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  • Patients, controls and clinical assessment: Our pilot study involved measuring MIF-concentrations in the diagnostically obtained CSF from 20 patients with optic neuritis (ON) as first inflammatory episode in clinically isolated syndrome (CIS, n = 9) or relapsing-remitting MS (RRMS, n = 11), according to the McDonald criteria (2010) [25]. The second group of CSF-MIF measurements were from 18 patients who had been diagnosed with CIS (n = 9) / MS (n = 9) but had not presented with an acute clinical relapse within the preceding 4 weeks or received any steroids within the 8 weeks (CIS/MS without acute relapse = CIS/MS w/o) prior to study inclusion (mean [SD] latency between last relapse and lumbar puncture = 31 [39] months). CSF was additionally acquired from a hospital-based cohort of n = 20 healthy controls (HC). In these healthy individuals the presence of a neurological disorder had been suspected, but was not confirmed. In addition to the clinical classification, patients included in the control group also fulfilled the following Reiber laboratory criteria defining a non-inflammatory CSF (< 5 cells/μl, > 500 mg protein/ml, < 2 mmol/l lactate, no disruption of the blood/CSF barrier, no oligoclonal bands (OCB) in the CSF, and no intrathecal immunoglobulin (Ig) G, IgA, or IgM synthesis) [26]. Patients of all three groups were clinically evaluated in accordance with German guidelines (including the Expanded disability status scale [EDSS] [27]). Disease duration was defined as the time in months between symptom onset and lumbar puncture (LP). No patient had received any disease-modifying treatment before LP. In the ON group, visual acuity was measured preceding GC-treatment, on the last day of GC administration, as well as after therapy escalation including plasma exchange. To verify ON-induced axonal disintegration, visual evoked potentials (VEP) were recorded before GC-treatment in at least two trials for each eye, averaging >150 responses, with electrodes positioned at Oz (active) and Fz, in accordance with the International Society for Clinical Electrophysiology of Vision (ISCEV) standards [28]. Latencies of the P100 exceeding a 2.5 standard deviation (SD) from normative data were considered as abnormal VEPs. P100 peak-latencies were measured to reflect the degree of demyelination. VEPs with no stimulation response were excluded (n = 6/20). Brain MRI scans from patients originated from non-standardized protocols from differing MRI units and magnetic field strengths (1.5 or 3.0 Tesla) conducted close to the LP. All examinations included T1- and T2-weighted spin-echo sequences with the administration of gadolinium (Gd). Abnormalities including T1-hypointesities, T2-hyperintesities and Gd-enhanced T1-lesions were initially identified by a neuroradiologist and they were subsequently verified by a MS specialist (M.P. ). Irrespective of the degree of relapse-induced visual loss, ON patients were treated for at least 5 days with a high daily dose (1 g) of intravenous methylprednisolone. For this group, GC-responsive ON (GC-ON) was defined as visual improvement after 5 days of treatment, with a visual acuity correction of >10% compared to baseline, whereas GC-refractory ON (rGC-ON) was defined by a 0–10% change in visual acuity. All patients were recruited retrospectively in the Department of Neurology, Otto-von-Guericke University, Magdeburg, Germany, between 2012 and May 2017. Thus, no written informant consent could be obtained, but all parameters were taken from routine clinical diagnostics. The data were anonymized, precluding identification of individual patients. The study was approved by the Local Ethics Committee of the Faculty of Medicine at the University Hospital Magdeburg and Otto-von-Guericke University Magdeburg (No. 07/17). Immediately after LP, CSF cell concentration was determined, and total protein, albumin quotient (Qalb), and OCB were measured. The remaining CSF material was centrifuged at 4°C, aliquoted, and stored at -80°C until CSF-MIF analysis took place. The absolute CSF-MIF concentrations were measured using commercially available human MIF Quantikine ELISA (bio-techne, Mineapolis, MN), following the instructions provided by the manufacturer. All samples were run in duplicate, and the mean was used for statistical analysis. Statistical analysis was conducted using SPSS 21 (IBM). A one-way-ANOVA was conducted with group (HC vs. CIS/MS w/o vs. ON cases) as the independent variable, followed by pairwise post-hoc testing (Bonferroni-corrected). The groups were also compared with respect to categorical variables (using a chi-squared test) and continuous variables (using a t-test or Mann-Whitney U test), to determine group differences between GC-ON and rGC-ON cases, taking into account age, median visual acuity before and after GC administration, P100 latency, CSF cell count, Qalb, and CSF-MIF. A Wilcoxon test was used to determine whether visual improvement occurred after plasma exchange in the rGC-ON group. Spearman’s rank correlations were performed between CSF-MIF and age, further CSF measures (cell count, Qalb, relative monocyte fraction), disease duration, T2-lesion count and P100 latency. P-values ≤ 0.05 were deemed to be statistically significant.
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