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Inflammatory neuropathies are a heterogeneous group of rare diseases of the peripheral nervous system that include acute and chronic diseases, such as Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). The etiology and pathophysiological mechanisms of inflammatory neuropathies are only partly known, but are considered autoimmune disorders in which an aberrant immune response, including cellular and humoral components, is directed towards components of the peripheral nerve causing demyelination and axonal damage. Therapy of these disorders includes broad-spectrum immunomodulatory and immunosuppressive treatments, such as intravenous immunoglobulin, corticosteroids, or plasma exchange. However, a significant proportion of patients do not respond to any of these therapies, and treatment selection is not optimized according to disease pathophysiology. Therefore, research on disease pathophysiology aiming to reveal clinically and functionally relevant disease mechanisms and the development of new treatment approaches are needed to optimize disease outcomes in CIDP and GBS. This topical review describes immunological progress that may help guide therapeutic strategies in the future in these two disorders.

A growing number of hereditary neuropathies have been assigned to causative gene defects in recent years. The study of human nerve biopsy samples has contributed substantially to the discovery of many of these neuropathy genes. Genotype–phenotype correlations based on peripheral nerve pathology have provided a comprehensive picture of the consequences of these mutations. Intriguingly, several gene defects lead to distinguishable lesion patterns that can be studied in nerve biopsies. These characteristic features include the loss of certain nerve fiber populations and a large spectrum of distinct structural changes of axons, Schwann cells and other components of peripheral nerves. In several instances the lesion patterns are directly or indirectly linked to the known functions of the mutated gene. The present review is designed to provide an overview on these characteristic patterns. It also considers other aspects important for the manifestation and pathology of hereditary neuropathies including the role of inflammation, effects of chemotherapeutic agents and alterations detectable in skin biopsies.

Despite the fact that there are published case reports and model work providing evidence of inflammation in Charcot–Marie–Tooth disorders (CMTs), in clinical practice, CMT and inflammatory neuropathies are always classified as two separate groups of disorders. This sharp separation of chronic neuropathies into two groups has serious clinical implications. As a consequence, the patients harboring CMT mutations are practically excluded from pharmacological anti-inflammatory treatments. In this review, we present that neuropathological studies of peripheral nerves taken from some patients representing familial aggregation of CMTs revealed the presence of inflammation within the nerves. This shows that neurodegeneration resulting from germline mutations and the inflammatory process are not mutually exclusive. We also point to reports demonstrating that, at the clinical level, a positive response to anti-inflammatory therapy was observed in some patients diagnosed with CMTs, confirming the role of the inflammatory component in CMT. We narrowed a group of more than 100 genes whose mutations were found in CMT-affected patients to the seven most common (MPZ, PMP22, GJB1, SEPT9, LITAF, FIG4, and GDAP1) as being linked to the coexistence of hereditary and inflammatory neuropathy. We listed studies of mouse models supporting the idea of the presence of an inflammatory process in some CMTs and studies demonstrating at the cellular level the presence of an inflammatory response. In the following, we discuss the possible molecular basis of some neuropathies involving neurodegenerative and inflammatory processes at both the clinical and morphological levels. Finally, we discuss the prospect of a therapeutic approach using immunomodulation in some patients affected by CMTs.

Background and purpose Peripheral neuropathy is a frequent complication of brentuximab vedotin (BV), used in CD30+ lymphoma treatment. Classic BV‐induced neuropathy (BV‐CN) is a mild distal sensory axonal polyneuropathy. Severe BV‐induced inflammatory neuropathies (BV‐IN) have been described. BV‐IN contribute to lymphoma‐associated morbidity but might be immunotherapy‐responsive. Our primary objective was to evaluate the rate of BV‐IN. Our secondary objectives were to determine risk factors and warning signs. Methods We conducted a retrospective cohort study on all patients treated with BV at our center between April 2014 and September 2021. Clinical, biological, and electrophysiological data were collected. BV‐induced neuropathy was defined as the occurrence of neuropathy up to 3 months after BV discontinuation. BV‐IN was defined with criteria adapted from European Academy of Neurology/Peripheral Nerve Society 2021 electrodiagnostic criteria for chronic inflammatory demyelinating polyradiculoneuropathy. Other neuropathies were classified as BV‐CN. Results Among 83 patients, 41 (49%) developed neuropathy: 35 BV‐CN and 6 BV‐IN. Thus, the rate of BV‐IN was 7.2%. Compared to patients with BV‐CN, no predisposing factor was identified. However, patients with BV‐IN more frequently presented muscle weakness (67% vs. 5.7%, p < 0.05), gait disorders (83% vs. 20%, p < 0.05), or acute or subacute onset (67% vs. 14%, p < 0.05). BV‐IN was frequently more severe (Common Terminology Criteria for Adverse Events grade ≥3; 50% vs. 0%, p < 0.05). Four patients were treated with immunotherapy. Conclusions Brentuximab vedotin‐induced neuropathy is an overlooked complication. Based on four easily identifiable “red flags”, we provide an algorithm to help non‐neurologist physicians that care for BV‐treated patients to detect BV‐IN. The aim of the algorithm is to decrease the diagnostic and management delay of this disabling neuropathy.

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.

Utilize immune cell profiles in the cerebrospinal fluid (CSF) to advance the understanding and potentially support the diagnosis of inflammatory neuropathies. We analyzed CSF cell flow cytometry data of patients with definite Guillain-Barré syndrome (GBS, = 26) and chronic inflammatory demyelinating polyneuropathy (CIDP, = 32) based on established diagnostic criteria in comparison to controls with relapsing-remitting multiple sclerosis (RRMS, = 49) and idiopathic intracranial hypertension (IIH, = 63). Flow cytometry revealed disease-specific changes of CSF cell composition with a significant increase of NKT cells and CD8+ T cells in CIDP, NK cells in GBS, and B cells and plasma cells in MS in comparison to IIH controls. Principal component analysis demonstrated distinct CSF immune cells pattern in inflammatory neuropathies vs. RRMS. Systematic receiver operator curve (ROC) analysis identified NKT cells as the best parameter to distinguish GBS from CIDP. Composite scores combing several of the CSF parameters differentiated inflammatory neuropathies from IIH and GBS from CIDP with high confidence. Applying a novel dimension reduction technique, we observed an intra-disease heterogeneity of inflammatory neuropathies. Inflammatory neuropathies display disease- and subtype-specific alterations of CSF cell composition. The increase of NKT cells and CD8+ T cells in CIDP and NK cells in GBS, suggests a central role of cytotoxic cell types in inflammatory neuropathies varying between acute and chronic subtypes. Composite scores constructed from multi-dimensional CSF parameters establish potential novel diagnostic tools. Intra-disease heterogeneity suggests distinct disease mechanisms in subgroups of inflammatory neuropathies.

Background We proposed to investigate high-dose pharmaceutical-grade biotin in a population of demyelinating neuropathies of different aetiologies, as a proof-of-concept. Methods Phase IIb open label, uncontrolled, single center, pilot study in 15 patients (three groups of five patients) with chronic demyelinating peripheral neuropathy, i.e. chronic inflammatory demyelinating polyradiculoneuropathy, anti-myelin-associated glycoprotein neuropathy and Charcot-Marie-Tooth 1a or 1b. The investigational product was high-dose pharmaceutical-grade biotin (100 mg taken orally three times a day over a maximum of 52 weeks. The primary endpoint was a 10% relative improvement in 2 of the following 4 electrophysiological variables: motor nerve conduction velocity, distal motor latency, F wave latency, duration of the compound muscle action potential. The secondary endpoints included Overall Neuropathy Limitations Scale (ONLS) score, Medical Research Council (MRC) sum score, Inflammatory Neuropathy Cause and Treatment (INCAT) sensory sum score, 10-m walk test, 6-min walk test, posturography parameters, and nerve excitability variables. Results The primary endpoint was reached in one patient. In the full population analysis, some secondary endpoints parameters improved: MRC score, INCAT sensory sum score, 6-min walk distance, strength-duration time constant, and rheobase. There was a positive correlation between the improvement in the 6-min walk distance and the strength-duration time constant. Regarding the safety results, 42 adverse events occurred, of which three were of severe intensity but none was considered as related to the investigational product. Conclusions Even if the primary endpoint was not met, administration of high-dose pharmaceutical-grade biotin led to an improvement in various sensory and motor parameters, gait abilities, and nerve excitability parameters. The tolerance of the treatment was satisfactory. Trial registration ClinicalTrials.gov Identifier: NCT02967679; date 2016/12/05.

This multi-center Italian prospective observational study reports the 4 months follow-up data of 87 patients affected by chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy (MMN) shifted from intravenous to subcutaneous immunoglobulin treatment. A therapeutic shift from intravenous to subcutaneous immunoglobulin was performed in 87 patients (66 CIDP; 21 MMN) affected by immune-mediated peripheral neuropathies with evidence of a sustained clinical response to intravenous immunoglobulin. Patients were evaluated by means of the Overall Neuropathy Limitation Scale, Medical Research Council Scale and Life Quality Index questionnaire, both at the time of therapeutic shift and after 4 months of subcutaneous immunoglobulin treatment. A sustained clinical efficacy was observed after the switch to subcutaneous immunoglobulin: the Overall Neuropathy Limitation Scale score improved in the group of 66 CIDP patients ( P  = 0.018), with only one subject reporting a worsening of 1 point, and remained stable in the group of 21 MMN patients ( P  = 0.841), with one subject reporting a worsening of two points. An improvement in the patient’s perception of therapeutic setting was reported in both groups. This large multi-center study confirms the short-term clinical equivalence of subcutaneous versus intravenous immunoglobulin and a possible improvement in the patient’s perception of therapeutic setting with the subcutaneous administration. However, further studies are required to extend the results to a longer observational period.

Background To evaluate whether ongoing axonal loss can be prevented in multifocal motor neuropathy (MMN) treated with immunoglobulin G (IgG), a group of patients with a median disease duration of 15.7 years (range: 8.3–37.8), treated with titrated dosages of immunoglobulins, was studied electrophysiologically at time of diagnosis and at follow‐up. Results At follow‐up, the Z‐score of the compound motor action potential amplitude of the median, fibular, and tibial nerves and the neurological performances were determined. In seven patients with a treatment‐free period of 0.3 years (0.2–0.4), there was no progression of axonal loss (p = 0.2), whereas a trend toward further axonal loss by 1.3 Z‐scores (0.9–17.0, p = 0.06) was observed in five patients with a treatment‐free period of 4.0 years (0.9–9.0). The axonal loss in the group with a short treatment delay was significantly smaller than in the group with a longer treatment delay (p = 0.02). Also, there was an association between treatment delay and ongoing axonal loss (p = 0.004). The electrophysiological findings at follow‐up were associated with the isokinetic strength performance, the neurological impairment score, and the disability, supporting the clinical relevance of the electrophysiological estimate of axonal loss. Conclusion Swift initiation of an immediately titrated IgG dosage can prevent further axonal loss and disability in continuously treated MMN patients.

The novel criteria for the diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP) have established imaging with nerve ultrasound (NUS) and magnetic resonance neurography (MRN) as complementary methods for CIDP diagnosis. Our goal was to investigate the role of MRN and NUS for CIDP monitoring. We longitudinally examined 12 CIDP patients from 2016 to 2022 using NUS, MRN, nerve conduction studies (NCS), and clinical parameters (inflammatory neuropathy cause and treatment (INCAT)/overall disability sum score (ODSS)). NUS evaluated the cross-sectional area (CSA) of the median, ulnar, radial, tibial, fibular, and sural nerve as well as the intranerve CSA variability (INV ) of the tibial, fibular, ulnar, and median nerve, whereas MRN evaluated T2-weighted sequences of the fibular and tibial nerve at the popliteal fossa. Five patients showed clinical improvement/stability with corresponding improved or stable NCS/NUS parameters (number of nerves with increased CSA and INV ). Seven deteriorating patients showed deteriorating NCS and either increasing or decreasing NUS markers possibly indicating inflammatory activity or degenerative CSA reduction. The difference ΔINCAT/ODSS correlated positively with NUS ΔINV (  = 0.007,  = 0.731,  = 12) and with NUS ΔCSA of the tibial nerve (  = 0.0005,  = 0.865,  = 12). Further, NUS-CSA of the tibial nerve in the popliteal fossa in 2016 correlated inversely with the difference of the INCAT/ODSS score (ΔINCAT/ODSS ;  = -0.653;  = 0.033;  = 11). Finally, the Bland-Altman analyses for the tibial and fibular nerve showed a bias of -1.903 and 2.195 mm (bias = NUS-CSA - MRN-CSA) accordingly revealing a difference between MRN and NUS measurements for deeper nerves. CSA and INV of the tibial and fibular nerve can be used for monitoring in CIDP, and increased CSA of the tibial nerve is a good prognostic marker. MRN is more reliable for evaluating inflammation in proximal leg nerve segments.