Transient spurious intrathecal immunoglobulin synthesis in neurological patients after therapeutic apheresis

Background The analysis of cerebrospinal fluid (CSF) is usually done under steady-state conditions, when proteins (e.g., immunoglobulins) reach diffusion equilibrium between blood and CSF. However, little data has been published on CSF analysis under non-steady-state conditions after therapeutic apheresis. By reducing serum proteins (e.g., immunoglobulins), while leaving CSF unchanged, therapeutic apheresis might cause spuriously altered intrathecal immunoglobulin fractions. Methods Based on the incidental finding of plasma exchange-induced increased intrathecal immunoglobulin fractions in a cohort of 12 unsystematically selected patients with various neurological disorders, we retrospectively investigated CSF results that had been raised during routine diagnostic work-up from 41 consecutive neurological patients (predominantly Guillain-Barré syndrome and autoimmune encephalitis) treated with plasmapheresis or immunoadsorption in a tertiary care university hospital in whom lumbar puncture (LP) was performed after a varying number of treatments of therapeutic apheresis. Results Only when LP was performed 1 day after therapeutic apheresis, spurious quantitative intrathecal immunoglobulin (Ig) synthesis of at least one subclass (IgG, IgA and/or IgM) was found in 68.4 % of the patients, irrespective of the number of treatments, in all age groups and independent of other previous immunotherapies (e.g., steroids). This phenomenon occurred only transiently and was almost always accompanied by an elevation of the IgG index. In one patient, an elevated IgG index was noticed even 2 days after plasmapheresis. Neither quantitative Ig synthesis, nor elevated IgG index was observed when the LP was performed three or more days after therapeutic apheresis. Conclusions Spurious quantitative intrathecal Ig synthesis and increased IgG index are common findings shortly after plasmapheresis or immunoadsorption due to altered serum immunoglobulin levels. Knowledge of this phenomenon is needed for clinicians to prevent false interpretations leading to unnecessary diagnostic and therapeutic procedures. Misdiagnoses can be avoided by considering the characteristic CSF constellation including absence of oligoclonal bands and the close temporal relation to therapeutic apheresi

Glial Activation Markers in CSF and Serum From Patients With Primary Progressive Multiple Sclerosis: Potential of Serum GFAP as Disease Severity Marker?

Background: In progressive multiple sclerosis (MS), glial activation is thought to be a relevant mechanism of disability progression. Therefore, in vivo assessment of the glial cell activity is, in the emerging treatment era of primary progressive MS (PPMS), more important than ever. Objectives: To test the association of cerebrospinal fluid (CSF) and serum markers of glial activation in PPMS patients;including glial fibrillary acidic protein (GFAP), chitinase-3-like protein 1 (CHI3L1), soluble variant of triggering receptor expressed on myeloid cells 2 (sTREM2), and marker of neuroaxonal damage (Neurofilament light chain, NfL) as well as clinical severity. Methods: CSF and serum samples from PPMS patients were collected in the MS-centers at Universities of Freiburg (n = 49), Ulm (n = 27), Muenster (n = 11), and Rostock (n = 6). sTREM2 and CHI3L1 levels were measured using the previously reported ELISA assays, while NfL and GFAP were measured using SIMOA assays. Clinical data included age, gender, disease duration, treatment status, and Expanded Disability Status Scale (EDSS). Results: 93 CSF samples and 71 matching serum samples were analyzed. The median age of patients was 49 years and disease duration 4.5 years. GFAP(serum) correlated with EDSS after correction for age (beta = 0.3, p = 0.001). Furthermore, EDSS was higher in patients with a GFAP(serum) level >= 151.7 pg/ml compared to patients with GFAP(serum) below this cut-off (5.5 vs. 4.0, p = 0.009). Other markers did not correlate with the clinical severity. Moreover, we found a correlation between NfL(CSF) and GFAP(CSF), sTREM2 and CHI3L1 (rho = 0.4 for GFAP(CSF) and sTREM2, rho = 0.3 for CHI3L1, p < 0.01 for sTREM2 and CHI3L1 and <0.001 for GFAP(CSF)). CHI3L1 did not correlate with GFAP(CSF) but with sTREM2 (rho = 0.4, p < 0.01). Discussion: The correlation between the glial activation markers in CSF with the markers of neuroaxonal demise supports the notion of the glial involvement in PPMS. The positive correlation between GFAP(CSF) with disease duration and GFAP(serum) with the clinical severity of the disease may highlight a particular role of the astrocytes in PPMS and mark the potential of GFAPserum as a disease severity marker

Alterations in Cerebrospinal Fluid in Patients with Bipolar Syndromes

Bipolar disorder (BD) is a severe and lifelong condition. Primary endogenic polygenetic forms are common. Secondary organic forms have received increasing interest recently due to the detection of immunological encephalopathies that mimic various psychiatric syndromes, including bipolar disorder. However, only limited data about routine findings of cerebrospinal fluid (CSF) analyses in bipolar disorder are available. Therefore, we investigated the frequency of alterations in the CSF in patients with BD and the association with autoantibodies, cerebral magnetic resonance imaging, and electroencephalography findings.CSF samples of patients with BD collected from January 1998 until December 2015 were analyzed retrospectively. Patients with preexisting causes for alterations in the CSF (e.g., patients with obvious past or current neurological disorders) were excluded. In total, 63 patients with BD fulfilled the inclusion criteria for the study. In 1.6% of the patients with BD, an increased white blood cell count was found in the CSF. Increased albumin quotients were found in 12.9% of the patients, oligoclonal bands (OCBs) in 1.6%, and increased immunoglobulin (Ig) G indices in 3.2% (OCBs were not measured in case of increased IgG indices). No significant differences in CSF findings were found between patients with manic and depressive episodes. The main findings of this open uncontrolled study are that alterations in the CSF may be found in a small but potentially relevant subgroup of patients with BD. These findings are discussed in light of the new concepts of mild encephalitis and immunological encephalopathy. The detection of patients with possibly secondary organic bipolar syndromes could open up new causal treatment options with immunomodulatory medication

The MRZ-Reaction and Specific Autoantibody Detection for Differentiation of ANA-Positive Multiple Sclerosis From Rheumatic Diseases With Cerebral Involvement

Objective: Rheumatic diseases with involvement of the central nervous system (RDwCNS) may mimic multiple sclerosis (MS). Inversely, up to 60% of MS-patients have antinuclear autoantibodies (ANAs) and may be misdiagnosed as RDwCNS. The detection of antibodies against extractable nuclear antigens (ENA) and oligoclonal bands (OCB) are established valuable diagnostic tools in the differential diagnosis of RDwCNS and MS. The MRZ-reaction (MRZR) is defined by three antibody indices (AIs) against neurotropic viruses and is frequently positive in MS. To investigate the added value of MRZR combined with testing for antibodies against ENAs and OCB detection to distinguish RDwCNS from ANA positive MS.Methods: MRZR was evaluated in RDwCNS (n = 40) and 68 ANA positive MS-patients. Two stringency levels, MRZR-1 and MRZR-2 (at least one respectively two of three AIs positive) were applied. Autoantibody testing included ANA plus ENA and anti-dsDNA antibodies, antiphospholipid antibodies, and anti-neutrophil cytoplasmic antibodies.Results: Most of the RDwCNS patients (n = 32; 80%) suffered from systemic lupus erythematosus. Within the RDwCNS group 20% had a positive MRZR-1 and 8.5% a positive MRZR-2 compared to 80.9 and 60%, respectively within the MS-group (p &lt; 0.0001 for both comparisons). Oligoclonal bands were found in 28.6% of the RDwCNS patients and 94.3% of the MS-patients (p &lt; 0.0001). Conversely, autoantibodies to specific nuclear antigens or phospholipids were found more frequently in RDwCNS. A positive MRZR in conjunction with the absence of ENA autoantibodies distinguished MS from RDwCNS with high specificity (97.5%).Conclusions: We suggest combining MRZR, OCBs, and specific autoantibody diagnostics to differentiate RDwCNS from MS

Glial Activation Markers in CSF and Serum From Patients With Primary Progressive Multiple Sclerosis: Potential of Serum GFAP as Disease Severity Marker?

Background: In progressive multiple sclerosis (MS), glial activation is thought to be a relevant mechanism of disability progression. Therefore, in vivo assessment of the glial cell activity is, in the emerging treatment era of primary progressive MS (PPMS), more important than ever.Objectives: To test the association of cerebrospinal fluid (CSF) and serum markers of glial activation in PPMS patients; including glial fibrillary acidic protein (GFAP), chitinase-3-like protein 1 (CHI3L1), soluble variant of triggering receptor expressed on myeloid cells 2 (sTREM2), and marker of neuroaxonal damage (Neurofilament light chain, NfL) as well as clinical severity.Methods: CSF and serum samples from PPMS patients were collected in the MS-centers at Universities of Freiburg (n = 49), Ulm (n = 27), Muenster (n = 11), and Rostock (n = 6). sTREM2 and CHI3L1 levels were measured using the previously reported ELISA assays, while NfL and GFAP were measured using SIMOA assays. Clinical data included age, gender, disease duration, treatment status, and Expanded Disability Status Scale (EDSS).Results: 93 CSF samples and 71 matching serum samples were analyzed. The median age of patients was 49 years and disease duration 4.5 years. GFAPserum correlated with EDSS after correction for age (β = 0.3, p = 0.001). Furthermore, EDSS was higher in patients with a GFAPserum level ≥ 151.7 pg/ml compared to patients with GFAPserum below this cut-off (5.5 vs. 4.0, p = 0.009). Other markers did not correlate with the clinical severity. Moreover, we found a correlation between NfLCSF and GFAPCSF, sTREM2 and CHI3L1 (ρ = 0.4 for GFAPCSF and sTREM2, ρ = 0.3 for CHI3L1, p &lt; 0.01 for sTREM2 and CHI3L1 and &lt;0.001 for GFAPCSF). CHI3L1 did not correlate with GFAPCSF but with sTREM2 (ρ = 0.4, p &lt; 0.01).Discussion: The correlation between the glial activation markers in CSF with the markers of neuroaxonal demise supports the notion of the glial involvement in PPMS. The positive correlation between GFAPCSF with disease duration and GFAPserum with the clinical severity of the disease may highlight a particular role of the astrocytes in PPMS and mark the potential of GFAPserum as a disease severity marker

Neurogenic inflammation in a new chronic model for allergic bronchial asthma

In der Pathogenese von allergischem Asthma bronchiale (Asthma) spielen Wechselwirkungen zwischen immunologischen und neuronalen Faktoren im Sinne einer neurogenen Entzündung (NE) eine wichtige Rolle. Bisherige Untersuchungen hierzu wurden überwiegend in Tiermodellen mit akuter Allergenexposition durchgeführt. Chronische Provokationsmodelle sind im Hinblick auf humanes Asthma wahrscheinlich aussagekräftiger, können jedoch zur Entwicklung einer Allergentoleranz bei wiederholten Provokationen führen. Frühere Studienergebnisse zur NE implizieren, dass insbesondere Nerve Growth Factor (NGF) über eine Tachykinin-Induktion in Atemwegsneuronen an der Entstehung von Asthma-typischen Symptomen beteiligt ist. Dabei scheint der Pan-Neurotrophin- Rezeptor (p75NTR) von Bedeutung zu sein. Für Studien zu Asthma gilt das Meerschweinchen wegen seiner großen Ähnlichkeit zum humanen Atemwegssystem in vielerlei Hinsicht als das geeignetste Tiermodell. In der vorliegenden Arbeit wurden daher erstmals die NGF-Konzentration in den Atemwegen sowie die Tachykinin- und p75NTR-Immunreaktivität (IR) in sensiblen Atemwegsneuronen in einem neuen chronischen Asthma-Tiermodell an Meerschweinchen untersucht. Hierfür wurden 30 Meerschweinchen in sechs Gruppen randomisiert, von denen fünf durch intraperitoneale Injektionen mit Ovalbumin (OVA) sensibilisiert wurden. Die Kontrollgruppe (KTL) erhielt lediglich das Vehikel. Anschließend erfolgten bis zu sechs inhalative Allergenexpositionen mit steigender OVA- Dosis. Folgende Aspekte konnten in dieser Arbeit festgestellt werden: 1\. Nur die sensibilisierten Tiere entwickelten während der Provokationen weitgehend konstant ausgeprägte Symptome einer akuten bronchialen Obstruktion wie Steigerung der Atemfrequenz, zunehmende Tiefe der Atemexkursionen und Husten. Diese Expositionssymptomatik war der von Asthma-Patienten sehr ähnlich und zeigte keinen Anhalt für eine Allergentoleranzentwicklung. 2\. Im Gegensatz zur KTL zeigten die sensibilisierten Tiere während und auch noch eine Woche nach den Provokationen ausgedehnte peribronchiale Infiltrate in Periodic acid- Schiff(PAS)-gefärbten Lungenschnitten und eine stärkere Eosinophilie in der Bronchoalveolären Lavage (BAL). Beides spricht für eine im Tiermodell erfolgreich induzierte Asthma-ähnliche Atemwegsentzündung ohne Allergentoleranzentwicklung. 3\. Erstmals in einem chronischen Tiermodell wurden während mehrfacher Allergenexpositionen mittels Enzyme linked immunosorbent assay (ELISA) erhöhte NGF-Konzentrationen in der BAL nachgewiesen. Dieser NGF-Anstieg hatte sich trotz der anhaltenden Atemwegsentzündung bereits 72 h nach Abschluss der Provokationen vollständig zurückgebildet. Für die NGF-Induktion in den Atemwegen scheint demzufolge v.a. die direkte Allergenexposition und weniger das alleinige Vorhandensein von Entzündungszellen entscheidend zu sein. 4\. Entgegen der Erwartungen aus Akutmodellen blieb die Tachykinin-IR in den sensiblen Atemwegsneuronen im Ganglion nodosum zunächst unverändert und nahm im weiteren Verlauf der wiederholten Allergenexpositionen vorübergehend ab. Möglicherweise ist dies Folge einer ausgeprägten Freisetzung von Tachykininen in die Atemwege während mehrfacher Provokationen. Die erstmals an Meerschweinchen untersuchte p75NTR- IR sowie Co-IR für Tachykinine und p75NTR zeigten eine ähnliche Entwicklung wie die Tachykinin-IR. Dies könnte dazu beigetragen haben, dass es trotz erhöhter NGF-Konzentrationen in den Atemwegen insgesamt zu keiner nachweisbaren Tachykinin-Induktion in den Atemwegsneuronen kam. Die vorliegende Arbeit liefert neue Erkenntnisse über die komplexe neuroimmunologische Pathogenese von allergischem Asthma bronchiale, in der Neurotrophine und Tachykinine potentielle Angriffspunkte bei der Entwicklung neuer therapeutischer Möglichkeiten darstellen. Hierfür kann auf das in dieser Arbeit neu etablierte chronische Asthma-Tiermodell zurückgegriffen werden. Darüber hinaus könnten diese Ergebnisse auch für andere chronisch-entzündliche Erkrankungen, bei denen ebenfalls eine neuroimmunologische Pathogenese vermutet wird, von Bedeutung sein.In the pathophysiology of allergic bronchial asthma interactions between immunological and neuronal factors play an important role. So far, studies dealing with these mechanisms mostly have been conducted with acute allergen challenge. Nevertheless repetitive challenges are probably more relevant to the situation of human asthma, although they can induce allergen tolerance. Results from earlier studies suggest, that especially nerve growth factor (NGF) is involved in the origin of asthmatic symptoms via induction of tachykinins in sensory airway neurons. The pan-neurotrophin receptor (p75NTR) could be crucial for that. Concerning studies about asthma guinea pigs are regarded as the most suitable animal model due to the similarity of the anatomy and physiology of the airway system. In this study, we evaluated for the first time changes in NGF-concentration in the airways, tachykinin und p75NTR immunoreactivity (IR) in sensory airway neurons in a new chronic model for bronchial asthma. Therefore 30 guinea pigs were randomly divided into six groups and five of them were sensitized to ovalbumin (OVA). All animals were exposed to the allergen by nebulization of OVA solution. The following aspects resulted from the present study: 1\. Only sensitized animals showed constant asthma symptoms like increase of breathing frequency or cough without any signs for tolerance development. 2\. In contrast to control animals prior sensitized guinea pigs had severe peribronchial inflammatory infiltrates during and after repetitive challenges and a stronger eosinophilia in bronchoalveolar lavage fluids (BAL). These findings implicate a successful induction of an allergic airway inflammation. 3\. For the first time elevated levels of NGF in BAL during repetitive challenges were measured with enzyme linked immunosorbent assay (ELISA). NGF concentration returned to prechallenge values three days after the last challenge. So, concerning the NGF induction in allergic airway inflammation the direct challenge seems to be more important than the sole existence of peribronchial inflammatory cells. 4\. Contrary to expectations from acute challenge studies, tachykinin IR in sensory airway neurons did not increase significantly after one challenge. During repetitive challenges tachykinin IR even decreased. Possibly, this could be due to enhanced release of tachykinins into the airways. p75NTR IR and double IR for tachykinins and p75NTR showed similar courses. This could have contributed to the fact that in spite of elevated NGF levels during repetitive challenges, no increase of tachykinin IR in sensory airway neurons was detected. The present study provides new findings about the complex neuroimmunological pathophysiology of allergic bronchial asthma, where neurotrophins and tachykinins could be potential targets for future therapies. Additionally, this newly established chronic challenge model can be used in future studies dealing with allergic airway inflammation. Further on, the data presented in this study could also be relevant to other neuroimmunological diseases

Efficacy and safety of pharmacological treatments for Lyme neuroborreliosis in children: a systematic review

International audienceBACKGROUND: Many aspects of pharmacological treatment of Lyme neuroborreliosis in children, such as choice of drug, dosage, and duration are subject to intense debates, leading to uncertainties in patients' parents and healthcare providers alike. To assess the available evidence for pharmacological treatment for children with Lyme neuroborreliosis we conducted a systematic review.METHODS: The comprehensive systematic literature search included randomized-controlled trials (RCTs) and non-randomized studies (NRS) on treatment of Lyme neuroborreliosis in children (age <18 years). Our primary outcome was neurological symptoms after treatment. Risk of bias was assessed with the Cochrane risk of bias tools for RCTs and NRS. Quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.RESULTS: Two RCTs and four NRS were eligible for inclusion. Risk of bias in RCTs and NRS was generally high. Reporting of studies was generally poor. Regarding the primary outcome neurological symptoms at 1-3 months, no statistically significant difference could be found in cohort studies between doxycycline and beta-lactam antibiotics. In two RCTs comparing penicillin G and ceftriaxone, no patient experienced residual neurological symptoms at the last reported time points. Quality of evidence according to GRADE was judged very low.CONCLUSIONS: Data is scarce and with limited quality. Several issues could not be addressed due to scarcity of information. No eligible study compared different treatment durations. According to the available evidence, there seems to be no difference between different antibiotic agents for the treatment of Lyme neuroborreliosis in children regarding neurological symptoms. We found no evidence that supports extended antibiotic regimes.REVIEW REGISTRATION: Systematic review registration: CRD42014008839