Fat Malabsorption and Ursodeoxycholic Acid Treatment in Children With Reduced Organic Solute Transporter-α (SLC51A) Expression.

Objectives: A bile acid homeostasis disorder was suspected in 2 siblings and their second cousin who presented in infancy with fat malabsorption, severe fat-soluble vitamin deficiency, rickets, and mild liver involvement. Our aims were to identify the genetic cause, describe the disease, and evaluate the response to ursodeoxycholic acid (UDCA) treatment. Methods: Whole exome sequencing, immunohistochemistry of duodenal biopsies and candidate variant testing in a cell-based model was performed. Fecal fat excretion, serum bile acids, 7α-hydroxy-4-cholesten-3-one (C4), and fibroblast growth factor 19 (FGF19) were quantified in both siblings on and off UDCA treatment. Results: A novel homozygous variant of SLC51A, which encodes the bile acid carrier organic solute transporter (OST)-α, was identified in all affected children. OSTα protein expression was readily detected by immunohistochemistry in duodenum of pediatric control subjects but not in the affected siblings. The siblings had low serum levels of bile acids and C4 and high serum levels of FGF19 consistent with repression of hepatic bile acid synthesis. On treatment with UDCA, fecal fat excretion was reduced and serum levels of C4, FGF19, and liver enzymes normalized. Conclusions: We report an apparent deficiency of OSTα associated with early onset fat malabsorption and mild liver involvement. The clinical presentation partially overlaps previous reports for 3 patients with OSTα or OSTß deficiency and extends the clinical spectrum associated with loss of SLC51A expression. Our data suggest that repression of hepatic bile acid synthesis contributes to fat malabsorption in OSTα-OSTß deficiency but can be partly reversed with UDCA treatment.

Cerebrospinal fluid cytokines and chemokines in children with Lyme neuroborreliosis; pattern and diagnostic utility.

BACKGROUND: Lyme neuroborreliosis (LNB) is characterized by cerebrospinal fluid (CSF) inflammation with several cytokines/chemokines and B-lymphocytes. Clinically, LNB in children may be difficult to discriminate from non-Lyme aseptic meningitis (NLAM). We aimed to identify CSF cytokine/chemokine patterns in children with LNB, NLAM and controls and elucidate the diagnostic value of these cytokines/chemokines alone or in combination to discriminate between LNB and NLAM. METHODS: Children with symptoms suggestive of LNB were included prospectively and categorized as LNB, NLAM or controls (no pleocytosis). Cytokines/chemokines in CSF were measured by multiplex bead assays and levels were compared between the three groups by nonparametric statistical tests. Previous results from the same children on the established biomarker, CXCL13, were included in the statistical analyses. The diagnostic properties of cytokines/chemokines to discriminate between LNB and NLAM were determined by receiver operating characteristic curve analyses with estimates of area under curve (AUC). To explore diagnostic properties of combinations of cytokines/chemokines, prediction models based on logistic regression were used. RESULTS: We included 195 children with LNB (n = 77), NLAM (n = 12) and controls (n = 106). Children with LNB had higher CSF levels of CCL19, CCL22 and CXCL13 compared to NLAM and controls, whereas INFγ was higher in NLAM than in LNB and controls. CXCL13 was the superior single cytokine/chemokine to discriminate LNB from NLAM (AUC 0.978). The combination CXCL13/CCL19 (AUC 0.992) may possibly improve the specificity for LNB, especially for children with moderate CXCL13 levels. CONCLUSIONS: The intrathecal immune reaction in LNB is characterized by B cell associated chemokines. Whether the combination CXCL13/CCL19 further improves discrimination between LNB and NLAM beyond the diagnostic improvements by CXCL13 alone needs to be tested in new studies.

The B-lymphocyte chemokine CXCL13 in the cerebrospinal fluid of children with Lyme neuroborreliosis: associations with clinical and laboratory variables.

Background: The B-lymphocyte chemokine CXCL13 is increasingly considered as a useful early phase diagnostic marker of Lyme neuroborreliosis (LNB). However, the large variation in level of CXCL13 in the cerebrospinal fluid (CSF) observed in LNB patients is still unexplained. We aimed to identify factors associated with the level of CXCL13 in children with LNB, possibly improving the interpretation of CXCL13 as a diagnostic marker of LNB. Methods: Children with confirmed and probable LNB were included in a prospective study on CXCL13 in CSF as a diagnostic marker of LNB. The variables age, sex, facial nerve palsy, generalized inflammation symptoms (fever, headache, neck-stiffness and/or fatigue), duration of symptoms, Borrelia antibodies in CSF, Borrelia antibody index (AI), CSF white blood cells (WBC), CSF protein and detection of the genospecies Borrelia garinii by PCR were included in simple and multivariable regression analyses to study the associations with the CXCL13 level. Results: We included 53 children with confirmed and 17 children with probable LNB. CXCL13 levels in CSF were positively associated with WBC, protein and Borrelia antibodies in CSF in both simple and multivariable analyses. We did not find any associations between CXCL13 and age, sex, clinical symptoms, duration of symptoms, AI or the detection of Borrelia garinii. Conclusions: High levels of CSF CXCL13 are present in the early phase of LNB and correlate with the level of CSF WBC and protein. Our results indicate that CSF CXCL13 in children evaluated for LNB can be interpreted independently of clinical features or duration of symptoms.

Direct Molecular Detection and Genotyping of Borrelia burgdorferi Sensu Lato in Cerebrospinal Fluid of Children with Lyme Neuroborreliosis.

The current diagnostic marker of Lyme neuroborreliosis (LNB), the Borrelia burgdorferisensu lato antibody index (AI) in the cerebrospinal fluid (CSF), has insufficient sensitivity in the early phase of LNB. We aimed to elucidate the diagnostic value of PCR for B. burgdorferisensu lato in CSF from children with symptoms suggestive of LNB and to explore B. burgdorferisensu lato genotypes associated with LNB in children. Children were prospectively included in predefined groups with a high or low likelihood of LNB based on diagnostic guidelines (LNB symptoms, CSF pleocytosis, and B. burgdorferisensu lato antibodies) or the detection of other causative agents. CSF samples were analyzed by two B. burgdorferisensu lato-specific real-time PCR assays and, if B. burgdorferisensu lato DNA was detected, were further analyzed by five singleplex real-time PCR assays for genotype determination. For children diagnosed as LNB patients (58 confirmed and 18 probable) (n = 76) or non-LNB controls (n = 28), the sensitivity and specificity of PCR for B. burgdorferisensu lato in CSF were 46% and 100%, respectively. B. burgdorferisensu lato DNA was detected in 26/58 (45%) children with AI-positive LNB and in 7/12 (58%) children with AI-negative LNB and symptoms of short duration. Among 36 children with detectable B. burgdorferisensu lato DNA, genotyping indicated Borrelia garinii (n = 27) and non-B. garinii (n = 1) genotypes, while 8 samples remained untyped. Children with LNB caused by B. garinii did not have a distinct clinical picture. The rate of detection of B. burgdorferisensu lato DNA in the CSF of children with LNB was higher than that reported previously. PCR for B. burgdorferisensu lato could be a useful supplemental diagnostic tool in unconfirmed LNB cases with symptoms of short duration. B. garinii was the predominant genotype in children with LNB.

Cerebrospinal Fluid B-lymphocyte Chemoattractant CXCL13 in the Diagnosis of Acute Lyme Neuroborreliosis in Children.

BACKGROUND: Current markers of Lyme neuroborreliosis (LNB) in children have insufficient sensitivity in the early stage of disease. The B-lymphocyte chemoattractant CXCL13 in the cerebrospinal fluid (CSF) may be useful in diagnosing LNB, but its specificity has not been evaluated in studies including children with clinically relevant differential diagnoses. The aim of this study was to elucidate the diagnostic value of CSF CXCL13 in children with symptoms suggestive of LNB. METHODS: Children with symptoms suggestive of LNB were included prospectively into predefined groups with a high or low likelihood of LNB based on CSF pleocytosis and the detection of Borrelia antibodies or other causative agents. CSF CXCL13 levels were compared between the groups, and receiver-operating characteristic analyses were performed to indicate optimal cutoff levels to discriminate LNB from non-LNB conditions. RESULTS: Two hundred and ten children were included. Children with confirmed LNB (n=59) and probable LNB (n=18) had higher CSF CXCL13 levels than children with possible LNB (n=7), possible peripheral LNB (n=7), non-Lyme aseptic meningitis (n=12), non-meningitis (n=91) and negative controls (n=16). Using 18 pg/mL as a cutoff level, both the sensitivity and specificity of CSF CXCL13 for LNB (confirmed and probable) were 97%. Comparing only children with LNB and non-Lyme aseptic meningitis, the sensitivity and specificity with the same cutoff level were 97% and 83%, respectively. CONCLUSION: CSF CXCL13 is a sensitive marker of LNB in children. The specificity to discriminate LNB from non-Lyme aseptic meningitis may be more moderate, suggesting that CSF CXCL13 should be used together with other variables in diagnosing LNB in children.

Gender Differences in Childhood Lyme Neuroborreliosis.

BACKGROUND: Many neurological diseases show differences between genders. We studied gender differences in childhood Lyme neuroborreliosis (LNB) in an endemic area of Lyme borreliosis in Norway. METHODS: In a population based study, all children (<14 years of age) with symptoms suspicious of LNB, including all children with acute facial nerve palsy, were evaluated for LNB by medical history, clinical examination, blood tests, and lumbar puncture. LNB was diagnosed according to international criteria. RESULTS: 142 children were diagnosed with LNB during 2001-2009. Facial nerve palsy was more common in girls (86%) than in boys (62%) (p < 0.001), but headache and/or neck stiffness as the only symptom was more common in boys (30%) than in girls (10%) (p = 0.003). The girls were younger than boys and had a shorter duration of symptoms, but boys had a higher level of pleocytosis than girls. In a multivariate analysis, both gender and having headache and neck stiffness were associated with a higher level of pleocytosis. CONCLUSION: Girls and boys have different clinical presentations of LNB, and boys have a higher level of inflammation than girls independent of the clinical presentation.

Borrelia miyamotoi is widespread in Ixodes ricinus ticks in southern Norway.

From April to October 2007, host-seeking Ixodes ricinus ticks were collected from four locations in southern Norway; Farsund, Mandal, Søgne and Tromøy, respectively. Larvae (n=210), nymphs (n=1130) and adults (n=449) were investigated for infection with Borrelia miyamotoi by real-time polymerase chain reaction (PCR) amplification of part of the 16S rRNA gene. Results were verified by direct sequencing of the PCR amplicon generated from the rrs (16S)-rrl (23S) intergenetic spacer. B. miyamotoi was detected at all sites and throughout the period of questing activity, with infection prevalence (≤1.26%) similar to what has been seen in other European countries. Detection of the relapsing fever spirochete at all locations indicates a wide distribution in southern Norway. This is the first report of B. miyamotoi prevalence in ticks collected from Norway. As not much is known about the spatiotemporal dynamics of this relatively recently discovered pathogen, the conclusions of this study significantly add to the knowledge regarding B. miyamotoi in this region.

Lyme meningitis, the major cause of childhood meningitis in an endemic area: a population based study.

OBJECTIVE: To evaluate the epidemiology of infectious meningitis in children in a Lyme borreliosis (LB) endemic area, and to study how clinical and laboratory characteristics may distinguish between different types of childhood meningitis. DESIGN: Retrospective, population based study. SETTING: A paediatric department serving all children (62 000) in a costal LB endemic region of southwestern Norway. PATIENTS: All children with cerebrospinal fluid pleocytosis aged 3 months to 14 years. MAIN OUTCOME MEASURES: Epidemiological, clinical and laboratory characteristics of different types of childhood meningitis. RESULTS: Infectious meningitis was diagnosed in 211 children (annual incidence 38/100 000). Lyme meningitis (LM) was identified in 142 children (67%), non-Lyme aseptic meningitis in 46 children (22%) and bacterial meningitis in 23 children (11%). Age, month of admission and clinical and laboratory characteristics differed between the groups. An aetiological agent was found in 89% of children. The positive predictive value for having LM if the child had facial nerve palsy or head and/or neck stiffness (meningism) as the only symptom was 97% for both variables. Symptoms of cerebral involvement or signs of systemic inflammation were rare in children with LM compared to children non-Lyme aseptic meningitis. CONCLUSION: LM was diagnosed in two-thirds of children with infectious meningitis in this LB endemic area. Distinct clinical characteristics distinguished the majority of children with LM from children with non-Lyme aseptic meningitis and bacterial meningitis.

Laboratory data in children with Lyme neuroborreliosis, relation to clinical presentation and duration of symptoms.

The occurrence of IgM and IgG antibodies against Borrelia burgdoferi in serum and cerebrospinal fluid (CSF) and intrathecal synthesis of antibodies (antibody index) were studied in relation to clinical presentation and the duration of symptoms before diagnosis in 146 children diagnosed with neuroborreliosis. Lymphocytic meningitis was demonstrated in 141 of these children. Levels of white blood cells (WBC) and protein in CSF correlated significantly to numbers of d with symptoms. Children were divided into 3 clinical groups: A (n = 37): only cranial neuropathy; B (n = 68): both cranial neuropathy and other neurological symptoms; C (n = 41): neurological symptoms without cranial neuropathy. Levels of WBC and protein in CSF as well as the proportion of children with antibodies in serum and CSF were generally lowest in group A, intermediate in group B and highest in group C. The proportion of children with antibodies in serum and CSF and a positive antibody index was also related to duration of symptoms; the antibody index was present in 51% of children with symptoms < or = 7 d, and in 80% of children with symptoms > 7 d (p<0.01). The clinical presentation and duration of symptoms must be considered when interpreting laboratory data in children with suspected neuroborreliosis.

Clinical characteristics of childhood Lyme neuroborreliosis in an endemic area of northern Europe.

Neuroborreliosis may be caused by different species of Borrelia burgdorferi (BB) and the clinical presentation of neuroborreliosis in children may differ between geographical areas due to occurrence of different BB genospecies. The aim of this study was to evaluate the clinical characteristics in children with neuroborreliosis in an endemic area of Scandinavia. During 1996-2006, children with suspected neuroborreliosis referred to Stavanger University Hospital were investigated by a standard procedure including a lumbar puncture. A total of 143 children were diagnosed with neuroborreliosis, and all cases were diagnosed from April to December. The most common clinical presentations were symptoms of mild meningitis (75%) and/or facial nerve palsy (69%). Radicular pain was present in only 10 children. In all but 5 children, laboratory signs of meningitis were present. Erythema migrans preceded the neurological symptoms in only 27% of the children. In conclusion, we have found that in an endemic area of northern Europe, meningitis is present in the majority of children with neuroborreliosis, and that symptoms of a mild meningitis or facial nerve palsy are the most common presentations.

[Increase in childhood neuroborreliosis]. / Økt forekomst av nevroborreliose hos barn.

BACKGROUND: Data from the Norwegian Institute of Public Health suggest that the incidence of neuroborreliosis has increased in Norway during recent years. However, this may also be due to a change in diagnostic procedures and increased awareness of the disease. MATERIAL AND METHODS: At the pediatric department in Stavanger University Hospital we have systematically diagnosed and registered data on all children with neuroborreliosis in a database since 1996. RESULTS: The number of children diagnosed with neuroborreliosis increased in the entire period from 1996 to 2007 (p < 0.001). The median number of children diagnosed per year increased from 10.5 to 18.5 from the first to the second 6 year-period (p = 0.004). INTERPRETATION: There has been a real increase in childhood neuroborreliosis during the last 12 years.

Acute facial nerve palsy in children: how often is it lyme borreliosis?

Acute facial nerve palsy in children may be caused by infection by Borrelia burgdorferi, but the incidence of facial nerve palsy and the proportion of facial nerve palsy caused by Lyme borreliosis may vary considerably between areas. Furthermore, it is not well known how often facial nerve palsy caused by Lyme borreliosis is associated with meningitis. In this population-based study, children admitted for acute facial nerve palsy to Stavanger University Hospital during 9 y from 1996 to 2004 were investigated by a standard protocol including a lumbar puncture. A total of 115 children with facial nerve palsy were included, giving an annual incidence of 21 per 100,000 children. 75 (65%) of these were diagnosed as Lyme borreliosis, with all cases occurring from May to November. Lymphocytic meningitis was present in all but 1 of the children with facial nerve palsy caused by Lyme borreliosis where a lumbar puncture was performed (n = 73). In this endemic area for Borrelia burgdorferi, acute facial nerve palsy in children was common. The majority of cases were caused by Lyme borreliosis, and nearly all of these were associated with lymphocytic meningitis.