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Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is the most common chronic inflammatory neuropathy. CIDP is diagnosed according to the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) criteria, which combine clinical features with the electrophysiological evidence of demyelination. However, firstly, diagnosis is challenging, as some patients e.g. with severe early axonal damage do not fulfil the criteria. Secondly, objective and reliable tools to monitor the disease course are lacking. Thirdly, about 25% of CIDP patients do not respond to evidence-based first-line therapy. Recognition of these patients is difficult and treatment beyond first-line therapy is based on observational studies and case series only. Individualized immunomodulatory treatment does not exist due to the lack of understanding of essential aspects of the underlying pathophysiology. Novel diagnostic imaging techniques and molecular approaches can help to solve these problems but do not find enough implementation. This review gives a comprehensive overview of novel diagnostic techniques and monitoring approaches for CIDP and how these can lead to individualized treatment and better understanding of pathophysiology.

Background Only few studies describe the impact of nutritive factors on chronic inflammatory demyelinating polyneuropathy (CIDP), an inflammatory disease of the peripheral nervous system. The active component of chili pepper, capsaicin, is the direct agonist of the transient receptor potential channel vanilloid subfamily member 1. Its anti-inflammatory effect in the animal model experimental autoimmune neuritis (EAN) has been previously demonstrated. Methods In the present study, we describe the anti-inflammatory and anti-oxidative influence of capsaicin on Schwann cells (SCs) in an in vitro setting. Hereby, we analyze the effect of capsaicin on Schwann cells’ gene expression pattern, major histocompatibility complex class II (MHC-II) presentation, and H 2 O 2 -induced oxidative stress. Furthermore, the effect of capsaicin on myelination was examined in a SC-dorsal root ganglia (DRG) coculture by myelin basic protein staining. Finally, in order to investigate the isolated effect of capsaicin on SCs in EAN pathology, we transplant naïve and capsaicin pre-treated SCs intrathecally in EAN immunized rats and analyzed clinical presentation, electrophysiological parameters, and cytokine expression in the sciatic nerve. Results In SC monoculture, incubation with capsaicin significantly reduces interferon gamma-induced MHC-II production as well as toll-like receptor 4 and intercellular adhesion molecule 1 mRNA expression. Calcitonin gene-related peptide mRNA production is significantly upregulated after capsaicin treatment. Capsaicin reduces H 2 O 2 -induced oxidative stress in SC in a preventive, but not therapeutic setting. In a SC-DRG coculture, capsaicin does not affect myelination rate. After intrathecal transplantation of naïve and capsaicin pre-treated SCs in EAN-immunized rats, naïve, but not capsaicin pre-treated intrathecal SCs, ameliorated EAN pathology in rats. Conclusions In conclusion, we were able to demonstrate a direct immunomodulatory and anti-oxidative effect of capsaicin in a SC culture by reduced antigen presentation and expression of an anti-inflammatory profile. Furthermore, capsaicin increases the resistance of SCs against oxidative stress. A primary effect of capsaicin on myelination was not proven. These results are in concordance with previous data showing an anti-inflammatory effect of capsaicin, which might be highly relevant for CIDP patients.

Background Autoimmune neuropathies are common PNS disorders and effective treatment is challenging. Environmental influence and dietary components are known to affect the course of autoimmune diseases. Capsaicin as pungent component of chili-peppers is common in human nutrition. An influence of capsaicin on autoimmune diseases has been postulated. Methods We tested capsaicin in the animal model of experimental autoimmune neuritis (EAN) in Lewis rat. Rats were immunized with P2-peptide and were treated with capsaicin in different preventive settings. Electrophysiological, histological, and molecular biological analyses of the sciatic nerve were performed to analyze T-cell and macrophage cell count, TRPV1, and cytokine expression. Moreover, FACS analyses including the intestinal immune system were executed. Results We observed an immunomodulatory effect of an early preventive diet-concept, where a physiological dosage of oral capsaicin was given 10 days before immunization in EAN. A reduced inflammation of the sciatic nerve was significant detectable clinically, electrophysiologically (CMAPs reduced in control group p  < 0.01; increase of nerve conduction blocks in control group p  < 0.05), histologically (significant reduction of T-cells, macrophages and demyelination), and at cytokine level. In contrast, this therapeutic effect was missing with capsaicin given from the day of immunization onwards. As possible underlying mechanism, we were able to show changes in the expression of the capsaicin receptor in the sciatic nerve and the small intestine, as well as altered immune cell populations in the small intestine. Conclusion This is the first report about the immunomodulatory effect of the common nutrient, capsaicin, in an experimental model for autoimmune neuropathies.

Dimethyl fumarate (DMF) exerts immunomodulatory and neuroprotective effects in the animal model of experimental autoimmune neuritis (EAN) in the Lewis rat. DMF has been shown to modulate gut microbiota in veterinary medicine, however the effects of oral DMF on the gut-associated lymphoid tissue (GALT) remain unknown. Lewis rats were treated orally twice daily with DMF up to day 10 after immunization with immunogenic P2 peptide. Histological, flow cytometric and RT-PCR analyses of the GALT (intraepithelial layer, lamina propria, and Peyer patches) in duodenum, jejunum, and ileum were performed . Moreover, cell transfer experiments were used to examine the protective effects of GALT regulatory T cells of the Peyer patches. In the upper layers of duodenum, DMF induced a reduction of the toll-like receptor 4 (TLR4) mRNA expression. This was combined by a decrease of the pro-inflammatory lamina propria IFN-γ mRNA expression. In the ileum, we detected an immunoregulatory phenotype characterized by an increase of FoxP3 mRNA expression and of the nuclear factor (erythroid-derived-2)- like 2 (Nrf2) downstream molecule heme oxygenase-1 (HO-1) mRNA. Finally, CD4 CD25 regulatory T cells were increased in the Peyer patches. , the protective effect of these regulatory cells was verified by cell transfer into recipient EAN rats. Our results identified a novel immunomodulatory effect of DMF through the different regions and layers of the small intestine, which led to an increase of regulatory T cells, exerting a protective role in experimental neuritis.

Short-chain fatty acids (SCFAs), including propionic acid (PA), are key in immunological research. Supplementing PA has shown benefits for autoimmune diseases. A comprehensive understanding of the PA pharmacokinetics is essential for the optimal design and execution of studies utilizing orally administered PA. We propose two methods of measuring PA in serum, carried out by different laboratories. Blood samples from 20 volunteers were collected hourly following PA supplementation. Serum propionate quantification was performed with two independent mass spectrometry-based (MS) analyses, including liquid-chromatography (LC)-MS and direct-infusion (DI)-MS. PA levels increased within 1 h of ingestion of 500 mg PA. Serum concentrations ranged from 1.3 to 4.5 µmol/L, rising significantly after 1 h (  < 0.05). Serum levels returned to baseline within 2 h. No significant differences were found regarding sex or diet. The shown pharmacokinetics can be used in future PA research.

Background Corticosteroids dominate in the treatment of chronic autoimmune neuropathies although long-term use is characterized by devastating side effects. Methods We introduce the intrathecal application of the synthetic steroid triamcinolone (TRIAM) as a novel therapeutic option in experimental autoimmune neuritis in Lewis rats Results After immunization with neuritogenic P2 peptide, we show a dose-dependent therapeutic effect of one intrathecal injection of 0.3 or 0.6 mg/kg TRIAM on clinical and electrophysiological parameters of neuritis with a lower degree of inflammatory infiltrates (T cells and macrophages) and demyelination in the sciatic nerve. In vitro studies in Schwann cell cultures showed an increased expression of IL-1 receptor antagonist and reduced expression of Toll-like receptor 4 after incubation with TRIAM as well as a protective effect of TRIAM against oxidative stress after H 2 O 2 exposure. Conclusion Intrathecal TRIAM application could be a novel immunomodulatory and potentially neuroprotective option for autoimmune neuropathies with a direct effect on Schwann cells.

We report the case of a 27‐year‐old patient with subacute anti‐neurofascin‐155 neuropathy with bifacial palsy, who showed excellent response to rituximab. We provide longitudinal data of established clinical scores, nerve conduction studies, antibody titers, and novel imaging methods (nerve ultrasonography and corneal confocal microscopy). Clinical and electrophysiological improvement followed the reduction of serum antibody titer and correlated with a reduction of corneal inflammatory cellular infiltrates whereas the increase in the cross‐sectional area of the peripheral nerves remained 12 months after first manifestation. Our findings suggest that novel techniques provide useful follow‐up parameters in paranodopathies.

Severe autoimmune-mediated neuropathies, such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and paranodopathies, often remain refractory to established immunotherapies. 1–3 Anti-CD19 chimeric antigen receptor (CAR) T cells have shown promising therapeutic potential in autoimmune conditions through substantial and sustained B-cell depletion. 4,5 Here, we report treatment of two patients with severe, treatment-refractory autoimmune neuropathies using autologous anti-CD19 CAR T cells ( appendix pp 2–3). In March, 2023, the patient first presented to our university hospital with rapid progression to symmetric tetraplegia despite extensive immunotherapy (intravenous immunoglobulin, corticosteroids, plasmapheresis, cyclophosphamide, rituximab, obinutuzumab, and bortezomib; appendix pp 4–6). JM declares stock ownership from Amgen, Bayer, and Sanofi; travel grants from Alnylam, Biogen Idec, Novartis, Teva, Eisai, Neuraxpharm, Bristol Myers Squibb, and Kyverna; consulting fees from Novartis and Alnylam; and research funding from Klaus Tschira Foundation, Ruhr-University Bochum (FoRUM program), Deutsche Multiple Sklerose Gesellschaft, Hertie Foundation, Novartis, and Kyverna, not related to this work.

Introduction Ofatumumab (Kesimpta ® ) is a subcutaneous CD20-targeting antibody approved in Germany in 2021 for the treatment of relapsing multiple sclerosis (RMS). After careful instruction, patients can administer the treatment themselves. We previously reported data of 101 patients (Klimas et al. in Nervenarzt 94:923–933, 2023). The objective of this longitudinal study is to explore the tolerability and acceptability of ofatumumab from a patient perspective over a follow up period of 6 months. Methods In this prospective observational real-world study, we report follow up data of 81 patients. We evaluated sociodemographic data, disease duration, duration and side effects of ofatumumab use, expanded disability status scale (EDSS), Beck Depression Inventory II (BDI-II), Short-Form 36 (SF-36), Fatigue Scale of Motor and Cognitive Functions (FSMC), and modified Multiple Sclerosis Functional Composite Test (MSFC). In addition, we asked for subjective treatment outcomes, such as impact on quality of life, walking distance, concentration, mood, medication adherence, fatigue and the subjective course of MS on a numerical rating scale (1 = very negative; 5 = very positive). Furthermore, treatment discontinuations were recorded. Results The average duration of ofatumumab treatment was 10 months. In comparison to previous published data of our cohort, patients reported a significant increase in headache (10% up to 26%, p = 0.004) and limb pain (5% up to 26%, p < 0.001) as persistent side effects after the injections. More patients reported a very positive effect (p < 0.0001) on quality of life. 4 confirmed relapses occurred but no EDSS worsening, and no treatment discontinuations were documented during the observation period. Discussion As previously described, our prospective study indicates that patients have a good tolerability of ofatumumab, precisely because of the mild and few side effects at the first administration. However, the longer the observation period, the more headaches and limb pain occurred after the injections. Despite this, patients’ subjective quality of life improved. There were no discontinuations during the follow-up period, with the limitation of a high loss to follow-up.

Introduction The value of a sural nerve biopsy for the diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is controversial. Evidence-based recommendations for its implementation are lacking. We investigated factors leading to biopsy and analyzed biopsy outcomes and consequences, assessed the predictability of biopsy outcomes through clinical parameters to avoid unnecessary biopsies, and compared results with electrophysiological and clinical severity to determine their prognostic value. Methods 190 sural nerve biopsies were analyzed in two cohorts. One consisted of 163 biopsies and the second of 72 biopsies from the prospective Immune-mediated Neuropathies Biomaterial and Data registry (INHIBIT). Both have an intersection of 45 patients. 75 data sets from patients without biopsy were used. Analysis of nerve conduction studies, treatment, overall disability sum score (ODSS), biopsy outcomes, and diagnosis was performed. Results 51% of biopsied patients received the diagnosis CIDP (77% fulfilled EFNS/PNS criteria), 21% were not CIDP typical, and 27% were unspecific. Biopsied patients responded less frequently to immunotherapies at time of biopsy than non-biopsied patients ( p  = 0.003). Immunotherapy was initiated more frequently after biopsy ( p  < 0.001) and more often with intravenous immunoglobulins ( p  < 0.0001). 76% of all biopsied patients met the electrophysiological criteria for CIDP. Sensory nerve action potential amplitudes of 0 µV still provide 73% of histological diagnostic value. Histologic signs of degeneration predicted ODSS worsening after 1 year ( p  = 0.028) but disease severity did not correlate with histological damage severity. Discussion The main indication for nerve biopsy was the treatment of refractory cases of autoimmune neuropathies with the therapeutic consequence of treatment initiation or escalation. Sural biopsy also provided prognostic information. Even with extinguished sural SNAP, the biopsy can still have diagnostic value.