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.

Growth hormone secretion, fatigue and quality of life after childhood traumatic brain injury.

CONTEXT: Traumatic brain injury (TBI) is a recognised cause of hypopituitarism in adults but the prevalence after childhood TBI remains controversial. OBJECTIVE: To investigate long-term endocrine outcomes and quality of life (PedsQL and QoL-AGHDA (Quality of Life in Adult Growth Hormone Deficiency Assessment)) following childhood TBI. DESIGN: Prospective study. METHODS: Participants with moderate/severe TBI (n = 31) and controls (n = 17). Mean (range) age: 19.8 ± 4.2 (11-26), time post TBI: 9 (7-11) years. Detailed endocrine evaluation of stimulated (insulin tolerance test (ITT)) and spontaneous GH secretion (overnight profile) was undertaken in the TBI group; QoL and neuroimaging in both groups. RESULTS: No participant had seizures, short stature, precocious puberty or hypothyroidism. In 6/25 the ITT GH response was below age-defined cut-offs and cortisol <500 nmol/L in 2/25. Mean spontaneous GH secretion was <3.1 µg/L in 16/22 but peak GH was low only in 1/22 profiles. One patient had abnormal spontaneous and stimulated GH secretion and hypogonadism. Fatigue and depression scores were higher in TBI patients (P = .011 and P = .020). Fatigue correlated with measures of spontaneous but not stimulated GH secretion. Overall QoL (PedsQL) did not differ between groups but specific attributes of health state (cognition, memory) were impaired in TBI patients. Pituitary neuroimaging was normal in all participants. CONCLUSIONS: Fatigue and depression were common 8-10 years post childhood TBI. One individual had GHD (1/22) using rigorous diagnostic criteria. A single ITT potentially over-diagnosed GHD in 25% (6/25) without clear correlation with symptoms underlying the importance of using two diagnostic tests in TBI survivors.

Fitting and flailing: recognition of paediatric antiphospholipid syndrome.

Antiphospholipid syndrome (APS) is a systemic autoimmune condition where the presence of antiphospholipid antibodies is thought to predispose to thrombotic events. It is uncommon in the paediatric population, but current diagnostic criteria are based on adult population studies, making assessment of its true paediatric prevalence difficult. We present two cases of paediatric APS, who presented with primary neurological events, and discuss approaches to diagnosis, interpretation of screening investigations, including antinuclear antibodies (ANA), anti-extractable nuclear antigen (ENA) antibodies and lupus anticoagulant. Possible approaches to the management of paediatric APS are discussed.

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.

A possible new approach to understanding mental disorder.

The aetiology of mental disorders is not fully understood. This paper presents an analysis of the conceptual control process exploring the tools of conceptual application and the phases and the mechanism of the control process and seeks to show how the illness states of mental disorder naturally come to occur. Living occurs in a world of change. For living to occur some control is required and to exert control, to provide direction for the conceptual process, some interpretation of significance, some definition of need is also required. Such interpretation, monitoring significance in relation to the many aspects of change, forms the base on which living occurs. Change in human terms is intrinsically insecure and interpretation of significance is an interpretation of security, an interpretation of control in living. Conceptual control is a process applied to maintain security, to maintain a secure base for the interpretation of significance, it is a process applied to produce and hold a sense of control. Powering a process, producing and holding a sense of control, is an active process and so requires some form of energy. Human beings have a sense of that energy, something exhibited in terms such as full of energy, tired, exhausted. As energy is required to power the control process, accompanying the sense of energy is a sense of the ability to provide power, is a sense of the ability to hold and maintain control, is a sense of security. As available energy reduces there is difficulty holding the same sense of control, a person in the same setting comes to feel more insecure. This can result in a person experiencing mental disorder from mild to severe degree. Mild where conceptual process is applied to manage just one or a very few particular needs, severe and more general where the insecurity affects the base of interpretation. In this later case seeking to protect security can lead to mania, mood-incongruent delusions, schizophrenia. Failing ability to protect can lead to generalized anxiety disorder, mood-congruent delusions, different presentations and degrees of depression.

Identification of factors influencing shark catch and mortality in the Marshall Islands tuna longline fishery and management implications.

Recent average annual catches of sharks by tuna longline vessels fishing in the Republic of the Marshall Islands (RMI) are estimated to be between 1583 and 2274 t. Although 22 shark species have been recorded by the observer programme for this fishery, 80% of the annual catch comprises only five species: blue shark Prionace glauca, silky shark Carcharhinus falciformis, bigeye thresher shark Alopias superciliosus, pelagic thresher shark Alopias pelagicus and oceanic whitetip shark Carcharhinus longimanus. Wire leaders (i.e. branch lines or traces) were also used by nearly all observed vessels. Generalized additive model (GAM)-based analyses of catch rates indicated that P. glauca and A. superciliosus are caught in higher numbers when vessels fish in relatively cooler waters, at night, close to the full moon, when the 27° C thermocline is close to the surface and during El Niño conditions. In contrast, C. falciformis, A. pelagicus and C. longimanus are caught in higher numbers when shark lines are used (all three species) or hooks are set at a shallow depth (A. pelagicus and C. longimanus and, also, P. glauca). These findings are generally consistent with current knowledge of these species' habitat preferences, movement and distribution. The results of these analyses were combined with information pertaining to shark condition and fate upon capture to compare the likely effectiveness of a range of potential measures for reducing shark mortality in the longline fishery. Of the options considered, the most effective would be to combine measures that reduce the catch rate (e.g. restrictions on the use of wire leaders, shark baits and shark lines) with measures that increase survival rates after post-capture release (e.g. finning bans).

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.

The PATRIARCH Study. Using outcome measures for league tables: can a North American prediction of admission score be used in a United Kingdom children's emergency department? PRISA And Triage In A Regional Children's Hospital.

OBJECTIVES: The use of league tables has become predominant in the healthcare culture of the United Kingdom. These tables are often based on measures that are viewed with scepticism by clinicians. This study was designed to test the validity of a North American risk of admission score, the PRISA, for use in a United Kingdom population of accident and emergency (A&E) attendees. METHODS: All attendees to a children's A&E department were scored using the PRISA for a single calendar month (November 2000) RESULTS: 701 children were studied in total. The results show that the PRISA applied to this population gives an area under the receiver operator curve of 0.76. Of the 701 patients studied, 206 (29.4%) were admitted. The PRISA predicted a total of 206.10 admissions. Of the 50 patients discharged with the highest PRISA scores (that is, with the highest likelihood of admission), none were admitted in the 48 hours after their original attendance. CONCLUSIONS: These results show that the PRISA is suitable as a measure of paediatric A&E department performance in the United Kingdom and it is highly promising as a future measure of quality.

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.

Subdural haemorrhages in infants: population based study.

OBJECTIVES: To identify the incidence, clinical outcome, and associated factors of subdural haemorrhage in children under 2 years of age, and to determine how such cases were investigated and how many were due to child abuse. DESIGN: Population based case series. SETTING: South Wales and south west England. SUBJECTS: Children under 2 years of age who had a subdural haemorrhage. We excluded neonates who developed subdural haemorrhage during their stay on a neonatal unit and infants who developed a subdural haemorrhage after infection or neurosurgical intervention. MAIN OUTCOME MEASURES: Incidence and clinical outcome of subdural haemorrhage in infants, the number of cases caused by child abuse, the investigations such children received, and associated risk factors. RESULTS: Thirty three children (23 boys and 10 girls) were haemorrhage. The incidence was 12.8/100 000 children/year (95% confidence interval 5.4 to 20.2). Twenty eight cases (85%) were under 1 year of age. The incidence of subdural haemorrhage in children under 1 year of age was 21.0/100 000 children/year and was therefore higher than in the older children. The clinical outcome was poor: nine infants died and 15 had profound disability. Only 22 infants had the basic investigations of a full blood count, coagulation screen, computed tomography or magnetic resonance imaging, skeletal survey or bone scan, and ophthalmological examination. In retrospect, 27 cases (82%) were highly suggestive of abuse. CONCLUSION: Subdural haemorrhage is common in infancy and carries a poor prognosis; three quarters of such infants die or have profound disability. Most cases are due to child abuse, but in a few the cause is unknown. Some children with subdural haemorrhage do not undergo appropriate investigations. We believe the clinical investigation of such children should include a full multidisciplinary social assessment, an ophthalmic examination, a skeletal survey supplemented with a bone scan or a skeletal survey repeated at around 10 days, a coagulation screen, and computed tomography or magentic resonance imaging. Previous physical abuse in an infant is a significant risk factor for subdural haemorrhage and must be taken seriously by child protection agencies.

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.