Beyond LNB: Real life data on occurrence and extent of CSF CXCL13 in neuroinflammatory diseases.

To evaluate occurrence and extent of CSF CXCL13 elevations beyond Lyme neuroborreliosis, we investigated CXCL13 in an unselected patient cohort with neuroinflammatory disease. From March 2016 to March 2017, 180 in-patients with CSF pleocytosis were categorized into following groups: pyogenic CNS infections, aseptic meningoencephalitis, neuroimmunological diseases, and reactive pleocytosis. We provide evidence that CXCL13 elevation occurs at variable extent in the majority of neuroinflammatory diseases. The exact role of CXCL13 in CSF is elusive, but the broad occurrence in neuroinflammation points at CNS immune activation, which is not exclusive for LNB.

Cerebrospinal fluid CXLC13 indicates disease course in neuroinfection: an observational study.

BACKGROUND: The chemokine CXCL13 is an intensively investigated biomarker in Lyme neuroborreliosis (LNB). Its role in other neuroinfections is increasingly recognized but less clear. OBJECTIVE: To determine the significance of CXCL13 in established central nervous system (CNS) infections other than LNB by matching cerebrospinal fluid (CSF) CXCL13 elevations with severity of the disease course. METHODS: We investigated 26 patients with bacterial (n = 10) and viral (n = 16; tick-borne encephalitis, n = 6; varicella zoster infection, n = 10) neuroinfections of whom CSF CXCL13 levels were available twice, from lumbar punctures (LP) performed at admission and follow-up. As outcome classification, we dichotomized disease courses into "uncomplicated" (meningitis, monoradiculitis) and "complicated" (signs of CNS parenchymal involvement such as encephalitis, myelitis, abscesses, or vasculitis). CXCL13 elevations above 250 pg/ml were classified as highly elevated. RESULTS: Eight of 26 patients (31%) with both bacterial (n = 4) and viral (n = 4) neuroinfections had a complicated disease course. All of them but only 3/18 patients (17%) with an uncomplicated disease course had CSF CXCL13 elevations > 250 pg/ml at the follow-up LP (p < 0.001). At admission, 4/8 patients (50%) with a complicated disease course and 3/18 patients (17%) with an uncomplicated disease course showed CXCL13 elevations > 250 pg/ml. All four patients with a complicated disease course but only one with an uncomplicated disease course had sustained CXCL13 elevations at follow-up. Patient groups did not differ with regard to age, time since symptom onset, LP intervals, type of infections, and anti-pathogen treatments. CONCLUSION: Our study revealed pronounced CXCL13 elevations in CSF of patients with severe disease courses of bacterial and viral neuroinfections. This observation indicates a role of CXCL13 in the CNS immune defense and points at an additional diagnostic value as biomarker for unresolved immune processes leading to or associated with complications.

From natalizumab to fingolimod in eight weeks - Immunological, clinical, and radiological data in quest of the optimal switch.

Natalizumab (NZB) discontinuation during a treatment change is associated with recurrence of disease activity in a significant proportion of multiple sclerosis (MS) patients. The immunological basis why disease reactivation occurs in selected patients is unresolved. In search of a prognostic biomarker for a safe and effective transition from NZB to fingolimod, we monitored five parameters related to pharmacokinetic and pharmacodynamic effects of the two drugs in 12 MS patients until six months on fingolimod. Clearance of free and cell-bound NZB, re-expression of alpha-4, and fingolimod-mediated changes on CD8+ and CD4+ T cell subsets showed pronounced interindividual variability. Higher frequencies of memory CD8+ T cells after six months on fingolimod were the sole association with disease reactivation. None of the investigated parameters thus had potential as prognostic biomarker for the outcome of the switch. Our findings rather support the thesis of broad interindividual differences in the immunopathogenesis of MS.

Adaptive Immune Responses in a Multiple Sclerosis Patient with Acute Varicella-Zoster Virus Reactivation during Treatment with Fingolimod.

Fingolimod, an oral sphingosine 1-phosphate (S1P) receptor modulator, is approved for the treatment of relapsing forms of multiple sclerosis (MS). The interference with S1P signaling leads to retention particularly of chemokine receptor-7 (CCR7) expressing T cells in lymph nodes. The immunological basis of varicella zoster virus (VZV) infections during fingolimod treatment is unclear. Here, we studied the dynamics of systemic and intrathecal immune responses associated with symptomatic VZV reactivation including cessation of fingolimod and initiation of antiviral therapy. Key features in peripheral blood were an about two-fold increase of VZV-specific IgG at diagnosis of VZV reactivation as compared to the previous months, a relative enrichment of effector CD4+ T cells (36% versus mean 12% in controls), and an accelerated reconstitution of absolute lymphocytes counts including a normalized CD4+/CD8+ ratio and reappearance of CCR7+ T cells. In cerebrospinal fluid (CSF) the lymphocytic pleocytosis and CD4+/CD8+ ratios at diagnosis of reactivation and after nine days of fingolimod discontinuation remained unchanged. During this time CCR7+ T cells were not observed in CSF. Further research into fingolimod-associated VZV reactivation and immune reconstitution is mandatory to prevent morbidity and mortality associated with this potentially life-threatening condition.

Monitoring of the heparinization in the rabbit animal model during endovascular interventions.

INTRODUCTION: The purpose of this study was to monitor and to optimize heparinization during endovascular procedures in the New Zealand White Rabbit (NZWR) model. METHODS: Right common carotid artery aneurysms were surgically created in 43 NZWR, with an average weight of 4,330 g (range 3,500-5,430 g). The activated partial thromboplastin time (aPTT) was measured during different stages of the interventional procedures. Blood samples were taken before and 10 min after administration of heparin and at the end of each endovascular procedure. We compared three different experimental groups: 100 U heparin, 500 U heparin and 100 U heparin plus pretreatment with aspirin and clopidogrel. The individual aPTT values were measured using a ball coagulometer. RESULTS: The average baseline aPTT in the rabbit is 75.2 ± 18.9 s compared to a mean of 33 s (range 26-40 s) in humans. The dosages of heparin used achieved anticoagulation in all cases. Five hundred units of heparin increased the aPTT significantly more than 100 U. No difference was found between the aPTT obtained from the 100 U and the 100 U plus pretreatment group, as aspirin and clopidogrel do not affect the coagulation cascade. CONCLUSION: One hundred units of heparin can achieve anticoagulation in a similar magnitude as needed in interventional procedures in humans. This fact enhances suitability of the rabbit animal model for the testing of intravascular devices.

Lymphocyte subsets show different response patterns to in vivo bound natalizumab--a flow cytometric study on patients with multiple sclerosis.

Natalizumab is an effective monoclonal antibody therapy for the treatment of relapsing-remitting multiple sclerosis (RRMS) and interferes with immune cell migration into the central nervous system by blocking the α(4) subunit of very-late activation antigen-4 (VLA-4). Although well tolerated and very effective, some patients still suffer from relapses in spite of natalizumab therapy or from unwanted side effects like progressive multifocal leukoencephalopathy (PML). In search of a routine-qualified biomarker on the effectiveness of natalizumab therapy we applied flow cytometry and analyzed natalizumab binding to α(4) and α(4) integrin surface levels on T-cells, B-cells, natural killer (NK) cells, and NKT cells from 26 RRMS patients under up to 72 weeks of therapy. Four-weekly infusions of natalizumab resulted in a significant and sustained increase of lymphocyte-bound natalizumab (p<0.001) which was paralleled by a significant decrease in detectability of the α(4) integrin subunit on all lymphocyte subsets (p<0.001). We observed pronounced natalizumab accumulations on T and B cells at single measurements in all patients who reported clinical disease activity (n = 4). The natalizumab binding capacity of in vitro saturated lymphocytes collected during therapy was strongly diminished compared to treatment-naive cells indicating a therapy-induced reduction of α(4). Summing up, this pilot study shows that flow cytometry is a useful method to monitor natalizumab binding to lymphocytes from RRMS patients under therapy. Investigating natalizumab binding provides an opportunity to evaluate the molecular level of effectiveness of natalizumab therapy in individual patients. In combination with natalizumab saturation experiments, it possibly even provides a means of studying the feasability of patient-tailored infusion intervals. A routine-qualified biomarker on the basis of individual natalizumab saturation on lymphocyte subsets might be an effective tool to improve treatment safety.

Natalizumab therapy decreases surface expression of both VLA-heterodimer subunits on peripheral blood mononuclear cells.

Natalizumab interferes with immune cell migration into the central nervous system via blocking the alpha-4 subunit of very-late activation antigen-4 (VLA-4). Occurrence of rare but serious progressive multifocal leukoencephalopathy during prolonged natalizumab therapy of multiple sclerosis (MS) calls for a more detailed understanding of potential coeffects. We longitudinally studied alpha-4 and beta-1 surface levels on blood cells from 18 MS patients by flow cytometry. Expectedly, detectability of natalizumab-blocked alpha-4 was diminished on all investigated cell subsets. In addition, we report a concurrent and significant decrease of beta-1 surface levels on T-cells, B-cells, natural killer cells, and natural killer T cells, but not on monocytes. Uncovering secondary effects of natalizumab is mandatory to increase safety in MS therapy.

Clinical decision rules for the use of liquor diagnostics in hospitalized neurology patients reduced costs without affecting clinical outcomes.

OBJECTIVES: Excessive use of laboratory diagnostics has been common. This study aimed to evaluate whether clinical decision rules for the use of liquor diagnostics would enable cost containment without affecting medical care. METHODS: This was a single-center, retrospective, cost-minimization study based on the records of all 16,319 patients hospitalized and discharged at a Neurology Clinic in Austria between 2004 and 2006. Cost of liquor diagnostics, discharge diagnosis, duration of hospital stay, and mortality were compared along the line before, during, and after implementation of decision rules in mid-2005. RESULTS: There were no significant changes in patient characteristics over time, not in the diagnoses at discharge, nor in the percentage of patients undergoing liquor diagnostics. The average number of tests per patient significantly decreased. Standard tests largely replaced serological tests for infections, regardless of diagnosis. Annual costs for liquor diagnostics decreased by 32.9 percent. Overall, the duration of hospital stay and mortality significantly decreased as well; however, differences were not significant for any single diagnosis-related group. CONCLUSIONS: Diagnostic algorithms may allow cost containment without affecting medical care.