Aquaporin-4 IgG antibody-related disorders in patients with juvenile systemic lupus erythematosus.

OBJECTIVE: The aim of this study was to: (a) screen a large group of unselected patients with juvenile systemic lupus erythematosus for anti-aquaporin 4 antibodies (AQP4-Ab); (b) identify clinical and laboratory predictors of the presence of AQP4-Ab positivity in juvenile systemic lupus erythematosus. METHODS: Sera from 90 patients with juvenile systemic lupus erythematosus were tested for the presence of AQP4-Ab using a cell-based assay. Demographics, clinical and immunological features, treatment received were summarized. Fisher's exact test was used to identify clinical predictors of positivity for AQP4-Ab. RESULTS: Five of 90 (5.5%) patients tested positive for AQP4-Ab, all of which had neurological involvement, mainly transverse myelitis and optic neuritis. AQP4-Ab-positive patients were more likely to have neurological symptoms (P = 0.002), less likely to experience dermatological manifestations (P = 0.045), and less likely to have detectable anti-dsDNA antibodies (P = 0.022). These patients were also more likely to have received anti-epileptic (P = 0.023) and anti-coagulant (P = 0.007) drugs. CONCLUSIONS: The findings of this study indicate that some patients with juvenile systemic lupus erythematosus develop antibodies against aquaporin-4 and may be at risk of developing a neurological clinical phenotype. We suggest that all juvenile systemic lupus erythematosus patients should be systematically screened for the presence of AQP4-Ab and this may help identify a high risk for neurological involvement in juvenile systemic lupus erythematosus.

Spectrum of movement disorders and neurotransmitter abnormalities in paediatric POLG disease.

OBJECTIVES: To describe the spectrum of movement disorders and cerebrospinal fluid (CSF) neurotransmitter profiles in paediatric patients with POLG disease. METHODS: We identified children with genetically confirmed POLG disease, in whom CSF neurotransmitter analysis had been undertaken. Clinical data were collected retrospectively. CSF neurotransmitter levels were compared to both standardised age-related reference ranges and to non-POLG patients presenting with status epilepticus. RESULTS: Forty-one patients with POLG disease were identified. Almost 50% of the patients had documented evidence of a movement disorder, including non-epileptic myoclonus, choreoathetosis and ataxia. CSF neurotransmitter analysis was undertaken in 15 cases and abnormalities were seen in the majority (87%) of cases tested. In many patients, distinctive patterns were evident, including raised neopterin, homovanillic acid and 5-hydroxyindoleacetic acid levels. CONCLUSIONS: Children with POLG mutations can manifest with a wide spectrum of abnormal movements, which are often prominent features of the clinical syndrome. Underlying pathophysiology is probably multifactorial, and aberrant monoamine metabolism is likely to play a role.

Correction to: Spectrum of movement disorders and neurotransmitter abnormalities in paediatric POLG disease.

Due to a typesetting error the wrong Table 2 was used. The correct Table 2 is shown here.

Paediatric acute disseminated encephalomyelitis followed by optic neuritis: disease course, treatment response and outcome.

BACKGROUND AND PURPOSE: Acute disseminated encephalomyelitis followed by optic neuritis (ADEM-ON) is a rare demyelinating syndrome that is different from multiple sclerosis and neuromyelitis optica spectrum disorder. The aim of this study was to describe the disease course, treatment response and outcome of children with ADEM-ON. METHODS: Children of <18 years of age were identified from six countries of the EU Paediatric Demyelinating Disease Consortium. Patients fulfilled the diagnostic criteria for ADEM followed by at least one ON. Anti-myelin oligodendrocyte glycoprotein (MOG) antibodies were tested in all patients. RESULTS: In this study of 17 patients (nine boys) with ADEM-ON, anti-myelin oligodendrocyte glycoprotein (MOG) antibodies were identified in 16 patients. Age at onset was 6.1 years (interquartile range, 5.1-9.2 years). Twelve patients received oral prednisolone and 10 received maintenance immunosuppression (e.g. azathioprine, intravenous immunoglobulins, Rituximab). During a follow-up of 5.3 years (interquartile range, 1.8-10.2 years), 54 relapses occurred with a median of 3 relapses per patient (range, 1-9 per patient). Patients relapsed on all treatments but no relapses occurred on a prednisolone dose >10 mg/day. Visual and cognitive residual deficits were common in this group. CONCLUSIONS: Acute disseminated encephalomyelitis followed by optic neuritis is an anti-MOG antibody-associated relapsing disorder that can have a heterogeneous disease course. Patients were refractory for maintenance immunosuppression and appeared to be corticosteroid-dependent. Further international collaborations are now required to unify guidelines in this difficult-to-manage group of patients.

Paediatric multiple sclerosis: examining utility of the McDonald 2010 criteria.

The new McDonald 2010 criteria have been recommended in paediatric multiple sclerosis (PMS). We aimed to assess the utility of McDonald 2010 criteria in comparison with 2007 International Paediatric Multiple Sclerosis Study Group (IPMSSG)-recommended criteria for PMS diagnosis. Retrospective analysis of 38 PMS cases from three UK demyelination clinics was conducted. Dissemination in space (DIS) and time (DIT) for both McDonald and IPMSSG criteria were noted on initial and follow-up magnetic resonance imaging (MRI). At first MRI scan, IPMSSG DIS criteria were fulfilled in 68% of scans and McDonald DIS criteria in 84%. In total, 11/18 children given gadolinium contrast fulfilled both McDonald DIS and DIT criteria on initial scan. The 2010 McDonald criteria appear more sensitive than IPMSSG and may allow PMS diagnosis at first presentation of CIS in at least a half of cases.

Spectrum of Neuroradiologic Findings Associated with Monogenic Interferonopathies.

The genetic interferonopathies are a heterogeneous group of disorders thought to be caused by the dysregulated expression of interferons and are now commonly considered in the differential diagnosis of children presenting with recurrent or persistent inflammatory phenotypes. With emerging therapeutic options, recognition of these disorders is increasingly important, and neuroimaging plays a vital role. In this article, we discuss the wide spectrum of neuroradiologic features associated with monogenic interferonopathies by reviewing the literature and illustrate these with cases from our institutions. These cases include intracerebral calcifications, white matter T2 hyperintensities, deep WM cysts, cerebral atrophy, large cerebral artery disease, bilateral striatal necrosis, and masslike lesions. A better understanding of the breadth of the neuroimaging phenotypes in conjunction with clinical and laboratory findings will enable earlier diagnosis and direct therapeutic strategies.

Severe acute disseminated encephalomyelitis: a paediatric intensive care population-based study.

There is a paucity of literature on the epidemiology of severe acute disseminated encephalomyelitis (ADEM). We describe a Paediatric Intensive Care Unit (PICU) population-based study to determine the epidemiology and clinical characteristics of children with ADEM requiring PICU admission or resulting in death. Anonymized data from the Paediatric Intensive Care Audit Network (PICANet) were obtained for all children under 16 years with a diagnosis of ADEM admitted to 25 PICUs in England and Wales (2004-2008). The Office for National Statistics (ONS) mortality database was also searched. In total, 27 PICANet cases (13 females:14 males; median age 4.8 years) were ascertained and all were alive on discharge. In addition, three cases were identified from the ONS mortality database. Of the 27 PICANet cases, clinical features included; seizures (n = 5); upper airway respiratory obstruction/stridor (n = 2); unspecified encephalopathy (n = 27); and polyfocal neurological deficits (n = 6). The median duration of ventilation was 3 days. Inotropic support was required in 4/27 patients, and one patient had invasive intracranial pressure monitoring. None received plasmapheresis. We conclude that the incidence of childhood ADEM admitted to the PICU in England and Wales is approximated at 0.5 per million children/year, thus representing approximately one quarter of children admitted with ADEM (denominator: 2009 Canadian surveillance data).

MRI Patterns in Pediatric CNS Hemophagocytic Lymphohistiocytosis.

BACKGROUND AND PURPOSE: Neuroimaging has an important role in detecting CNS involvement in children with systemic or CNS isolated hemophagocytic lymphohistiocytosis. We characterized a cohort of pediatric patients with CNS hemophagocytic lymphohistiocytosis focusing on neuroradiologic features and assessed whether distinct MR imaging patterns and genotype correlations can be recognized. MATERIALS AND METHODS: We retrospectively enrolled consecutive pediatric patients diagnosed with hemophagocytic lymphohistiocytosis with CNS involvement treated at 2 pediatric neurology centers between 2010 and 2018. Clinical and MR imaging data were analyzed. RESULTS: Fifty-seven children (40 primary, 70%) with a median age of 36 months (interquartile range, 5.5-80.8 months) were included. One hundred twenty-three MR imaging studies were assessed, and 2 broad imaging patterns were identified. Pattern 1 (significant parenchymal disease, 32/57, 56%) was seen in older children (P = .004) with worse clinical profiles. It had 3 onset subpatterns: multifocal white matter lesions (21/32, 66%), brainstem predominant disease (5, 15%), and cerebellitis (6, 19%). All patients with the brainstem pattern failed to meet the radiologic criteria for chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids. An attenuated imaging phenotype (pattern 2) was seen in 25 patients (44%, 30 studies) and was associated with younger age. CONCLUSIONS: Distinct MR imaging patterns correlating with clinical phenotypes and possible genetic underpinnings were recognized in this cohort of pediatric CNS hemophagocytic lymphohistiocytosis. Disruptive mutations and missense mutations with absent protein expression correlate with a younger onset age. Children with brainstem and cerebellitis patterns and a negative etiologic work-up require directed assessment for CNS hemophagocytic lymphohistiocytosis.

Enamel erosion in dietary acids: inhibition by food proteins in vitro.

The aim of this study was to investigate the effects of two common food proteins on human enamel erosion in vitro. Erosion was measured by non-contact profilometry in citric, malic and lactic acids at pH 2.8, 3.2 and 3.8 and five commercially available soft drinks, in the presence of a salivary pellicle. Whole milk casein or hen egg ovalbumin was added to the acid solutions and drinks at 0.2% w/v, and the effect on erosion was determined by comparison with the corresponding solution without protein. Casein significantly reduced erosion in all but two solutions. The effects of the individual subfractions of casein in citric acid at pH 3.2 were similar to that of whole casein. Ovalbumin reduced erosion in some solutions, but the magnitude of the reduction was less than that with casein. A greater proportional reduction in erosion was seen in citric acid than in malic or lactic acids. We postulate that the mechanism involves adsorption of proteins to the pellicle or the enamel surface, forming a protein film with enhanced erosion-inhibiting properties. The citrate ion may play an active stabilising role, since erosion reduction was less in the other acids. In conclusion, casein and, to a lesser extent, ovalbumin show promise as potential anti-erosive additives to drinks.

Warming of patients during Caesarean section: a telephone survey.

We contacted the duty obstetric anaesthetist in 219 of the 220 consultant-led maternity units in the UK (99.5%) and asked about departmental and individual practice regarding temperature management during Caesarean section. Warming during elective Caesarean section was routine in 35 units (16%). Intravenous fluid warmers were available in 213 units (97%), forced air warmers were available in 211 (96%) and warming mattresses were available in 42 (19%). Only 18 (8%) departments had specific guidelines for temperature management during Caesarean section. Personal intra-operative practice was variable, although all of those contacted would initiate some form of active temperature management after a mean (SD) volume of blood loss of 1282 (404) ml, length of surgery of 78 (24) min, or core body temperature (if measured) of median (IQR [range]), 36 (35.5-36 [34-37.2]) degrees C.

Epidural lidocaine-bicarbonate-adrenaline vs levobupivacaine for emergency Caesarean section: a randomised controlled trial.

Epidural mixtures containing lidocaine with or without additives are commonly used to convert epidural analgesia in labour to anaesthesia for emergency Caesarean section, but direct comparisons with alternative, single agents in this situation are few. In a prospective double-blinded trial, we compared a freshly prepared lidocaine-bicarbonate-adrenaline mixture (final concentrations 1.8%, 0.76% and 1:200,000, respectively) with our standard agent, levobupivacaine 0.5%, for extending epidural blockade for emergency Caesarean section. Using a sequential analysis technique, with data analysed in blocks of 40, women receiving epidural analgesia in labour who required top-up for Caesarean section were randomly assigned to receive 20 ml of epidural solution over 3 min. The first analysis (n = 40) indicated that the study should be stopped, as significant differences were found in our primary outcome data. Median (IQR [range]) times to reach a block to touch to T5 and cold to T4 were, respectively, 7 (6-9 [5-17]) min and 7 (5-8 [4-17]) min for lidocaine-bicarbonate-adrenaline, and 14 (10 -17 [9-31]) min and 11 (9-14 [6-30]) min for levobupivacaine (p = 0.00004 and 0.001, respectively). Pre- and intra-operative supplementation/pain, maternal side-effects and neonatal outcomes (excluding five women who underwent instrumental delivery) were similar between the groups. Intra-operative maternal sedation (scored by the mother on a 10-point scale) was greater with lidocaine-bicarbonate-adrenaline (4.5 (3-8 [1-9])) than with levobupivacaine (3 (1-4 [1-7])), but not significantly so (p = 0.07). We conclude that epidural lidocaine-bicarbonate-adrenaline halves the onset time when extending epidural analgesia for Caesarean section although there is a possibility of increased maternal sedation.

Inhibition of hydroxyapatite dissolution by ovalbumin as a function of pH, calcium concentration, protein concentration and acid type.

Hydroxyapatite is the main constituent of the dental hard tissues, and in vivo its dissolution in acids leads to the pathological condition of dental erosion. Food proteins which inhibit hydroxyapatite dissolution may find application as erosion-reducing agents in food and drink products. The aim of this study was to investigate the egg protein ovalbumin as a potential inhibitor of hydroxyapatite dissolution in acidic solutions, with conditions representative of dental erosion. The dissolution rate of hydroxyapatite discs was measured in an acidic solution as a function of pH, calcium concentration, ovalbumin concentration and acid type. All experiments were performed in triplicate. 0.2% w/v ovalbumin significantly reduced the dissolution rate in citric acid by 50-75% over the pH range 2.80-4.00, and by 45-60% in solutions with calcium concentrations of up to 20 mM (p < 0.05). The effect was persistent for several rinses after the initial exposure to the protein. 0.02% w/v ovalbumin significantly reduced the dissolution of hydroxyapatite in citric acid by 30-55%. Ovalbumin did not, however, statistically significantly reduce the hydroxyapatite dissolution rate in malic or lactic acids. The effect is ascribed to adsorption and partial, reversible denaturation of ovalbumin on the hydroxyapatite surface. There may be some interaction between ovalbumin and the citrate ion which promotes the adsorption of protein in the presence of citric acid. Ovalbumin shows promise as a potential erosion-reducing additive to citrus-based drinks.

Erosion of enamel by non-carbonated soft drinks with and without toothbrushing abrasion.

OBJECTIVE: To investigate how enamel loss due to erosion, and due to cycling of erosion and abrasion, depends on compositional parameters of soft drinks, and particularly whether the thickness of the erosive softened layer is a function of drink composition. SETTING: University dental hospital research laboratory in the UK, 2004. MATERIALS AND METHODS: Six drinks were chosen based on their popularity and composition: apple juice, orange juice, apple drink, orange drink, cranberry drink and 'ToothKind' blackcurrant drink. Group A samples (n = 36) were exposed to soft drinks at 36 degrees C for six consecutive 10 minute periods. Group B samples (n = 36) were subjected to alternating erosion and toothbrushing, repeated six times. Enamel loss was measured using optical profilometry. RESULTS: Group A: significant enamel loss was seen for all drinks (p < 0.001). Erosion was correlated with pH and calcium concentration but not phosphate concentration or titratable acidity. Group B: significant additional material loss due to toothbrush abrasion occurred with all drinks. Abrasive enamel loss differed between the drinks and was positively correlated with drink erosive potential. CONCLUSION: Enamel loss by erosion is exacerbated by subsequent abrasion. The amount of softened enamel removed by toothbrushing is a function of the chemical composition of the erosive medium.

The regulation of acetyl-CoA carboxylase--a potential target for the action of hypolipidemic agents.

ACC exists as two major isoforms ACC1 or ACC alpha, and ACC2 or ACC beta, and there is evidence that they play separate roles in the production of malonyl-CoA for fatty acid synthesis and the control of mitochondrial beta-oxidation, respectively. ACC alpha can be regulated at the level of gene expression, allosteric regulation of the enzyme, and reversible phosphorylation by AMP-PK. Emerging lines of research suggest that similar mechanisms of regulation exist for ACC beta. Its inactivation in heart and skeletal muscle through phosphorylation by AMP-PK is becoming well-established. ACC is an important target of certain hypolipidemic drugs such as the fibrates. This is not simply because ACC alpha inhibition decreases the synthesis of a lipid component of VLDL because fatty acids synthesized de novo in liver are not always major contributors to VLDL lipid (158); it is also because ACC beta inhibition leads to a decrease in malonyl-CoA levels and the disinhibition of fatty acid oxidation. Partitioning fatty acids towards oxidation and away from esterification is an important aspect of the lipid-lowering effects of fibrates. Fibrates could use any of the mechanisms of ACC regulation to decrease activity. They could repress ACC gene expression through the activation of PPAR alpha, and fibroyl-CoA esters could inhibit ACC allosterically just as TOFyl-CoA does. However, we have demonstrated a rapid inactivation of ACC in cultured rat hepatocytes by gemfibrozil that is mediated by activation of AMP-PK and the subsequent phosphorylation of ACC. The end result is the inhibition of hepatic fatty acid synthesis and a possible activation of beta-oxidation as evidenced by the increased production of ketone bodies. The mechanism through which fibrates activate the AMP-PK cascade, the role of PPAR alpha, the physiological responses of biosynthesis and oxidation and the use of these mechanisms by other hypolipidemic agents are areas of ongoing investigation.

The effect of carbamazepine and sodium valproate on the blood and serum values of children from a third-world environment.

In third-world countries many children with epilepsy also suffer from malnutrition, anemia, liver disease, and immunosuppression. Doctors might have reservations about the use of anticonvulsants that could aggravate these disorders. The purpose of this study was to establish the prevalence of abnormal blood and serum values in children receiving carbamazepine or sodium valproate as monotherapy who attended a child neurology clinic serving a third-world community in Cape Town, South Africa Blood samples were taken at routine follow-up visits from 104 children who had been on carbamazepine or sodium valproate monotherapy for at least 6 months. Hematology, serum chemistry, immunoglobulins, and anticonvulsant levels were measured by standard laboratory procedures. Very few subjects had any values outside accepted normal ranges. When clinically indicated and available, carbamazepine and sodium valproate can be prescribed for children from a third-world environment. Frequent blood and serum testing is not necessary in asymptomatic individuals.

Management of suspected viral encephalitis in children - Association of British Neurologists and British Paediatric Allergy, Immunology and Infection Group national guidelines.

In the 1980s the outcome of patients with herpes simplex encephalitis was shown to be dramatically improved with aciclovir treatment. Delays in starting treatment, particularly beyond 48 h after hospital admission, are associated with a worse prognosis. Several comprehensive reviews of the investigation and management of encephalitis have been published. However, their impact on day-to-day clinical practice appears to be limited. The emergency management of meningitis in children and adults was revolutionised by the introduction of a simple algorithm as part of management guidelines. In February 2008 a group of clinicians met in Liverpool to begin the development process for clinical care guidelines based around a similar simple algorithm, supported by an evidence base, whose implementation is hoped would improve the management of patients with suspected encephalitis.

Severe iron deficiency anaemia and ischaemic stroke in children.

Iron deficiency anaemia (IDA) has a peak prevalence of 4-8% in children aged 1-3 years of age and is known to be associated with developmental delay, lethargy, irritability and cognitive problems. Rarely, IDA has also been reported as a risk factor for stroke in otherwise healthy children. We report a series of four young children aged 14 months to 48 months with significant IDA. Three children had venous sinus thrombosis and one had arterial ischaemic stroke, without other risk factors. We discuss the potential underlying mechanisms and review the relevant literature. This report further consolidates the evidence for a strong association between IDA and childhood stroke and highlights an easily treatable (and preventable) risk factor.

Two unusual clinical and radiological presentations of biotinidase deficiency.

Biotinidase deficiency is due to a defect in recycling of biotin and is a treatable autosomal recessive inherited disorder. We describe two cases with unusual presenting symptoms and rarely described MRI findings. We propose that the diagnosis of biotinidase deficiency should be considered when there are symmetrical MRI changes in the medial thalamus, dorsal brainstem, medulla and spinal cord as in our two cases. As long as there isn't newborn screening for biotinidase deficiency in the UK; increased awareness of this disorder and recognition of biotinidase deficiency as a cause of bilateral symmetrical MRI patterns similar to our patients, would facilitate early diagnosis and prevent many of the devastating neurological sequelae associated with missing the condition.

Intra-operative fluid warming in elective caesarean section: a blinded randomised controlled trial.

BACKGROUND: We assessed the effect of warming intravenous fluids during elective caesarean section under combined spinal-epidural anaesthesia in a blinded, randomised controlled trial. METHOD: Seventy-five women having elective caesarean section were randomly assigned to receive all intravenous fluids at room temperature, or heated in a cabinet set at 45 degrees C or via a Hotline fluid warmer (Smiths Medical International Ltd, Watford, Herts, UK). After 10 mL/kg crystalloid preload, combined spinal-epidural anaesthesia was performed. Core and ambient temperatures, thermal comfort and shivering were measured every 15 min thereafter. The primary outcome was the temperature at 60 min. RESULTS: Temperature decreased in all groups. Although the temperature decrease at 60 min was similar in the heated cabinet and Hotline groups, the room temperature group exhibited a greater decrease [difference 0.4 degrees C (95% CI 0.2-0.6 degrees C); P=0.015]. More women felt cold in the room temperature group (8: 32%) than in the heated cabinet set (3: 12%) and Hotline (1: 4%) groups (P=0.02), but the incidence of shivering was similar: 11 (44%), 9 (36%) and 7 (28%) respectively. Apgar scores and neonatal cord gases were similar. CONCLUSION: Warming intravenous fluids mitigates the decrease in maternal temperature during elective caesarean section under combined spinal-epidural anaesthesia and improves thermal comfort, but does not affect shivering. Intravenous fluids should be warmed routinely in elective caesarean section, especially for cases of expected long duration, but the use of pre-warmed fluids is as efficient and cheaper than using a Hotline fluid warmer.

The development of participatory health research among incarcerated women in a Canadian prison.

This paper describes the development of a unique prison participatory research project, in which incarcerated women formed a research team, the research activities and the lessons learned. The participatory action research project was conducted in the main short sentence minimum/medium security women's prison located in a Western Canadian province. An ethnographic multi-method approach was used for data collection and analysis. Quantitative data was collected by surveys and analysed using descriptive statistics. Qualitative data was collected from orientation package entries, audio recordings, and written archives of research team discussions, forums and debriefings, and presentations. These data and ethnographic observations were transcribed and analysed using iterative and interpretative qualitative methods and NVivo 7 software. Up to 15 women worked each day as prison research team members; a total of 190 women participated at some time in the project between November 2005 and August 2007. Incarcerated women peer researchers developed the research processes including opportunities for them to develop leadership and technical skills. Through these processes, including data collection and analysis, nine health goals emerged. Lessons learned from the research processes were confirmed by the common themes that emerged from thematic analysis of the research activity data. Incarceration provides a unique opportunity for engagement of women as expert partners alongside academic researchers and primary care workers in participatory research processes to improve their health.