Nerve cross-sectional area in advanced uremic neuropathy: A nerve ultrasound pilot study.

BACKGROUND AND PURPOSE: Uremic neuropathy (UN) is a disabling neuropathy in end-stage kidney disease (ESKD) affecting the majority of patients receiving long-term hemodialysis (HD). One previous nerve ultrasound study reported an increased cross-sectional area (CSA) of the median nerve in moderate UN, while another study found enlarged sural nerves in small-fiber polyneuropathy associated with ESKD. The present cohort study aims to analyze bilateral CSA of multiple nerves in UN. METHODS: Ten nondiabetic ESKD patients with UN on HD for at least 2 years and 10 healthy age-matched controls underwent bilateral ultrasound examinations with CSA measurements in 13 arm and leg nerve sites. Nerve conduction studies (NCS) and the total neuropathy score (TNS) were recorded. Pearson's coefficient and the Mann-Whitney U-test were used to analyze correlations and compare groups. RESULTS: ESKD patients presented advanced neuropathic symptoms (mean TNS 15.9). NCS showed significantly reduced motor and sensory amplitudes in the UN group compared to the control group, and a slightly reduced nerve CSA was observed in 5 of 13 nerve sites (p < .05); the other nerve sites were not enlarged. Sural nerve CSA (p < .05) and sensory amplitude (p < .01) were negatively correlated with the TNS. CONCLUSIONS: Nerve enlargement was not observed in the present study in advanced UN. A reduced nerve CSA observed in the sural nerve suggests an axonal loss associated with long-term HD in ESKD. During clinical workup of an acute disease of the peripheral nervous system in ESKD patients, nerve enlargement might be attributable to other causes than chronic UN.

Morphological Differentiation of Corneal Inflammatory Cells: Proposal of Pragmatic Protocol.

PURPOSE: Corneal confocal microscopy is a noninvasive imaging technique to analyze corneal nerve fibers and corneal inflammatory cells (CICs). The amount of CICs is a potential biomarker of disease activity in chronic autoinflammatory diseases. To date, there are no standardized criteria for the morphological characterization of CICs. The aim was to establish a protocol for a standardized morphological classification of CICs based on a literature search and to test this protocol for applicability and reliability. METHODS: A systematic review of the literature about definitions of CICs was conducted. Existing morphological descriptions were translated into a structured algorithm and applied by raters. Subsequently, the protocol was optimized by reducing and defining the criteria of the cell types. The optimized algorithm was applied by 4 raters. The interrater reliability was calculated using Fleiss kappa (K). RESULTS: A systematic review of the literature revealed no uniform morphological criteria for the differentiation of the individual cell types in CICs. Our first protocol achieved only a low level of agreement between 3 raters (K = 0.09; 1062 rated cells). Our revised protocol was able to achieve a higher interrater reliability with 3 (K = 0.64; 471 rated cells) and 4 (K = 0.61; 628 rated cells) raters. CONCLUSIONS: The indirect use of criteria from the literature leads to a high error rate. By clearly defining the individual cell types and standardizing the protocol, reproducible results were obtained, allowing the introduction of this protocol for the future evaluation of CICs in the corneal confocal microscopy.

Small fibre integrity and axonal pathology in the rat model of experimental autoimmune neuritis.

Experimental autoimmune neuritis is a common animal model for acute human immune-mediated polyneuropathies. Although already established in 1955, a number of pathophysiological mechanisms remain unknown. In this study, we extensively characterize experimental autoimmune neuritis progression in Lewis rats, including new insights into the integrity of small nerve fibres, neuropathic pain and macrophage activation. Acute experimental autoimmune neuritis was induced with P253-78 peptide and consequently investigated using the gait analysis system CatWalk XT, electrophysiological and histopathological analyses, quantitative polymerase chain reaction (PCR), dorsal root ganglia outgrowth studies, as well as the von Frey hair and Hargreaves tests. For the longitudinal setup, rats were sacrificed at Day (d) 10 (onset), d15 (peak), d26 (recovery) and d29 (late recovery). We confirmed the classical T-cell and macrophage-driven inflammation and the primarily demyelinating nature of the experimental autoimmune neuritis. The dual role of macrophages in experimental autoimmune neuritis is implicated by the high number of remaining macrophages throughout disease progression. Furthermore, different subpopulations of macrophages based on Cx3-motif chemokine receptor 1 (Cx3cr1), platelet factor 4 (Pf4) and macrophage galactose-type lectin-1 (Mgl1) expressions were identified. In addition, modulation of the sensory system in experimental autoimmune neuritis was detected. An outgrowth of small fibres in the plantar skin at the onset and peak of the experimental autoimmune neuritis was evident parallel to the development of acute hyperalgesia mediated through transient receptor potential vanilloid 1 modulation. Our data depict experimental autoimmune neuritis as a primary demyelinating disease with implicated axonal damage, a small unmyelinated fibre impairment throughout the disease progression course, and underline the pivotal role of macrophages in the effector and during the recovery stage.

Association of the neonatal Fc receptor promoter variable number of tandem repeat polymorphism with immunoglobulin response in patients with chronic inflammatory demyelinating polyneuropathy.

BACKGROUND AND PURPOSE: Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune disease with humoral and cellular autoimmunity causing demyelination of peripheral nerves, commonly treated with intravenous immunoglobulins (IVIg). The neonatal Fc receptor (FcRn), encoded by the FCGRT gene, prevents the degradation of immunoglobulin G (IgG) by recycling circulating IgG. A variable number of tandem repeat (VNTR) polymorphism in the promoter region of the FCGRT gene is associated with different expression levels of mRNA and protein. Thus, patients with genotypes associated with relatively low FcRn expression may show a poorer treatment response to IVIg due to increased IVIg degradation. METHODS: VNTR genotypes were analyzed in 144 patients with CIDP. Patients' clinical data, including neurological scores and treatment data, were collected as part of the Immune-Mediated Neuropathies Biobank registry. RESULTS: Most patients (n = 124, 86%) were VNTR 3/3 homozygotes, and 20 patients (14%) were VNTR 2/3 heterozygotes. Both VNTR 3/3 and VNTR 2/3 genotype groups showed no difference in clinical disability and immunoglobulin dosage. However, patients with a VNTR 2 allele were more likely to receive subcutaneous immunoglobulins (SCIg) than patients homozygous for the VNTR 3 allele (25% vs. 9.7%, p = 0.02) and were more likely to receive second-line therapy (75% vs. 54%, p = 0.05). CONCLUSIONS: The VNTR 2/3 genotype is associated with the administration of SCIg, possibly reflecting a greater benefit from SCIg due to more constant immunoglobulin levels without lower IVIg levels between the treatment circles. Also, the greater need for second-line treatment in VNTR 2/3 patients could be an indirect sign of a lower response to immunoglobulins.

High-resolution nerve ultrasound and corneal confocal microscopy in taxane-induced polyneuropathy.

BACKGROUND AND PURPOSE: The role of high-resolution nerve ultrasound (HRUS) and corneal confocal microscopy (CCM) in the early detection of taxane-induced polyneuropathy (TIPN) is unclear. The present prospective longitudinal controlled observational pilot study estimates the role of HRUS and CCM in the early diagnosis of TIPN in breast cancer patients. METHODS: Fifteen breast cancer patients receiving paclitaxel and 15 healthy age matched controls were included. Visits before and 3 weeks, 8 weeks and 6 months after treatment included clinical examination, the total neuropathy score, nerve conduction studies (NCS), monocular CCM including corneal nerve fibre length, density and branching and HRUS of bilateral median, ulnar, radial, tibial, peroneal and sural nerves. Patients were compared between different visits and to healthy controls. RESULTS: Total neuropathy score increased from 2.2 at baseline to 5.8 (p < 0.001) at week 8. NCS showed a decreased sensory amplitude in the sural, radial, ulnar and median nerve after 6 months (p < 0.001). HRUS revealed a significant increase of cross-sectional area in the sural nerve (p = 0.004), the median nerve (p = 0.003) at the carpal tunnel and the ulnar nerve in the forearm (p = 0.006) after 6 months. CCM showed no changes at different visits. CONCLUSIONS: Corneal confocal microscopy and HRUS do not detect early signs of TIPN during the paclitaxel treatment period. HRUS and NCS might detect congruent signs of an axonal, predominantly sensory polyneuropathy after 6 months. The clinical examination remains the most sensitive tool in the early detection of TIPN in breast cancer patients.

[Over one year of B­cell targeted therapy with Ofatumumab s.c.: first results of a prospective, patient-centered real-world observational study]. / Über ein Jahr B-Zell-gerichtete Therapie mit Ofatumumab s.c.: erste Ergebnisse einer prospektiven, patientenzentrierten Real-world-Beobachtungsstudie.

INTRODUCTION: Ofatumumab (Kesimpta™) is a s.c. applicable anti-CD20 antibody, which has been used in Germany since 2021 for the treatment of relapsing multiple sclerosis (RMS). The self-application offers a high degree of independence from intravenous forms of application with highly effective immunotherapy. In this study we recorded the patient-centered experience in 99 out of 127 patients who were adjusted to the drug by us. The aim was to investigate the tolerability and acceptance from the patient's perspective. METHODS: Data collection was carried out using doctor documentation, questionnaires and telephone interviews. RESULTS: The cohort consists of 127 patients. The patients received 2.8 (± SD 1.7) pre-therapies. The mean duration of therapy with Ofatumumab was 9.8 months (± SD 3.5). Structured data were collected from 99 patients. 23% of patients had no side effects during initial application. 19% rated the side effects as "very mild" and 18% as "mild". In addition to chills/fever (48%), headache (46%), limb pain (45%) and "other symptoms" (19%) also occurred. For subsequent injections, 72% of patients reported no side effects. 87% of patients found handling the medication "very easy". There was one relapse event during therapy. CONCLUSION: Our study shows that Ofatumumab is well accepted and tolerated by patients. There was one relapse event during the observation period. The side effects are mild and occur during initial application. No increased tendency to infection could be observed. The data suggest that Ofatumumab is also an effective and safe treatment option for patients with relapsing remitting multiple sclerosis in real-world use.

The impact of the SARS-CoV-2-pandemic on patients with chronic inflammatory neuropathies: results from the German INHIBIT register.

INTRODUCTION: SARS-CoV-2 pandemic is especially compromising for patients with autoimmune diseases with or without immunomodulatory treatment. This study aimed to investigate the longitudinal changes in the health care of patients with immune-mediated neuropathies during the COVID-19 pandemic. METHODS: We performed a longitudinal study using questionnaires in a prospective cohort of patients with immune-mediated neuropathies at two timepoints of the pandemic: May-July 2021 and May-July 2022. RESULTS: The cohort consisted of 73 patients (55 male), mean age 62 years, 68 patients with CIDP, 5 with other immune neuropathies. In 2021, 19.2% of the patients reported a reduced number of physician-patient-contacts, while 13.7% reported this in 2022. Nevertheless, the overall health-care situation worsened from 2021 to 2022: 15.1% reported reduced overall healthcare in 2021, 26.0% in 2022. In 2021, 29.4% of patients reported absence of physio-/occupational therapy, while 34.4% reported this in 2022. Switching immunomodulatory treatment and stretching of treatment intervals occurred more often in 2022 (38.4%) than in 2021 (27.4%). 12 COVID-19-infections occurred overall, with typical only mild symptoms. The rate of fully vaccinated patients was 61.6% and 98.6% in May-July 2021 and 2022, respectively. Only minor side-effects after vaccination were reported. CONCLUSION: Despite mitigation of COVID-19 restrictions from 2021 to 2022, the health-care situation of patients worsened in this time. Reasons could be the international shortage of immunoglobulins during the pandemic and reduced physio/ergotherapy due to lingering regulatory restrictions. Vaccination rate was high in our cohort of patients compared to the general German population and CIDP did not seem to be a risk factor for severe SARS-CoV-2 infections.

Dose-dependent immunomodulatory effects of bortezomib in experimental autoimmune neuritis.

Proteasome inhibition with bortezomib has been reported to exert an immunomodulatory action in chronic autoimmune neuropathies. However, bortezomib used for the treatment of multiple myeloma induces a painful toxic polyneuropathy at a higher concentration. Therefore, we addressed this controversial effect and evaluated the neurotoxic and immunomodulatory mode of action of bortezomib in experimental autoimmune neuritis. Bortezomib-induced neuropathy was investigated in Lewis rats using the von Frey hair test, electrophysiological, qPCR and histological analyses of the sciatic nerve as well as dorsal root ganglia outgrowth studies. The immunomodulatory potential of bortezomib was characterized in Lewis rats after experimental autoimmune neuritis induction with P253-78 peptide. Clinical, electrophysiological, histological evaluation, von Frey hair test, flow cytometric and mRNA analyses were used to unravel the underlying mechanisms. We defined the toxic concentration of 0.2 mg/kg bortezomib applied intraperitoneally at Days 0, 4, 8 and 12. This dosage induces a painful toxic neuropathy but preserves axonal regeneration in vitro. Bortezomib at a concentration of 0.05 mg/kg significantly ameliorated experimental autoimmune neuritis symptoms, improved experimental autoimmune neuritis-induced hyperalgesia and nerve conduction studies, and reduced immune cell infiltration. Furthermore, proteasome inhibition induced a transcriptional downregulation of Nfkb in the sciatic nerve, while its inhibitor Ikba (also known as Nfkbia) was upregulated. Histological analyses of bone marrow tissue revealed a compensatory increase of CD138+ plasma cells. Our data suggest that low dose bortezomib (0.05 mg/kg intraperitoneally) has an immunomodulatory effect in the context of experimental autoimmune neuritis through proteasome inhibition and downregulation of nuclear factor 'kappa-light-chain-enhancer' of activated B-cells (NFKB). Higher bortezomib concentrations (0.2 mg/kg intraperitoneally) induce sensory neuropathy; however, the regeneration potential remains unaffected. Our data empathizes that bortezomib may serve as an attractive treatment option for inflammatory neuropathies in lower concentrations.

Longitudinal study on nerve ultrasound and corneal confocal microscopy in NF155 paranodopathy.

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.

Immunomodulatory and anti-oxidative effect of the direct TRPV1 receptor agonist capsaicin on Schwann cells.

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 H2O2-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 H2O2-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.