BRAF V600E mutation in Juvenile Xanthogranuloma family neoplasms of the central nervous system (CNS-JXG): a revised diagnostic algorithm to include pediatric Erdheim-Chester disease.

The family of juvenile xanthogranuloma family neoplasms (JXG) with ERK-pathway mutations are now classified within the "L" (Langerhans) group, which includes Langerhans cell histiocytosis (LCH) and Erdheim Chester disease (ECD). Although the BRAF V600E mutation constitutes the majority of molecular alterations in ECD and LCH, only three reported JXG neoplasms, all in male pediatric patients with localized central nervous system (CNS) involvement, are known to harbor the BRAF mutation. This retrospective case series seeks to redefine the clinicopathologic spectrum of pediatric CNS-JXG family neoplasms in the post-BRAF era, with a revised diagnostic algorithm to include pediatric ECD. Twenty-two CNS-JXG family lesions were retrieved from consult files with 64% (n = 14) having informative BRAF V600E mutational testing (molecular and/or VE1 immunohistochemistry). Of these, 71% (n = 10) were pediatric cases (≤18 years) and half (n = 5) harbored the BRAF V600E mutation. As compared to the BRAF wild-type cohort (WT), the BRAF V600E cohort had a similar mean age at diagnosis [BRAF V600E: 7 years (3-12 y), vs. WT: 7.6 years (1-18 y)] but demonstrated a stronger male/female ratio (BRAF V600E: 4 vs WT: 0.67), and had both more multifocal CNS disease ( BRAFV600E: 80% vs WT: 20%) and systemic disease (BRAF V600E: 40% vs WT: none). Radiographic features of CNS-JXG varied but typically included enhancing CNS mass lesion(s) with associated white matter changes in a subset of BRAF V600E neoplasms. After clinical-radiographic correlation, pediatric ECD was diagnosed in the BRAF V600E cohort. Treatment options varied, including surgical resection, chemotherapy, and targeted therapy with BRAF-inhibitor dabrafenib in one mutated case. BRAF V600E CNS-JXG neoplasms appear associated with male gender and aggressive disease presentation including pediatric ECD. We propose a revised diagnostic algorithm for CNS-JXG that includes an initial morphologic diagnosis with a final integrated diagnosis after clinical-radiographic and molecular correlation, in order to identify cases of pediatric ECD. Future studies with long-term follow-up are required to determine if pediatric BRAF V600E positive CNS-JXG neoplasms are a distinct entity in the L-group histiocytosis category or represent an expanded pediatric spectrum of ECD.

The experience of mothers caring for a child with a brain tumour.

BACKGROUND: Brain tumours are the second most common form of childhood cancer, accounting for over 20% of all cases in European children. Understanding the impact of diagnosis and treatment of a brain tumour on the family is an essential pre-requisite to identifying ways to provide effective support. AIM: (1) To explore the impact of having a child with a brain tumour on the main caregiver in the family; (2) to describe mothers' experiences of coping with their child's illness, including personal barriers and strengths; and (3) to identify causes of stress and sources of support to inform improvements in care delivery. METHOD: Participants were drawn from a group of caregivers enrolled in a longitudinal study of outcome following diagnosis of a childhood brain tumour. Six caregivers took part, two from each of the high-, medium- and low-impact groups based on their Impact on Families Scale scores. Semi-structured interviews were used, with questions covering: (1) impact of the diagnosis on main caregiver and family; (2) personal barriers and strengths; and (3) causes of stress and sources of support. Interviews were transcribed verbatim and coded manually into five themes, which comprised 19 subthemes. FINDINGS: Coping methods and provision of help and support were major preoccupations for main caregivers from all impact groups. Caregivers in the high-impact group reported less conflict. High- and medium-impact group caregivers had experienced less 'hindrance and heartache', than those with low impact scores, suggesting that the stress associated with diagnosis and treatment of the tumour may have increased cohesion and acceptance within these families. CONCLUSION: Families of children diagnosed with a brain tumour experience considerable negative impact and may perceive themselves as struggling to cope. Provision of help and support, within and outside the extended family, including from health, education and other services, is perceived as helpful.

Cerebral venous sinus thrombosis: a case series including thrombolysis.

BACKGROUND: Cerebral venous sinus thrombosis (CVST) in children is associated with a high incidence of serious morbidity and mortality. The presenting features are variable. It can be diagnostically challenging and the optimal treatment is uncertain. AIM: To describe the features of a series of children with CVST treated in a single paediatric neurology centre and to discuss the role of local thrombolysis. METHODS: Electronic databases were searched using diagnostic labels and International Classification of Diseases (ICD) codes to identify children aged 1 month to under 17 years with CVST. Their records were reviewed. RESULTS: 21 children were identified over a period of 8.25 years with a median age of 7.1 years. The presenting symptoms included headache (15 children), vomiting (14 children) and visual disturbance (eight children). Signs found included papilloedema (16 children), fever (six children) and sixth nerve palsy (six children). The most common underlying condition was middle ear infection (13 children). All cases received unfractionated heparin and four severe cases received local pharmacological thrombolysis. 48% of cases had an adverse outcome (death, chronic intracranial hypertension, residual hemiparesis or sixth nerve palsy). DISCUSSION: CVST has non-specific presenting features and a high risk of significant morbidity. CVST is typically found in association with a predisposing condition. Although heparin is the mainstay of treatment, thrombolysis may reverse deterioration as seen in three cases in this series. However, there is insufficient evidence to recommend the routine use of thrombolysis at present.

Pneumocystis carinii, cytomegalovirus, and severe transient immunodeficiency.

Pneumocystis carinii infection is rare in infants, and raises strong concerns of immune deficiency. This report describes the unusual case of a male infant with concurrent chest infections caused by P carinii and cytomegalovirus. Investigation was complicated by the strong suspicion of non-accidental injury, including subdural haematomas. The case illustrates how to investigate for possible immunodeficiency. Low immune function tests at presentation slowly improved and have remained normal on longterm follow up. Possible explanations for the transient severe clinical immunodeficiency in this case are discussed.

Time costs of caring for children with severe disabilities compared with caring for children without disabilities.

To assess time costs of caring for children with severe disabilities in the community compared to caring for children without disabilities, a diary- and questionnaire-based study was carried out. Sixteen complete data sets were obtained from families with children who have disabilities (mean age 8.7 years) and 31 complete data sets from families with normally developing children (mean age 4.9 years). Diagnoses in the study group included cerebral palsy, autism, Sanfillipo syndrome, lissencephaly, and osteogenesis imperfecta. Items of personal care per waking hour were significantly greater in children with disabilities than non-disabled children (p<0.001). In the study group, there was no correlation (r=-0.12) between age and frequency of care whereas a significant correlation was observed between degree of disability as measured by the Functional Independence Measure for children (WeeFIM) and frequency of care items (r=0.89). Twelve of the 16 mothers in the study group were not in paid employment. Twelve had little or no extended family support. Benefits awarded did not correlate with the degree of disability as measured by the WeeFIM (r=-0.11). Care needs of children with severe disabilities are significantly greater than those of non-disabled children and do not decrease with advancing age. Mothers of children with disabilities are unable to work outside the home because of these care needs. This brings the family income, even when benefits are included, to a level that is less than peer families with non-disabled children. A Functional Disability Score may help to achieve more appropriate allocation of state resources.

Glucocorticoids modulate the NGF mRNA response in the rat hippocampus after traumatic brain injury.

Nerve growth factor (NGF) expression in the rat hippocampus is increased after experimental traumatic brain injury (TBI) and is neuroprotective. Glucocorticoids are regulators of brain neurotrophin levels and are often prescribed following TBI. The effect of adrenalectomy (ADX) and corticosterone (CORT) replacement on the expression of NGF mRNA in the hippocampus after TBI has not been investigated to date. We used fluid percussion injury and in situ hybridisation to evaluate the expression of NGF mRNA in the hippocampus 4 h after TBI in adrenal-intact or adrenalectomised rats (with or without CORT replacement). TBI increased expression of NGF mRNA in sham-ADX rats, but not in ADX rats. Furthermore, CORT replacement in ADX rats restored the increase in NGF mRNA induced by TBI. These findings suggest that glucocorticoids have an important role in the induction of hippocampal NGF mRNA after TBI.

The hypothalamo-pituitary-adrenal axis response to experimental traumatic brain injury.

Alterations in the hypothalamo-pituitary-adrenal (HPA) axis following traumatic brain injury have not been documented in detail. We used fluid percussion injury (FPI) to evaluate the early changes in components of the HPA axis following experimental traumatic brain injury. Wistar rats were sacrificed at 2 or 4 h following sham or FPI surgery. In situ hybridization histochemistry was used to determine the expression of mRNAs of corticotrophin releasing hormone (CRH) and arginine vasopressin (AVP) in the hypothalamus and pro-opiomelanocortin (POMC) in the pituitary. A group of animals undergoing no surgery were used as control. Repeated blood sampling from an indwelling catheter demonstrated that plasma corticosterone (CORT) levels peaked 30 min following surgery in sham and FPI animals but there was no significant difference in CORT concentration between these groups at any time. Pituitary POMC expression was increased following sham and FPI surgery (compared with control non-operated animals) but with no significant difference between the two groups undergoing surgery. Hypothalamic CRH mRNA expression was significantly higher in animals undergoing FPI compared with sham surgery. Hypothalamic AVP mRNA expression was not significantly increased when compared with control nonoperated animals. These data indicate that the anaesthesia and/or surgery associated with FPI or sham surgery induces a generalised activation of the HPA axis. The selective increase in CRH mRNA in animals undergoing FPI may be due to specific effects of traumatic brain injury rather than a general stress response and may suggest an additional neurotransmitter role for CRH following head injury. The absence of an AVP response suggests that the effects of FPI may be mediated through the CRH-alone-containing subpopulation of neurons.

Glucocorticoids modulate BDNF mRNA expression in the rat hippocampus after traumatic brain injury.

Brain-derived neurotrophic factor (BDNF) expression in rat hippocampus is increased after experimental traumatic brain injury (TBI) and may be neuroprotective. Glucocorticoids are important regulators of brain neurotrophin levels and are often prescribed following TBI. The effect of adrenalectomy (ADX) on the expression of BDNF mRNA in the hippocampus after TBI has not been investigated to date. We used fluid percussion injury (FPI) and in situ hybridization to evaluate the expression of BDNF mRNA in the hippocampus 4 h after TBI in adrenal-intact or adrenalectomized rats (with or without corticosterone replacement). FPI and ADX independently increased expression of BDNF mRNA. In animals undergoing FPI, prior ADX caused further elevation of BDNF mRNA and this upregulation was prevented by corticosterone replacement in ADX rats. These findings suggest that glucocorticoids are involved in the modulation of the BDNF mRNA response to TBI.

Cerebral blood flow and metabolism in children with severe head injury. Part 1: Relation to age, Glasgow coma score, outcome, intracranial pressure, and time after injury.

Understanding the pathophysiology of paediatric head trauma is essential for rational acute management. It has been proposed that the response to severe head injury in children differs from that in adults, with increased cerebral blood flow (cerebral hyperaemia) representing the most common cause of raised intracranial pressure, but this has recently been disputed. The relation between the pathophysiological response and time after injury has not been defined in children. This paper describes 151 serial measurements of cerebral blood flow, arteriojugular venous oxygen difference (AJVDO2), and cerebral metabolic rate for oxygen (CMRO2) that were performed in 21 children with severe head injury, mean age 8 (range 2-16) years, Glasgow coma score < or = 8. Absolute cerebral hyperaemia was uncommon, only 10 (7%) of the 151 cerebral blood flow values being at or above the upper limit of the range published in normal children. There was an inverse correlation between cerebral blood flow and intracranial pressure. (r = -0.24, p = 0.009). Contrary to the widespread assumption that cerebral metabolic rate in patients with head injury is always low, CMRO2 was initially within the normal range in 17/21 (81%) children. Both CMRO2 and AJVDO2 fell significantly between the first and third days after injury. There was a non-significant rise in cerebral blood flow over time. These data represent the first evidence that the temporal change in cerebral metabolic rate reported in experimental models of traumatic brain injury also occurs in patients with head injury. The changes in the pathophysiological response over time suggest that the management may need to be modified accordingly. If cerebral metabolic rate and cerebral oxygen extraction are maximal shortly after injury in children with severe head injury then the children are most likely to sustain secondary damage during this period.

Cerebral blood flow and metabolism in children with severe head injuries. Part 2: Cerebrovascular resistance and its determinants.

It has been proposed that in children with severe head injuries the cerebral circulation does not respond appropriately to normal physiological control mechanisms, making children more susceptible than adults to low cerebrovascular resistance, increased cerebral blood flow (cerebral hyperaemia), and raised intracranial pressure. To investigate this issue, 122 serial measurements of cerebrovascular resistance in 17 children with severe head injuries have been performed and related to cerebral perfusion pressure, arterial CO2 (PaCO2), arterial oxygen content (AO2), and the cerebral metabolic rate of oxygen (CMRO2). Cerebrovascular resistance values (mean (SD) 1.54 (0.61) mm Hg.ml-1.100 g.min) were normal or raised in most cases; 71 values (58%) were within the normal range, 39 (32%) above the upper limit, and only 12 (10%) below the lower limit. There was a significant correlation between cerebral perfusion pressure and cerebrovascular resistance (r = 0.32, p = 0.0003), suggesting preservation of pressure autoregulation. This correlation was absent in four of the five children who died or survived with severe handicap. Analysis by multilevel modelling indicated that, as in normal subjects, CMRO2, CPP, AO2, PaCO2, and cerebrovenous pH were important independent determinants of cerebrovascular resistance. The results indicate that normal cerebrovascular reactivity is often preserved in children with severe head injuries but may be impaired in the most severely injured patients.

Plasma and cerebrospinal fluid arginine vasopressin in patients with and without fever.

Hyponatraemia has been described in association with a number of acute infectious diseases, mainly bacterial and tuberculous meningitis and pneumonia, and has been attributed to inappropriate secretion of arginine vasopressin (AVP). The mechanism of inappropriate AVP production is uncertain, but there is experimental evidence to suggest that fever may stimulate secretion of AVP into plasma and cerebrospinal fluid. In this study, AVP concentrations in plasma and cerebrospinal fluid from 37 febrile children with infections have been compared with those from 27 afebrile control subjects. Ten of the febrile children had meningitis (eight bacterial, two viral) and the remainder a variety of other infectious diseases. Seventy four per cent of febrile infected children were hyponatraemic (serum sodium less than 135 mmol/l) compared with only 8% of the afebrile controls. Plasma AVP concentrations were significantly higher in the febrile patients (median 2.92 pmol/l, range 1.0-23.25, n = 28) than in controls (median 1.67 pmol/l, range 0.57-6.0, n = 14) but there was no significant difference in cerebrospinal fluid AVP concentrations. There was no difference in plasma AVP concentrations between patients with meningitis and those with infections not involving the central nervous system. Careful attention should be paid to fluid and electrolyte balance in all children with acute infections.

A practical method of serial bedside measurement of cerebral blood flow and metabolism during neurointensive care.

Acute encephalopathy is a major cause of death and neurological handicap in children. The principle aims of treatment are to provide adequate cerebral blood flow for the brain's metabolic needs and to prevent intracranial pressure rising above the level at which brain herniation occurs. Rational management requires an understanding of the pathophysiological changes in cerebral blood flow and metabolism which occur. The paucity of data on this subject reflects the perceived difficulty of measuring cerebral blood flow and cerebral metabolism in children. A modification of the Kety Schmidt technique of measuring cerebral blood flow and cerebral metabolism is described. This modification makes it possible to perform serial bedside measurements in children receiving intensive care. This method was used to perform 348 measurements in 58 children. The method was reproducible and no significant complications were encountered. The results indicated that appreciable changes in cerebral blood flow and metabolism could occur in individual patients over time, emphasising the importance of serial measurements. This technique may provide a practical means of monitoring cerebral blood flow and metabolism in very sick children receiving neurointensive care and evaluating the efficacy of treatment.

Hypoplastic left heart syndrome: more potential transplant recipients than suitable donors.

Neonatal cardiac transplantation offers the prospect of survival for babies with hypoplastic left heart syndrome--but only if suitable donors are available. In a retrospective survey in the Northern health region of England and Wales, the likely need for neonatal cardiac transplantation far outweighed the potential availability of donors. Over 8 years (1983-90) hypoplastic left heart syndrome was identified in 38 newborn babies and in 9 fetuses in utero. Of 41 live births (including 3 diagnosed prenatally) 31 would have been candidates for a cardiac transplant, but only 4 suitable donors could be identified (3 with anencephaly born alive during the same period and 1 who died between 1979 and 1986 after a head injury). Analysis of all infant deaths in 1987-89 revealed only 3 potential donors from 426 deaths in the 3 years. Although more widespread antenatal diagnosis may lead to fewer liveborn babies with hypoplastic left heart syndrome, these findings indicate that an alternative source of donors needs to be identified before neonatal cardiac transplantation can be widely used in the treatment of this disorder.

Causes of fatal childhood accidents involving head injury in northern region, 1979-86.

OBJECTIVE: To examine the causes and circumstances surrounding fatal accidents involving head injuries in children in the Northern region. DESIGN: Retrospective review of the hospital case notes, necropsy reports, and records of the coroners' inquests. SETTING: Northern Regional Health Authority. PATIENTS: All 255 children aged less than 16 years who died with a head injury during 1979-86. MAIN OUTCOME MEASURES: Cause of injury and circumstances of accident according to reports of inquests; injury severity score; number of fatal accidents and mortality per 100,000 children in 10 groups of local authority wards ranked according to their score on the overall deprivation index; and distance of site of accident from child's home. RESULTS: Of the 255 children who died after a head injury, 136 (53%) children were playing at the time of the accident. 195 (76%) children sustained the head injury in road traffic accidents, 135 as pedestrians, 35 as cyclists, and 25 as passengers in a vehicle. In 120 accidents in child pedestrians the primary cause of accident was the unsafe behaviour of the child. 172 (67%) accidents occurred within one to two km of the child's home and 153 (63%) between 3 pm and 9 pm. The mortality was significantly related to social deprivation; excluding eight children injured while on holiday in the region, 15-fold decrease in mortality was recorded between the local authority wards that ranked highest on the overall deprivation index and those that ranked lowest (14.0/100,000 children, group 10 v 0.9/100,000, group 1 respectively, p less than 0.00001). CONCLUSIONS: The finding that most accidents occurred in children living in deprived areas who were playing unsupervised near their home suggests that childhood mortality might be appreciably reduced if children at play were protected from traffic, particularly in socially deprived areas.

Avoidable factors contributing to death of children with head injury.

OBJECTIVE: To assess the incidence of potentially avoidable complications contributing to death of children with head injuries. DESIGN: Retrospective review of children who died with head injuries from 1979 to 1986 from data of the Office of Population Censuses and Surveys, Hospital Activity Analyses, case notes, coroners' records, and necropsy reports. SETTING: District general hospitals and two regional neurosurgical centres in Northern region. RESULTS: 255 Children died from head injury in the region, the mortality being 5.3 per 100,000 children per year. Head injury was the single most important cause of death in children aged greater than 1 year, accounting for 15% of deaths in children aged 1-15 years and a quarter for those aged 5-15 years. 121 Potentially avoidable factors possibly or probably contributing to death occurred in 81 children (32%). Half the children (125) died before admission, 27 of whom (22%) had potentially avoidable factors possibly or probably contributing to death, and 130 died after admission, 54 of whom (42%) had 93 such factors, which included failure of diagnosis or delayed recognition of intracranial haemorrhage or associated injury, inadequate management of the airways, and poor management of the transfer between hospitals. IMPLICATIONS: Regions should revise urgently their guidelines for optimal management and indications for neurosurgical referral to include children with severe head injuries and audit their systems of care for all patients with head injuries.

Lethal respiratory failure in preterm infants due to cystic fibrosis. The first case reports.

We present the first report of two preterm infants who died from respiratory failure secondary to cystic fibrosis which presented in the early neonatal period.