor development within the first 12 months of life (congenital myopathy) with causative variants located along the entire gene. The remaining patients had a distal or proximal phenotype and a childhood or later (noncongenital) onset. All noncongenital cases had at least one pathogenic variant in one of the final three TTN exons (362-364). CONCLUSION: Our findings suggest a novel association between the location of nonsense variants and the clinical severity of the disease.

Somatostatin receptor expression and mTOR pathway activation in glioneuronal tumours of childhood.

PURPOSE: To investigate the expression of somatostatin receptors (SSTRs) and markers of mTOR pathway in paediatric glioneuronal tumours and correlate these findings with tumour type, BRAFV600E mutational status and clinical characteristics such as tumour location, seizure frequency and duration, and age. METHOD: 37 children and adolescents with a neuropathological diagnosis of glioneuronal tumour were identified over a 22-year period. Immunohistochemical analyses for SSTRs type 1, 2A, 3, 5 and ezrin-radixin-moesin (ERM) and phosphorylated S6 (pS6), which are indicators of mTOR pathway activation, were performed in tumour specimens from 33 patients and evaluated using the immunoreactive score (IRS). The IRS were compared to tumour type, BRAFV600E status and clinical characteristics. RESULTS: Ganglioglioma (GG) was the most frequently encountered subgroup (n = 27), followed by dysembryoplastic neuroepithelial tumour (DNET; n = 4). GGs expressed SSTR2A and SSTR3 to a high extent, 56 % and 44 % respectively. Expression of SSTR2A was also found in DNETs. Signs of mTOR pathway activation were abundant in GGs, but only present in one DNET. No correlations with BRAFV600E presence or clinical characteristics were found. CONCLUSIONS: Expression of SSTRs and activation of mTOR pathway in paediatric glioneuronal tumour suggest that somatostatin analogues and mTOR inhibitors may have potential therapeutic implications in a subset of inoperable childhood glioneuronal tumours causing medically refractory epilepsy and/or tumour growth. Further clinical studies are warranted to validate these findings.

Cognition, health-related quality of life, and mood in children and young adults diagnosed with a glioneuronal tumor in childhood.

AIMS: The aim of this study was to investigate long-term cognitive outcome, health-related quality of life (HRQoL), and psychiatric symptoms in children and young adults diagnosed with a glioneuronal tumor in childhood. METHODS: Twenty-eight children and adolescents (0-17.99years) with a minimum postoperative follow-up time of five years were eligible for the study; four persons declined participation. A cross-sectional long-term follow-up evaluation was performed using the following study measures: Wechsler Intelligence Scale for Children (WISC-IV) or Wechsler Adult Intelligence Scale (WAIS-IV), Reys Complex Figure Test (RCFT), Short Form 36 version 2 (SF-36v2), Short Form 10 (SF-10), Quality of Life in Epilepsy 31 (QOLIE-31), Hospital Anxiety Depression Scale (HADS) or Beck Youth Inventory Scales (BYI), and Rosenberg Self-Esteem Scale. Historical WISC-III and RCFT data were used to compare cognitive longitudinal data. RESULTS: Mean follow-up time after surgery was 12.1years. Sixty-three percent (15/24) were seizure-free. Despite a successive postoperative gain in cognitive function, a significant reduction relative to norms was seen in the seizure-free group with respect to perceptual reasoning index (PRI), working memory index (WMI), and full-scale intelligence quotient (FSIQ). Seizure freedom resulted in acceptable HRQoL. Thirty-two percent and 16% exceeded the threshold level of possible anxiety and depression, respectively, despite seizure freedom. CONCLUSION: Although lower than in corresponding reference groups, cognitive outcome and HRQoL are good provided that seizure freedom or at least a low seizure severity can be achieved. There is a risk of elevated levels of psychiatric symptoms. Long-term clinical follow-up is advisable.

Intrathecal baclofen treatment an option in X-linked adrenoleukodystrophy.

BACKGROUND: X-linked adrenoleukodystrophy (X-ALD) is a genetic peroxisomal disorder associated with tissue accumulation of very long chain fatty acids (VLCFAs). In approximately one third of affected males, this causes progressive and irreversible damage to the brain white matter. Progress is often rapid with upper motor neuron damage leading to severe spasticity and dystonia. The increased muscle tone is frequently difficult to alleviate with oral drugs. Here, we describe two patients with X-ALD who have received treatment with intrathecal baclofen pumps (ITB). CASE STUDY: Both boys had a rapidly progressive cerebral form of the disorder resulting, among other things, in escalating spasticity and dystonia causing severe pain, dramatically reducing their quality of life. Both were treated with a variety of oral medications without adequate relief. Both patients tolerated ITB surgery without complications and the positive clinical effects of treatment with ITB became clear in the following weeks and months, with significantly reduced muscle tone, less pain and better sleep. Moreover, general caretaking became easier. CONCLUSION: The treatment of spasticity and dystonia in these patients is difficult partly due to the relentless nature of this progressive disorder. In our two patients, ITB has been effective from both a symptomatic and palliative perspective. We recommend that such treatment be considered as an early option for increased muscle tone in boys with the cerebral form of X-ALD.

Glioneuronal tumors in childhood - Before and after surgery. A long-term follow-up study.

AIM: To give a detailed description of the long-term outcome of a cohort of children with glioneuronal tumors regarding pre- and postsurgical factors, including "dual" and "double" pathology, seizure freedom, and psychosocial outcome. METHODS: During a fifteen-year period (1995-2009), all patients (age 0-17.99years) with a glioneuronal brain tumor diagnosed and treated at Uppsala University Children's Hospital were identified from the National Brain Tumor Registry and the National Epilepsy Surgery Registry. Hospital medical records were reviewed and neuroradiological and neuropathological findings were re-evaluated. A cross-sectional long-term follow-up prospective evaluation, including an interview, neurologic examination, and electroencephalogram, was accomplished in patients accepting participants in the study. RESULTS: A total of 25 out of 28 (89%) eligible patients were included. The M:F ratio was 1.5:1. Mean follow-up time after surgery was 12.1years (range 5.0-19.3). Twenty patients were adults (>18years) at follow-up. Seizure freedom was achieved in 64%. Gross total resection (GTR) was the only preoperative factor significantly correlating to seizure freedom (p=0.027). Thirty-eight percent were at some time postoperatively admitted for a psychiatric evaluation. There was a trend towards both higher educational level and employment status in adults who became seizure free. CONCLUSION: Long-term outcome is good regarding seizure freedom if GTR can be achieved, but late seizure recurrence can occur. "Dual" and "double" pathology is uncommon and does not influence seizure outcome. Obtaining seizure freedom seems to be important for psychosocial outcome, but there is a risk for psychiatric comorbidities and long-term follow-up by a multi-professional team is advisable.

Clinical characteristics and late effects in CNS tumours of childhood: Do not forget long term follow-up of the low grade tumours.

AIM: To investigate clinical characteristics and late effects of CNS tumours in childhood with a special focus on low-grade tumours, especially low-grade astrocytoma and glioneuronal tumours. METHODS: A retrospective population based study was performed at Uppsala University Children's Hospital, a tertiary referral centre for children with CNS tumours. Patients were identified from the National Brain Tumour Registry and the National Epilepsy Surgery Registry. Hospital medical records were analysed for patients with a follow up of ≥5 years after diagnosis. A re-evaluation of the neuro-pathological diagnosis was performed. RESULTS: A total of 193 patients (age 0-17.99 years) during a twelve-year period (1995-2006) were included; 149 survived ≥5 years. Three larger subgroups could be identified: astrocytic, embryonal and glioneuronal tumours. A supratentorial location was found in 52%. Medical late effects were mainly neurological and endocrinological, affecting 81% and 26% of surviving patients. Cognitive late effects were a frequent finding in the whole group but also in low-grade astrocytoma and glioneuronal tumours (53% and 67%). Thirty per cent had some kind of pedagogic support in school. CONCLUSION: Late effects are common in long-term survivors of CNS tumours in childhood. Low-grade astrocytoma and glioneuronal tumours are no exception, and the findings support the need for long-term follow up.