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      Cerebrospinal fluid CXCL13 in Lyme neuroborreliosis and asymptomatic HIV infection

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          Abstract

          Background

          It has been suggested that cerebrospinal fluid (CSF) CXCL13 is a diagnostic marker of Lyme neuroborreliosis (LNB), as its levels have been shown to be significantly higher in LNB than in several other CNS infections. Levels have also been shown to decline after treatment with intravenous ceftriaxone, but levels after treatment with oral doxycycline have previously not been studied. Like Borrelia burgdorferi, HIV also has neurotropic properties. Elevated serum CXCL13 concentrations have been reported in HIV patients, but data on CSF levels are limited.

          Methods

          We longitudinally analysed CSF CXCL13 concentrations in 25 LNB patients before and after oral doxycycline treatment. Furthermore, we analysed CSF CXCL13 concentrations in 16 untreated LNB patients, 27 asymptomatic untreated HIV-1 infected patients and 39 controls with no signs of infectious or inflammatory disease.

          Results

          In the longitudinal LNB study, initially high CSF CXCL13 levels declined significantly after doxycycline treatment, which correlated to a decreased CSF mononuclear cell count. In the cross-sectional study, all the LNB patients had CSF CXCL13 levels elevated above the lowest standard point of the assay (7.8 pg/mL), with a median concentration of 500 pg/mL (range 34–11,678). Of the HIV patients, 52% had elevated CSF CXCL13 levels (median 10 pg/mL, range 0–498). There was a clear overlap in CSF CXCL13 concentrations between LNB patients and asymptomatic HIV patients. All but one of the 39 controls had CSF CXCL13 levels below 7.8 pg/mL.

          Conclusions

          We confirm previous reports of highly elevated CSF CXCL13 levels in LNB patients and that these levels decline after oral doxycycline treatment. The same pattern is seen for CSF mononuclear cells. CSF CXCL13 levels are elevated in neurologically asymptomatic HIV patients and the levels overlap those of LNB patients. The diagnostic value of CSF CXCL13 in LNB remains to be established.

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          Most cited references19

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          A prospective study on the role of CXCL13 in Lyme neuroborreliosis.

          The definite diagnosis of acute Lyme neuroborreliosis (LNB) requires detection of an increased Borrelia burgdorferi-specific antibody index (AI). The B burgdorferi AI, however, is negative in up to 20% of patients with early LNB and can remain elevated for years after adequate therapy; both of these factors can make the diagnosis difficult. Recent retrospective studies suggested the chemokine CXCL13 as a potential biomarker for LNB. To evaluate its diagnostic value, we conducted a prospective study. From March 2008 to August 2009, CSF and serum samples from all patients in whom a B burgdorferi-specific AI was requested (n=692) and CSF analysis revealed CSF pleocytosis (n=192) were included in the study. Because of the low number of patients with untreated LNB, 13 additional retrospectively selected samples of patients with untreated LNB were added. CXCL13 concentrations were measured by ELISA and receiver operating characteristic curves were generated. CSF CXCL13 was highly elevated in all patients with untreated acute LNB (mean=15,149 pg/mL) compared with that in the patients without LNB (mean=247 pg/mL). At a cutoff of 1,229 pg/mL, the sensitivity of CXCL13 was 94.1%, which is higher than the AI (85.7%). Only 7 patients (5 with a CNS lymphoma and 2 with bacterial meningitis) had a CXCL13 level above the cutoff, resulting in a specificity equal to the AI of 96.1%. CXCL13 shows high sensitivity and specificity for acute, untreated LNB. This novel marker appears to be helpful in clinically atypical cases and, in particular, in early stages of the disease when the B burgdorferi AI is (still) negative. © 2011 by AAN Enterprises, Inc.
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            The chemokine CXCL13 in acute neuroborreliosis.

            Recent studies have suggested an important role of the B cell chemoattractant CXCL13 in acute neuroborreliosis (NB). Our aim was to confirm the diagnostic role of CXCL13 and to evaluate its relevance as a therapy response and disease activity marker in NB. CXCL13 was measured in cerebrospinal fluid (CSF) and serum of patients with NB (n=28), systemic borreliosis (SB, n=9), Guillain-Barré syndrome (GBS, n=11), Bell's palsy (BP, n=19), other cranial nerve palsies (CNP, n=5), cephalgia (C, n=20), bacterial CNS infections (B-CNS-I, n=16) and viral CNS infections (V-CNS-I, n=18). For follow-up studies, serial sample pairs were evaluated from 25 patients with NB (n=56), 11 with B-CNS-I (n=25) and 14 with V-CNS-I (n=36). CSF-CXCL13 was significantly elevated in NB compared with other neurological diseases (p<0.001). Using receiver operating characteristic analysis, 337 ng/g was determined as a cut-off with a sensitivity of 96.4% and a specificity of 96.9%. Of all the parameters investigated, CSF CXCL13 showed the fastest response to antibiotic therapy, decreasing significantly (p=0.008) within 1 week. In untreated patients, CSF CXCL13 was elevated in patients with a short duration of disease. Borrelia burgdorferi antibody index showed no significant (p=0.356) change over follow-up. The study confirms the relevance of CXCL13 as a diagnostic biomarker of NB and suggests that CSF CXCL13 in NB is linked to duration of disease and could be a marker of disease activity and response to antibiotic therapy.
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              CXCL13 as a cerebrospinal fluid marker for neurosyphilis in HIV-infected patients with syphilis.

              Asymptomatic neurosyphilis is more difficult to diagnose in human immunodeficiency virus (HIV)-infected patients because HIV itself can cause cerebrospinal fluid (CSF) pleocytosis. The proportion of CSF lymphocytes that are B cells is elevated in neurosyphilis, suggesting that the CSF concentration of the B cell chemoattractant, chemokine (C-X-C motif) ligand 13 (CXCL13) concentration may also be elevated. CSF and blood were collected from 199 HIV-infected patients with syphilis and neurosyphilis. Serum and CSF CXCL13 concentrations were determined. Patients with neurosyphilis had higher CSF and serum CXCL13 concentrations compared to patients with syphilis but not neurosyphilis. The odds of having symptomatic neurosyphilis were increased by 2.23-fold for every log increase in CSF CXCL13 concentration and were independent of CSF white blood cell and plasma HIV RNA concentrations, peripheral blood CD4+ T cell count and use of antiretroviral medications. A cut-off of 10 pg/mL CSF CXCL13 had high sensitivity and a cut-off of 250 pg/mL or evidence of intrathecal synthesis of CXCL13 had high specificity for diagnosis of both symptomatic and asymptomatic neurosyphilis. CSF concentrations of CXCL13 declined after treatment for neurosyphilis. CSF CXCL13 concentration may be particularly useful for diagnosis of neurosyphilis in HIV-infected patients because it is independent of CSF pleocytosis and markers of HIV disease.
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                Author and article information

                Journal
                BMC Neurol
                BMC Neurol
                BMC Neurology
                BioMed Central
                1471-2377
                2013
                7 January 2013
                : 13
                : 2
                Affiliations
                [1 ]Department of Infectious Medicine, Institute of Biomedicine, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
                [2 ]Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy, University of Gothenburg, Gothenburg and Mölndal, Sweden
                [3 ]Hydrocephalus Research Unit, Institute of Neuroscience and Physiology, Department of Clinical Neuroscience and Rehabilitation, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
                [4 ]UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK
                Article
                1471-2377-13-2
                10.1186/1471-2377-13-2
                3546953
                23294475
                6137d50c-a08d-4c92-b178-069dd9640d3c
                Copyright ©2013 Bremell et al.; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 11 May 2012
                : 3 January 2013
                Categories
                Research Article

                Neurology
                Neurology

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