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Background and Purpose: The predictive value of serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP) for apheresis outcome in steroid-refractory multiple sclerosis (MS) relapse has not yet been evaluated., Methods: We used pre- and postapheresis serum samples from 38 participants of the IAPEMS trial (clinicaltrials.gov: NCT02671682), which investigated the use of immunoadsorption versus plasma exchange for the treatment of steroid-refractory MS attacks. Response to apheresis was classified based on improvement on (i) the Expanded Disability Status Scale (EDSS), (ii) the affected functional system scores (FSS) of the EDSS, or (iii) the visual acuity for patients with optic neuritis, 4 weeks postapheresis. sNFL and sGFAP were measured by single molecule arrays., Results: Preprocedural sGFAP levels could discriminate between responders and nonresponders, determined by FSS improvement (p = 0.017). In multivariate logistic regression analysis, younger age (odds ratio [OR] = 0.781, 95% confidence interval [CI] = 0.635-0.962, p = 0.020) and lower sGFAP levels (OR = 0.948, 95% CI = 0.903-0.995, p = 0.031) could predict response to apheresis in the overall cohort. We could observe a trend towards a favourable apheresis outcome with higher sNfL levels (OR = 1.413, 95% CI = 0.965-2.069, p = 0.076). Analysis of the sNfL-to-sGFAP ratio showed an OR of 1.924 (95% CI = 1.073-3.451, p = 0.028) for predicting apheresis response. The ratio showed a better predictive value than the individual parameters. Neither biomarker was affected by the number of steroid cycles preapheresis., Conclusions: Lower sGFAP levels, a higher sNfL-to-sGFAP ratio, and younger age are associated with a favourable apheresis outcome., (© 2024 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Small fiber neuropathy (SFN) affects unmyelinated and thinly myelinated nerve fibers causing neuropathic pain with distal distribution and autonomic symptoms. In idiopathic SFN (iSFN), 30% of the cases, the underlying aetiology remains unknown. Gadolinium (Gd)-based contrast agents (GBCA) are widely used in magnetic resonance imaging (MRI). However, side-effects including musculoskeletal disorders and burning skin sensations were reported. We investigated if dermal Gd deposits are more prevalent in iSFN patients exposed to GBCAs, and if dermal nerve fiber density and clinical parameters are likewise affected. 28 patients (19 females) with confirmed or no GBCA exposure were recruited in three German neuromuscular centers. ISFN was confirmed by clinical, neurophysiological, laboratory and genetic investigations. Six volunteers (two females) served as controls. Distal leg skin biopsies were obtained according to European recommendations. In these samples Gd was quantified by elemental bioimaging and intraepidermal nerve fibers (IENF) density via immunofluorescence analysis. Pain phenotyping was performed in all patients, quantitative sensory testing (QST) only in a subset (15 patients; 54%). All patients reported neuropathic pain, described as burning (n = 17), jabbing (n = 16) and hot (n = 11) and five QST scores were significantly altered. Compared to an equal distribution significantly more patients reported GBCA exposures (82%), while 18% confirmed no exposures. Compared to unexposed patients/controls significantly increased Gd deposits and lower z-scores of the IENF density were confirmed in exposed patients. QST scores and pain characteristics were not affected. This study suggests that GBCA exposure might alter IENF density in iSFN patients. Our results pave the road for further studies investigating the possible role of GBCA in small fiber damage, but more investigations and larger samples are needed to draw firm conclusions., (© 2023. The Author(s).)

Background: Pain occurs in the majority of patients with late onset Pompe disease (LOPD) and is associated with a reduced quality of life. The aim of this study was to analyse the pain characteristics and its relation to a small nerve fiber involvement in LOPD patients., Methods: In 35 patients with LOPD under enzyme replacement therapy without clinical signs of polyneuropathy (19 females; 51 ± 15 years), pain characteristics as well as depressive and anxiety symptoms were assessed using the PainDetect questionnaire (PDQ) and the hospital anxiety and depression scale (HADS), respectively. Distal skin biopsies were analysed for intraepidermal nerve fiber density (IENFD) and compared to age- and gender-matched reference data. Skin biopsies from 20 healthy subjects served as controls to assure validity of the morphometric analysis., Results: Pain was reported in 69% of the patients with an average intensity of 4.1 ± 1.1 on the numeric rating scale (NRS; anchors: 0-10). According to PDQ, neuropathic pain was likely in one patient, possible in 29%, and unlikely in 67%. Relevant depression and anxiety symptoms occurred in 31% and 23%, respectively, and correlated with pain intensity. Distal IENFD (3.98 ± 1.95 fibers/mm) was reduced in 57% of the patients. The degree of IENFD reduction did not correlate with the durations of symptoms to ERT or duration of ERT to biopsy., Conclusions: Pain is a frequent symptom in treated LOPD on ERT, though a screening questionnaire seldom indicated neuropathic pain. The high frequency of small nerve fiber pathology in a treated LOPD cohort was found regardless of the presence of pain or comorbid risk factors for SFN and needs further exploration in terms of clinical context, exact mechanisms and when developing novel therapeutic options for LOPD., (© 2022. The Author(s).)

A 23-year old female was diagnosed with relapsing-remitting multiple sclerosis with two symptomatic attacks. Immunomodulatory treatment with Clift® (Glatiramer Acetate biosimilar) was initiated. Shortly after administration, an asymptomatic increase in liver enzymes was noticed, and therapy was paused. However, we observed an enormous increase in liver enzymes within a few days. Histological work up of a liver biopsy showed microfocal liver necrosis accompanied with increased numbers of CD38-positive lymphocytes as shown by immunohistology, indicating a drug-induced liver injury. Subsequently, under oral prednisolone treatment, liver enzymes normalized. This case highlights the importance of tight monitoring of liver function in the initial phase of a new immunotherapy to unravel asymptomatic hepatotoxicity in time and prevent further damage., Competing Interests: Declaration of Competing Interest SM has nothing to declare. EZ has nothing to declare. TFEB has nothing to declare. AW has received travel support from Merck Serono. TF has nothing to declare. DT has received speaker honoraria from Novartis and Sanofi, travel support from Bayer, Biogen, Celgene, Merck, Novartis, Sanofi and Teva. FB has nothing to declare. HT received funding for research projects, lectures and travel from Bayer, Biogen, Genzyme, Fresenius, Merck, Mylan, Novartis, Roche, Siemens Health Diagnostics, Teva, and received research support from Hertie-Stiftung, DMSG, BMBF, University of Ulm and Landesstiftung BW. MS received consulting and/or speaker honoraria as well as travel reimbursements from Bayer, Biogen, Celgene, Merck, Roche, Sanofi Genzyme and TEVA. She received research funding from the Hertha-Nathorff-Program., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Plasma exchange (PE) constitutes the standard therapy for steroid-refractory relapse in multiple sclerosis and clinically isolated syndrome. Immunoadsorption (IA) is an alternative method of apheresis which selectively removes immunoglobulines (Ig) while preserving other plasma proteins. Although IA is regarded as a well-tolerated, low-risk procedure, high-level evidence for its efficacy is lacking. Therefore, we sought to investigate whether IA is superior to PE in patients with acute relapse of multiple sclerosis or clinically isolated syndrome who had insufficiently responded to high-dose intravenous methylprednisolone (MP)., Methods: Patients with acute relapse of multiple sclerosis or clinically isolated syndrome and without complete clinical remission of symptoms after at least one cycle of high-dose intravenous MP therapy were enrolled to our randomised, controlled, parallel-group, monocentric trial. Eligible patients were aged at least 12 years and had no clinical or laboratory signs of systemic infection. Eligible patients were randomly assigned (1:1) to receive either IA or PE. Patients in both groups received 5 treatments on 5 consecutive days. In the IA group, the 2.0-fold individual total plasma volume was processed on day 1, and the 2.5-fold on days 2-5. In the PE group, 2 liters of plasma (corresponding to the 0.69 ± 0.12-fold individual total plasma volume) were removed each day and substituted by 5% human albumin solution. Patients were followed up directly after last apheresis as well as 2 and 4 weeks after last treatment. The primary endpoint was change of the Multiple Sclerosis Functional Composite (MSFC) after 4 weeks compared to baseline. Analyses of primary outcome and safety measures were done in all patients who received at least one treatment (intention-to-treat-population). The trial is registered with ClinicalTrials.gov, number NCT02671682., Findings: Between January 21, 2016, and October 26, 2018, 63 patients were screened for eligibility, and 61 patients were randomly assigned to receive IA ( n  = 31) or PE ( n  = 30). All randomised patients were included in the intention-to-treat-analysis. For the primary outcome, the median improvement of MSFC after 4 weeks compared to baseline was 0.385 (IQR 0.200-0.675; p  < 0.001) in the IA group and 0.265 (IQR 0.100-0.408; p  < 0.001) in the PE group. Improvement in the IA group was significantly larger ( p  = 0.034) compared to PE. Response rates after 4 weeks were 86.7% in the IA group and 76.7% in the PE group. One deep venous thrombosis occurred in each group., Interpretation: Both IA and PE were safe in patients with steroid-refractory relapse and resulted in significant improvements of the primary outcome MSFC after 4 weeks compared to baseline. IA patients showed significantly larger improvements of MSFC compared to PE patients after 4 weeks. The results indicate a potential superiority of IA compared to PE in treatment of steroid-refractory relapse in multiple sclerosis and clinically isolated syndrome, which has to be confirmed by future studies., Funding: Fresenius Medical Care Deutschland GmbH, Bad Homburg, Germany., Competing Interests: JDo reports personal fees and research grants from Fresenius Medical Care GmbH, Fresenius Medical Care Deutschland GmbH and Miltenyi Biotec GmbH. MS has received consulting or speaker honoraria as well as travel reimbursements from Bayer, Biogen, Celgene, Roche, Sanofi Genzyme and TEVA and research funding from the Hertha-Nathorff-Program and University of Ulm, none related to this study. HT reports personal fees and/or research grants from Fresenius Medical Care GmbH and Fresenius Medical Care Deutschland GmbH, Bayer, Biogen, Merck, Mylan, Novartis, Roche, Sanofi-Genzyme, Teva, DMSG, and BMBF. DT has received speaker honoraria from Sanofi-Genzyme and Novartis, as well as travel and accommodation reimbursements from Bayer, Biogen, Merck, Novartis, Sanofi Genzyme, and TEVA, none related to this study. TF, PE, JDr, SM, JS, and ACL report no conflicts of interest., (© 2019 Published by Elsevier Ltd.)

The polyspecific B-lymphocyte response to neurotropic viruses such as measles (M), rubella (R) and varicella zoster (Z), known as MRZ reaction, is to-date the most specific neurochemical marker for multiple sclerosis (MS). The aim of this study was to investigate a possible association of immunoglobulin (Ig) kappa (κ-) and lambda (λ-) free light chains (FLC) with the presence of the MRZ reaction in multiple sclerosis. Immunoglobulin κ- and λ-FLC, MRZ reaction, oligoclonal IgG bands (OCB), and cerebrospinal fluid (CSF) routine parameters were measured in 65 MS patients. OCB were detected in 97% of MS patients, intrathecal IgG synthesis according to Reiber was detectable in 57%, an elevated IgG index (>0.7) in 66% and the MRZR was positive in 45%. All investigated κ-values (CSF κFLC, CSF-serum ratio of κFLCs (QκFLC), and κFLC index (κFLC/QAlbumin)) were significantly higher in patients with positive MRZ reaction as compared to MRZ negative MS patients. In contrast, λ-values showed no significant differences. Additionally to the putative diagnostic sensitivity and prognostic value of κFLC, the association of κFLC with a highly specific neurochemical marker for MS - the MRZ reaction, especially the determination of κFLCs is an informative tool to assess the B-cell response and determine its extent in MS patients., (Copyright © 2019. Published by Elsevier B.V.)

Introduction: Patients suffering from multiple sclerosis often complain of fatigue and sleepiness. Patients often cannot distinguish between these symptoms. Daytime sleepiness, attention and concentration deficits affect life quality severely. Usually symptoms of MS are characterized by the Expanded Disability Status Scale (EDSS). In new studies the MSFC proves to be a more sensitive method especially estimating the cognitive deficits., Methods: 31 RRMS patients (18 women, 13 men, mean age 35.6 +/- 8.3 years) and 19 healthy controls (9 men, 1 woman, age: 55.1 +/- 7.8 years) were assessed by: 1) morning and evening protocols of the German Sleep Society, 2) Epworth Sleepiness Scale (ESS), 3) Extended Disability Status Scale (EDSS), 4) MS Functional Composite (MSFC) based on arm function, ambulation and cognition (paced auditory serial addition test, PASAT), 5) Fatigue Severity Scale (FSS)., Results: The EDSS-Score ranged from 1.0 to 6.5 (2.8 +/- 1.4). Mean Z-Score of MSFC was -0.19 +/- 0.63. Most deficits could be shown in the PASAT. Total sleep time correlated with recovery capacity of sleep (r = 0.42, P < 0.05). The ESS-Score was 6.1 +/- 2.9 (1 - 14). FSS-Score was raised with intraindividual variability (4,33 +/- 1.62, 1.4 - 7). The EDSS failed to correlate with the ESS- or FSS-Score. FSS correlated significantly with arm function (r = 0.465) und ambulation (r = 0.436) in the MSFC (P < 0.05)., Discussion: MS-Patients are often not able to distinguish between fatigue and sleepiness. By using different scales judging sleepiness and fatigue significant differences could be evaluated. Fatigue is mainly linked to motoric deficits scored by the MSFC. Therefore medication with stimulants seems not to be useful in fatigue therapy.

Objective: To compare the driving performance using a driving simulator with physical and cognitive functions as measured by the Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Functional Composite (MSFC) in patients suffering from the relapsing-remitting form of multiple sclerosis (RRMS)., Methods: 31 RRMS patients (18 women, 13 men, mean age 35.6 +/- 8.3 years, EDSS 2.8 +/- 1.4) were compared with 10 healthy controls (8 men, 2 woman, age 45.1 +/- 7.8 years)., Results: Compared with controls, the accident rate (5.3 +/- 3.8 vs. 1.3 +/- 1.5, p < 0.001) and concentration faults (21.1 +/- 15.5 vs. 7.1 +/- 2.6, p < 0.01) of RRMS patients using the driving simulator were increased. While there was no correlation with the EDSS score, the accident rate was correlated with the MSFC (r = -0.5, p < 0.05). Regarding the three dimensions of the MSFC, accidents were related to the number of correct answers and Z-score in the paced auditory serial addition test (PASAT) as a measure for cognitive function (r = -0.33, p < 0.05)., Conclusion: The current study demonstrates the need to focus also on driving skills in MS patients. The risk of accidents should be evaluated after relapses in particular. However, there are great interindividual differences. In the MSFC, most deficits could be evaluated in the PASAT. As there was a significant correlation between the accident rate in the driving simulator and the PASAT results, accidents seem to be more influenced by cognitive decline than by physical impairment. This indicates that the MSFC is a broader, more dimensional scale than the EDSS and should be preferred in the case of driving assessment. At the present time, the driving simulator seems to be a useful instrument judging driving ability, especially in cases with ambiguous neuropsychological results., (Copyright 2003 S. Karger AG, Basel)