Toscana virus encephalitis in Southwest Germany: a retrospective study.

BACKGROUND: Toscana virus (TOSV) is an arthropod-borne virus transmitted by phlebotomine sandflies (Phlebotomus sp.) widespread throughout the Mediterranean having the potential to cause meningoencephalitis in humans. In Germany, the vectors of TOSV are introduced recently and become endemic especially in Southwestern Germany. As TOSV is not investigated regularly in patients with meningoencephalitis, cases of TOSV-neuroinvasive disease may remain mostly undetected. METHODS: We conducted a retrospective cohort study on patients with meningoencephalitis without identification of a causal pathogen from 2006 to 2016. Serologic assessment for anti-TOSV-IgG and IgM was performed on serum and CSF. Demographic, clinical and CSF data from TOSV-positive patients were compared to a cohort of patients with meningoencephalitis due to enterovirus. Informed consent was obtained from all included patients. RESULTS: We found 138 patients with meningoencephalitis without identified causal pathogen. From 98 of these patients CSF and serum was available for further testing. Additionally, we included 27 patients with meningoencephalitis due to enterovirus. We identified two patients with serological confirmed TOSV-neuroinvasive disease (TOSV-IgM and IgG positive, 2%) and two patients with possible TOSV-neuroinvasive disease (isolated TOSV-IgM positive, 2%). Overall, TOSV-neuroinvasive was detected in 4% of our cases with suspected viral meningoencephalitis. None of them had a history of recent travel to an endemic area. CONCLUSIONS: We found cases of TOSV-neuroinvasive disease in our German cohort of patients with meningoencephalitis. As no recent history of travel to an endemic area was reported, it remains probable that these cases resemble autochthonous infections, albeit we cannot draw conclusions regarding the origin of the respective vectors. TOSV could be considered in patients with meningoencephalitis in Germany.

[Neuroborreliosis - Diagnostics, treatment and course]. / Neuroborreliose ­ Diagnostik, Therapie und Verlauf.

Lyme neuroborreliosis is a tick-borne infectious disease caused by the spirochete bacterium Borrelia burgdorferi sensu lato. Clinical manifestations are classified as early and late Lyme neuroborreliosis. Early manifestations are much more common than late manifestations. Serological testing should only be performed when typical neurological symptoms are present because false positive results are common due to a high seroprevalence in the population. Cerebrospinal fluid (CSF) analysis should be performed if Lyme neuroborreliosis is suspected. A systematic review found similar effects of beta-lactam antibiotics and doxycycline regarding the outcome of neurological symptoms and adverse effects. The prognosis after antibiotic treatment is usually favorable and residual symptoms can rarely persist. Impairments in quality of life, fatigue, depression and cognitive impairment are not more frequent in patients after treatment of Lyme neuroborreliosis than in the normal healthy population.

[Challenge of neuroborreliosis]. / Herausforderung Neuroborreliose.

Lyme borreliosis is the most frequent tick-borne infection in Europe. It is a multisystemic disease affecting the skin, joints, heart, in rare cases the eyes and regularly the nervous system. Taking current clinical and microbiological guidelines into account, neuroborreliosis can in general be diagnosed and treated successfully. An appropriate guideline-conform antibiotic treatment is effective and in most cases recovery from acute neuroborreliosis is complete. Nevertheless, the evidence base regarding pharmacological treatment needs reform and improvement. Contrary to this scientifically based medical opinion, divergent opinions presented in the media cause uncertainty and confusion among patients and also some physicians. The currently available scientific data on epidemiology, treatment and performance of microbiological testing reveals gaps and therefore a large scope for interpretation. In clinical practice, diagnostics and therapeutic methods that do not fulfill the criteria of evidence-based medicine are widely used due to the uncertain data situation. The Clinical Network Neuroborreliosis (KNN) is a publicly funded network of clinicians and clinical laboratory physicians with the goal to improve knowledge for disease-oriented evaluation of diagnostic and therapeutic methods. In addition, the Robert Koch Institute (RKI) and the KNN are performing an epidemiological study for collation and estimation of the number of neuroborreliosis cases in Germany (aNBorD study).

Efficacy and safety of pharmacological treatments for acute Lyme neuroborreliosis - a systematic review.

BACKGROUND AND PURPOSE: Our aim was to evaluate the available evidence for pharmacological treatment of acute Lyme neuroborreliosis as a basis for evidence-based clinical recommendations in a systematic review. METHODS: A systematic literature search of Medline, EMBASE, the Cochrane Library and three trial registries was performed. Randomized controlled trials (RCTs) and non-randomized studies (NRS) were evaluated. Risk of bias was assessed using the Cochrane risk of bias tools. The primary outcome was 'residual neurological symptoms' whilst the secondary outcomes were disability, quality of life, pain, fatigue, depression, cognition, sleep, adverse events and cerebrospinal fluid pleocytosis. The quality of the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: After screening 5779 records, eight RCTs and eight NRS were included. Risk of bias was generally high. No statistically significant difference was found between doxycycline and beta-lactam antibiotics in a meta-analysis regarding residual neurological symptoms at 4-12 months [risk ratio (RR) 1.27, 95% confidence interval (CI) 0.98-1.63, P = 0.07] or adverse events (RR 0.82, 95% CI 0.54-1.25, P = 0.35). Significantly fewer neurological symptoms for cefotaxime compared with penicillin were found (RR 1.81, 95% CI 1.10-2.97, P = 0.02). Adverse events were significantly fewer for penicillin (RR 0.56, 95% CI 0.38-0.84, P = 0.005). CONCLUSIONS: Evidence regarding pharmacological treatment of acute Lyme neuroborreliosis is scarce and therefore insufficient to recommend preference of beta-lactam antibiotics over doxycycline or vice versa. However, due to considerable imprecision, relevant differences between treatments cannot be excluded. No evidence suggesting benefits of extended antibiotic treatments could be identified. Further well-designed trials are needed. Individual treatment decisions should address patients' preferences and individual conditions like prior allergic reactions.

Methodological quality of guidelines for management of Lyme neuroborreliosis.

BACKGROUND: Many aspects of clinical management of Lyme neuroborreliosis are subject to intense debates. Guidelines show considerable variability in their recommendations, leading to divergent treatment regimes. The most pronounced differences in recommendations exist between guidelines from scientific societies and from patient advocacy groups. Assessment of the methodological quality of these contradictory guideline recommendations can be helpful for healthcare professionals. METHODS: Systematic searches were conducted in MEDLINE and databases of four international and national guideline organizations for guidelines on Lyme neuroborreliosis published from 1999-2014. Characteristics (e.g., year of publication, sponsoring organization) and key recommendations were extracted from each guideline. Two independent reviewers assessed the methodological quality of each guideline according to the Appraisal of Guidelines for Research and Evaluation II (AGREE II) tool. AGREE II scores from guidelines developed by scientific societies and from patient advocacy groups were compared across domains. RESULTS: We identified eight eligible guidelines of which n = 6 were developed by scientific societies and n = 2 by patient advocacy groups. Agreement on AGREE II scores was good (Cohen's weighted kappa = 0.87, 95% CI 0.83-0.92). Three guidelines, all from scientific societies, had an overall quality score of ≥ 50%. Two of them were recommended for use according to the AGREE II criteria. Across all guidelines, the AGREE II domain with the highest scores was "Clarity of Presentation" (65, SD 19%); all other domains had scores < 50% with the domain "Applicability" having the lowest scores (4, SD 4%). Guidelines developed by scientific societies had statistically significantly higher scores regarding clarity of presentation than guidelines from patient advocacy groups (p = 0.0151). No statistically significant differences were found in other domains. CONCLUSIONS: Current guidelines on Lyme neuroborreliosis vary in methodological quality and content. Health care providers and patients need to be aware of this variability in quality when choosing recommendations for their treatment decisions regarding Lyme neuroborreliosis. No statement can be given on quality of content and validity of recommendations, as these issues are not subject to assessment with the AGREE II tool and are prone to individual interpretation of the available evidence by the corresponding guideline panels. To enhance guideline quality, guideline panels should put more emphasis on linking recommendations to the available evidence, transparency in reporting how evidence was searched for and evaluated, and the implementation of recommendations into clinical practice.

Oligoclonal restriction of antiviral immunoreaction in oligoclonal band-negative MS patients.

OBJECTIVES: Presence of oligoclonal bands (OCB) in cerebrospinal fluid (CSF) is a diagnostic hallmark of multiple sclerosis (MS). However, up to 10% of patients were OCB negative in routine laboratory tests. The aim of this study was to determine whether there is at least an oligoclonal restriction of intrathecal antibody synthesis against measles, rubella and/or varicella zoster virus (MRZ-specific OCB) in CSF from oligoclonal bands-negative patients with MS. METHODS: CSF and serum samples from 17 well-defined OCB-negative patients with MS were analysed for MRZ-specific OCB. We performed isoelectric focusing (IEF) combined with affinity blotting using viral antigens, detection with a highly sensitive chemiluminescence technique and recording with X-ray films. Controls included 18 OCB-positive patients with MS and 11 patients with pseudotumor cerebri (PTC). RESULTS: Exclusive or predominant MRZ-specific OCB in CSF against at least one virus species were present in 8 of 17 patients with MS (47.1%; P = 0.0422), suggesting an oligoclonal intrathecal immune response, although OCB of total IgG were absent. Only a very weak oligoclonal reaction against varicella zoster virus in CSF from one of the PTC controls was detectable. Thirteen of 18 (72.2%; P = 0.0013) OCB-positive patients with MS showed also MRZ-specific oligoclonal bands against at least 1 neurotropic virus in CSF. CONCLUSIONS: MRZ-specific OCB argue for existence of a chronic intrathecal immune reaction also in routine laboratory-OCB-negative patients with MS. This phenomenon reflects oligoclonal restriction of the humoral immunoreaction as well as polyspecific intrathecal antibody synthesis, which are both characteristics in the chronic inflammatory process of MS.

Supratentorial white matter blurring associated with voltage-gated potassium channel-complex limbic encephalitis.

INTRODUCTION: Limbic encephalitis (LE) associated with voltage-gated potassium channel-complex antibodies (VGKC-LE) is frequently non-paraneoplastic and associated with marked improvement following corticosteroid therapy. Mesial temporal lobe abnormalities are present in around 80 % of patients. If associated or preceded by faciobrachial dystonic seizures, basal ganglia signal changes may occur. In some patients, blurring of the supratentorial white matter on T2-weighted images (SWMB) may be seen. The purpose of this study was to evaluate the incidence of SWMB and whether it is specific for VGKC-LE. METHODS: Two experienced neuroradiologists independently evaluated signal abnormalities on FLAIR MRI in 79 patients with LE while unaware on the antibody type. RESULTS: SWMB was independently assessed as present in 10 of 36 (28 %) compared to 2 (5 %) of 43 non-VGKC patients (p = 0.009). It was not related to the presence of LGI1 or CASPR2 proteins of VGKC antibodies. MRI showed increased temporomesial FLAIR signal in 22 (61 %) VGKC compared to 14 (33 %) non-VGKC patients (p = 0.013), and extratemporomesial structures were affected in one VGKC (3 %) compared to 11 (26 %) non-VGKC patients (p = 0.005). CONCLUSION: SWMB is a newly described MRI sign rather specific for VGKC-LE.

[Paraneoplastic neurological syndromes and autoimmune encephalitis]. / Paraneoplastische neurologische Syndrome und Autoimmunenzephalitiden.

Paraneoplastic neurological syndromes (PNS) are defined as remote effects on the central and peripheral nervous system that are not caused directly by the tumor, its metastases and treatment, or metabolic disorders. The most probable cause is a falsely initiated immune reaction. Well-defined classical PNSs are associated with distinct tumors and occur with onconeural antibodies directed against intracellular neuronal antigens. However, response to therapy is limited. Recently, new antibodies directed against neuronal surface antigens were described in encephalitic syndromes of autoimmune origin. These probably antibody-mediated disorders are more frequent than classical PNS, occur with or without tumor association and often show a good response to immunosuppressive treatment.

Spectrum of MRI findings in central nervous system affection in Lyme neuroborreliosis.

Affections of the central nervous system (CNS) rarely occur in Lyme neuroborreliosis (LNB). CNS manifestations can have residual neurological symptoms despite antibiotic treatment. We explored the spectrum of CNS affections in patients with LNB in a tertiary care center in a region endemic for Lyme borreliosis. We retrospectively included patients treated at a tertiary care center from January 2020-December 2021 fulfilling the case criteria for LNB as stated in the current German guideline on LNB. Clinical data, cerebrospinal fluid (CSF) findings and MRI imaging were collected. We included 35 patients with LNB, 24 with early manifestations and 11 with CNS-LNB. CNS-LNB patients had encephalomyelitis (n = 6) or cerebral vasculitis (n = 5). Patients with early LNB and CNS-LNB differed regarding albumin CSF/serum quotient and total protein in CSF. Duration from onset of symptoms until diagnosis was statistically significantly longer in patients with encephalomyelitis. MRI findings were heterogeneous and showed longitudinal extensive myelitis, perimedullar leptomeningeal enhancement, pontomesencephalic lesions or cerebral vasculitis. CNS-LNB can present with a variety of clinical syndromes and MRI changes. No clear pattern of MRI findings in CNS-LNB could be identified. The role of MRI consists in ruling out other causes of neurological symptoms.

Cerebrospinal fluid parameters of B cell-related activity in patients with active disease during natalizumab therapy.

Recently, the disappearance of oligoclonal bands (OCBs) from the cerebrospinal fluid (CSF) of a few natalizumab-treated patients with multiple sclerosis (MS) has been reported. This is interesting since CSF-restricted OCB are believed to persist in MS. We pooled CSF data from 14 MS centers to obtain an adequate sample size for investigating the suspected changes in central nervous system (CNS)-restricted humoral immune activities in the context of natalizumab therapy. In a retrospective chart analysis, CSF parameters of blood-CSF barrier integrity and intrathecal IgG production from 73 natalizumab-treated MS patients requiring a diagnostic puncture for exclusion of progressive multifocal leukoencephalopathy were compared with CSF data obtained earlier in the course of disease before natalizumab therapy. At the time of repeat lumbar puncture, local IgG production (according to Reibergram) was significantly reduced (p < 0.0001) and OCB had disappeared in 16% of the patients. We therefore conclude that natalizumab therapy interferes with intrathecal antibody production at least in a significant number of patients.

[Paraneoplastic neurological syndromes]. / Paraneoplastische neurologische Syndrome.

Paraneoplastic neurological syndromes (PNS) are very rare, remote effects of malignancies. Well-characterised antibodies against intracellular neuronal antigens are well-known in association with distinct tumors and with classical and non-classical syndromes. In this review article the current aspects of classification, pathophysiology, underlying tumors, antineuronal autoantibodies and diagnostic and therapeutic aspects of syndromes affecting the central nervous system are summarized.

SOX1 antibodies in sera from patients with paraneoplastic neurological syndromes.

OBJECTIVES: SOX1 antibodies have been described in patients with Lambert-Eaton myasthenic syndrome (LEMS) in association with voltage-gated calcium channel antibodies as serological markers of small cell lung cancer (SCLC). This study was aimed to screen for additional SOX1 autoimmunity in onconeural antibody-positive sera from patients with paraneoplastic neurological syndromes (PNS) other than LEMS and to identify the clinical-immunological profile and associated tumours of patients with coexisting SOX1 antibodies. METHODS: We retrospectively analysed sera from 55 patients with different PNS positive for well-characterized antineuronal antibodies for the presence of SOX1 antibodies by recombinant ELISA and immunoblot. RESULTS: Eight (14.5%) patients showed additional SOX1 antibodies in the ELISA and the recombinant immunoblot. Five patients had coexisting Hu antibodies, while the other three showed coexisting CV2/CRMP5, amphiphysin, and coexisting CV2/CRMP5 and Hu antibodies, respectively. PNS included (partially overlapping) subacute sensory neuropathy, subacute sensorimotor neuropathy, cerebellar degeneration, brainstem encephalitis, encephalomyelitis and limbic encephalitis. No tumour was detected in two patients, while the others had lung cancer (four SCLC and two non-SCLC). One patient showed SOX1-specific intrathecal antibody synthesis. CONCLUSIONS: We describe SOX1 reactivity for the first time overlapping with CV2/CRMP5 and amphiphysin antibodies. SOX1 reactivity is predominantly associated with Hu antibodies and SCLC, but can occur also in other types of lung cancer. Neurological manifestations present in patients with coexisting SOX1 antibodies and well-characterized antineuronal antibodies do not differ from those previously described in patients positive for antineuronal antibodies but no SOX1-specific anti-glial antibodies.

Paraneoplastic antibody during follow-up of a patient with anti-Ri-associated paraneoplastic neurological syndrome.

BACKGROUND: The role of classical antineuronal antibody determinations to confirm the paraneoplastic aetiology of a neurological syndrome is well established. However, the value of antineuronal antibody estimation during follow-up of paraneoplastic neurological syndromes (PNS) is not known. AIMS OF THE STUDY: Prospective analysis of antibody concentrations in follow-up serum samples from a patient with anti-Ri-associated PNS. METHODS: Semiquantitative estimation of antibody concentrations with an ELISA using recombinant Ri antigen. RESULTS: Semiquantitative estimation of circulating anti-Ri antibodies demonstrated a renewed increase in antibody levels preceding relapse of the cancer, as confirmed using F-fluorodeoxyglucose positron emission tomography (FDG-PET). CONCLUSIONS: This is the first prospective report on serial anti-Ri antibody determinations. As a large increase in antineuronal antibody concentrations in follow-up serum samples preceded relapse of the cancer, paraneoplastic antineuronal antibodies may represent a marker for tumour activity in this case. These results warrant further multicentre studies to investigate the ability of serial quantification of classical antineuronal antibodies in monitoring PNS and in predicting relapse of cancers.

Immunoblot reactivity at follow-up in treated patients with Lyme neuroborreliosis and healthy controls.

About 5-20% of the general population in endemic areas have seroprevalence for anti-borrelial antibodies. Previous studies have shown a high rate of 25-97% of persisting anti-borrelial antibodies in patients with treated Lyme neuroborreliosis (LNB) at follow-up. These studies used immunoblots with antigens from whole-cell sonicates, which could be less specific than modern recombinant antigens. We assessed the seroprevalence of anti-borrelial antibodies in serum from patients with definite LNB and healthy controls with a line immunoblot using highly specific recombinant antigens. We retrospectively identified patients with treated definite LNB who were treated at the Medical Center-University of Freiburg. Serum from LNB patients at a mean follow-up period of 4.9 years (SD: 3.3) and serum from healthy controls were assessed for anti-borrelial antibodies with a line immunoblot with recombinant antigens. A total of 45 patients with definite LNB and 40 healthy controls were included. Ten LNB patients (22.7%) had persisting antibodies (IgG and/or IgM) in serum at follow-up. Serum samples from six healthy controls (15%) were positive for anti-borrelial antibodies (IgG and or IgM). Prevalence of positive IgM or IgG antibodies showed no statistically significant difference between LNB patients at follow-up and healthy controls (IgM p = 0.32, IgG p = 0.54). Immunoblot reactivity patterns at follow-up in LNB patients did not have statistically significant differences from healthy controls. The discrepancy regarding earlier studies reporting higher amounts of LNB patients with persisting antibodies could be due to a higher specificity of the antigens used in recombinant immunoblots compared to other immunoblots (e.g., whole-cell sonicates). The results of our study should be replicated in a larger prospective multi-center study.

Polyspecific, antiviral immune response distinguishes multiple sclerosis and neuromyelitis optica.

BACKGROUND: A polyspecific, intrathecal humoral immune response against neurotropic viruses such as measles, rubella and varicella zoster virus (MRZ reaction, MRZR) is present in 80-100% of patients with multiple sclerosis (MS), but has not to date been evaluated in patients with neuromyelitis optica (NMO). AIMS: To evaluate whether MRZR distinguishes NMO and MS. METHODS: 20 patients with NMO and 42 with MS were included. The intrathecal synthesis of antibodies against measles, rubella and varicella zoster virus was detected by calculation of the respective antibody indices (AI). RESULTS: A positive MRZ reaction, as defined by a combination of at least two positive AIs, was found in 37/42 MS, but in only 1/20 NMO patients (p<0.0001). Median AI values differed significantly between the groups (p<0.0005). CONCLUSIONS: The polyspecific antiviral humoral immune response characteristic for MS is widely missing in NMO, irrespective of the NMO-IgG status of the patients. Our findings further strengthen the case for NMO being pathologically distinct from MS.

Qualitative evidence of Ri specific IgG-synthesis in the cerebrospinal fluid from patients with paraneoplastic neurological syndromes.

The presence of Ri-specific oligoclonal IgG bands in the CSF was investigated in five patients with paraneoplastic anti-Ri associated neurological syndromes (PNS) and six controls. In 4/5 CSF samples reactivity of IgG bands with recombinant Ri antigen was found using isoelectrofocusing combined with affinity blotting; in one patient with absence of oligoclonal bands of total IgG in CSF Ri-specific oligoclonal bands were detected with the same sample, indicating a higher sensitivity of Ri-specific affinity blotting as compared to affinity blotting with anti-human IgG antibodies. Our results confirm previous studies demonstrating IgG synthesis against onconeuronal antigens by intrathecal B-cell clones in PNS and extend this observation to patients with anti-Ri syndrome. The pathogenic relevance of these antibodies, however, is further challenged by the finding that specific intrathecal IgG synthesis might not be a prerequisite of CNS involvement, because it was missed in one of our patients.

Erythrophages do not develop when lumbar CSF and blood samples are mixed in vitro.

BACKGROUND: Cerebrospinal fluid (CSF) analysis is a crucial method in the diagnostic process for suspected subarachnoid hemorrhage (SAH), especially when cerebral imaging is negative or inconclusive. CSF cytology (detection of erythrophages or siderophages) is used to determine whether a bloodstained CSF resembles a genuine SAH. Whether erythrophages may develop in vitro after a traumatic puncture in case of delayed CSF analysis is unclear. An in vitro development of erythrophages after traumatic puncture would diminish the diagnostic properties of CSF analysis. We assessed whether erythrophagocytosis is detectable in CSF after an imitated traumatic lumbar puncture. METHODS: We mimicked a traumatic lumbar puncture by mixing surplus CSF with whole blood from the same patient. From this mixture, cytological specimens were obtained immediately and repeatedly at time intervals of 1 h, until 7 h after mixing, or until the mixture was exhausted. Each cytological specimen was microscopically examined independently by four experienced CSF cytologists for the presence of erythrophages. RESULTS: We studied 401 CSF cytological specimens of 96 punctures in 90 patients. We could not identify any erythrophages in all cytological specimens. Fleiss' Kappa for interrater-reliability was 1.0. CONCLUSIONS: We did not find evidence for an in vitro erythrophagocytosis after a mimicked traumatic lumbar puncture. Therefore, the occurrence of erythrophages in CSF cytology can be regarded as a reliable sign of an autochthonous bleeding in the subarachnoid space. Our results support the crucial role of CSF analysis in clinical practice in case of a suspected SAH but negative cerebral imaging.

Antigen-specific oligoclonal bands in cerebrospinal fluid and serum from patients with anti-amphiphysin- and anti-CV2/CRMP5 associated paraneoplastic neurological syndromes.

Using isoelectric focusing and affinity blotting employing paraneoplastic recombinant antigens, we investigated cerebrospinal fluid (CSF) and sera from three patients with positive anti-CV2/CRMP5- and one patient with positive anti-amphiphysin serology. CSF and sera were previously adjusted to total IgG concentrations of 20 mg/l. All patients suffered from paraneoplastic neurological syndromes (PNS) with predominant involvement of the central nervous system (CNS). Using affinity blot preloaded with paraneoplastic antigen, we detected in three of four patients more or stronger specific oligoclonal bands (OCB) in the CSF than in the corresponding serum, providing qualitative evidence of antigen specific intrathecal antibody synthesis. These results are in line with previous studies demonstrating specific OCB predominantly in CSF from patients with anti-Hu-, anti-Yo- and anti-Ri-associated PNS, supporting the hypothesis of autoimmunity in the pathogenesis of PNS. One patient harboured extensive anti-amphiphysin specific OCB, although OCB of total IgG could not be detected, indicating a higher sensitivity for detection of intrathecal antibody synthesis of the affinity blot preloaded with the paraneoplastic antigen, compared with investigation of total IgG OCB. These results could have implications concerning pathophysiological autoimmune aspects in other inflammatory diseases of CNS associated with total IgG OCB, provided that the target antigen is known.

Intrathecal IgM-synthesis does not correlate with the risk of relapse in patients with a primary demyelinating event.

The objective of this study was to investigate, whether the presence of oligoclonal immunoglobulin M bands (IgM-OCB) in cerebrospinal fluid (CSF) from patients with a clinically isolated syndrome (CIS), which is suggestive for the first clinical manifestation of multiple sclerosis (MS), anticipates the risk of a relapse during a retrospective study period of 21-106 months (mean 60 +/- 25). A relapse would lead to the diagnosis of clinically definite MS. Paired CSF and serum samples from 42 patients with a CIS and positive intrathecal IgG-synthesis were tested retrospectively for IgM-OCB, which are exclusively present in CSF, but not in the corresponding serum. Isoelectric focusing and affinity blot were used and clinical follow-up was based on telephone interviews. IgM-OCB were found in the CSF from 31 of 42 patients (74%). There was no correlation between the presence of IgM-OCB, the number of such bands or the IgM-Index on the one hand and the risk of a relapse during the follow-up in the cohort studied, on the other hand. These data do not support the idea that the presence of IgM-OCB in CSF might predict an unfavourable course in MS.