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BackgroundChronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an immune-mediated peripheral neuropathy that is currently classified into several clinical subtypes, which are presumed to have different pathogenic mechanisms. Recently, studies identified a subgroup of patients with CIDP who were positive for IgG4 autoantibodies against paranodal proteins, such as neurofascin-155 and contactin-1, who respond poorly to first-line therapies for typical CIDP, including intravenous immunoglobulin therapy. ObjectiveThis study aims to evaluate the efficacy and safety of intravenous rituximab according to IgG4 autoantibody status in patients with refractory CIDP. MethodsThe Evaluation of the Efficacy and Safety of Rituximab in Refractory CIDP Patients with IgG4 Autoantibodies in the Exploratory Clinical (RECIPE) trial consists of 2 cohorts: a multicenter, placebo-controlled, randomized study cohort of 15 patients with IgG4 autoantibody-positive CIDP (rituximab:placebo = 2:1) and an open-label trial cohort of 10 patients with antibody-negative CIDP. The primary endpoint is improvement in functional outcome assessed using the adjusted Inflammatory Neuropathy Cause and Treatment Disability Scale score at 26, 38, or 52 weeks after the start of treatment with rituximab in patients with CIDP and anti-paranodal protein antibodies. Secondary outcome measures include grip strength, manual muscle testing sum scores, results of nerve conduction studies, and other functional scales. ResultsWe plan to enroll 25 cases for the full analysis set. Recruitment is ongoing, with 14 patients enrolled as of January 2020. Enrollment will close in September 2020, and the study is planned to end in December 2021. ConclusionsThis randomized controlled trial will determine if rituximab is safe and effective in patients with anti-paranodal antibodies. An open-label study will provide additional data on the effects of rituximab in patients with antibody-negative CIDP. The results of the RECIPE trial are expected to provide evidence for the positioning of rituximab as a pathogenesis-based therapeutic for refractory CIDP. Trial RegistrationClinicalTrials.gov NCT03864185, https://clinicaltrials.gov/ct2/show/NCT03864185 ; The Japan Registry of Clinical Trials jRCT2041180037, https://jrct.niph.go.jp/en-latest-detail/jRCT2041180037 International Registered Report Identifier (IRRID)DERR1-10.2196/17117

Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) is a late‐onset, autosomal recessive neurodegenerative disorder caused by biallelic AAGGG/ACAGG repeat expansion (AAGGG‐exp/ACAGG‐exp) in RFC1. The recent identification of patients with CANVAS exhibiting compound heterozygosity for AAGGG‐exp and truncating variants supports the loss‐of‐function of RFC1 in CANVAS patients. We investigated the pathological changes in 2 autopsied patients with CANVAS harboring biallelic ACAGG‐exp and AAGGG‐exp. RNA fluorescence in situ hybridization of the 2 patients revealed CCTGT‐ and CCCTT‐containing RNA foci, respectively, in neuronal nuclei of tissues with neuronal loss. Our findings suggest that RNA toxicity may be involved in the pathogenesis of CANVAS. ANN NEUROL 2024;95:607–613 [ABSTRACT FROM AUTHOR]

Autoimmune autonomic ganglionopathy (AAG) is a disease of autonomic failure caused by ganglionic acetylcholine receptor (gAChR) autoantibodies. Although the detection of autoantibodies is important for distinguishing the disease from other neuropathies that present with autonomic dysfunction, other factors are important for accurate diagnosis. Here, we provide a comprehensive review of the clinical features of AAG, highlighting differences in clinical course, clinical presentation, and laboratory findings from other neuropathies presenting with autonomic symptoms. The first step in diagnosing AAG is careful history taking, which should reveal whether the mode of onset is acute or chronic, followed by an examination of the time course of disease progression, including the presentation of autonomic and extra-autonomic symptoms. AAG is a neuropathy that should be differentiated from other neuropathies when the patient presents with autonomic dysfunction. Immune-mediated neuropathies, such as acute autonomic sensory neuropathy, are sometimes difficult to differentiate, and therefore, differences in clinical and laboratory findings should be well understood. Other non-neuropathic conditions, such as postural orthostatic tachycardia syndrome, chronic fatigue syndrome, and long COVID, also present with symptoms similar to those of AAG. Although often challenging, efforts should be made to differentiate among the disease candidates. [ABSTRACT FROM AUTHOR]

Background and Objective: Chronic graft versus host disease (GVHD)‐associated myositis targeting skeletal muscle is a relatively rare but potentially debilitating complication following allogeneic hematopoietic stem cell transplantation (HSCT). We reviewed the clinicopathological features of GVHD‐associated myositis among patients receiving allogeneic HSCT to elucidate the cellular pathogenesis. Methods: We retrospectively reviewed clinical data and muscle biopsy results from 17 consecutive patients diagnosed with GVHD‐associated myositis at our institution between 1995 and 2019. Immunostaining findings of GVHD‐associated myositis were compared to those of patients with anti‐tRNA‐synthetase antibody‐associated myopathy (ASM) (n = 13) and dermatomyositis (DM) (n = 12). Results: The majority of patients with GVHD‐associated myositis showed subacute or chronic progression of mild to moderate limb weakness together with elevated serum creatine kinase. These patients also exhibited mild C‐reactive protein elevation but were negative for myositis‐related autoantibodies. Programmed death‐1 (PD‐1)‐positive cells were observed in muscle interstitium adjacent to myofibers expressing human leukocyte antigen (HLA)‐DR. The interstitium was also HLA‐DR‐positive, similar to biopsy samples from ASM patients but not DM patients. The proportions of HLA‐DR‐positive muscle fibers and PD‐1‐positive interstitial cells were significantly higher in GVHD and ASM samples than DM samples. The PD‐1‐positive cells were mostly CD‐8‐positive lymphocytes. Discussion: GVHD‐associated myositis is characterized by HLA‐DR‐positive myofibers and infiltration of PD‐1‐positive lymphocytes. These features distinguish GVHD‐associated myositis from DM but not from ASM. [ABSTRACT FROM AUTHOR]

Background: Despite the suggestion that direct compression by granuloma and ischemia resulting from vasculitis can cause nerve fiber damage, the mechanisms underlying sarcoid neuropathy have not yet been fully clarified. Methods: We examined the clinicopathological features of sarcoid neuropathy by focusing on electrophysiological and histopathological findings of sural nerve biopsy specimens. We included 18 patients with sarcoid neuropathy who had non‐caseating epithelioid cell granuloma in their sural nerve biopsy specimens. Results: Although electrophysiological findings suggestive of axonal neuropathy were observed, particularly in the lower limbs, all but three patients showed ≥1 abnormalities in nerve conduction velocity or distal motor latency. Additionally, a conduction block was observed in 11 of the 16 patients for whom waveforms were assessed; five of them fulfilled motor nerve conduction criteria strongly supportive of demyelination as defined in the European Academy of Neurology/Peripheral Nerve Society (EAN/PNS) guideline for chronic inflammatory demyelinating polyneuropathy (CIDP). In most patients, sural nerve biopsy specimens revealed a mild to moderate degree of myelinated fiber loss. Fibrinoid necrosis was observed in one patient, and electron microscopy analysis revealed demyelinated axons close to granulomas in six patients. Conclusions: Patients with sarcoid neuropathy may meet the EAN/PNS electrophysiological criteria for CIDP due to the frequent presence of conduction blocks. Based on our results, in addition to the ischemic damage resulting from granulomatous inflammation, demyelination may play an important role in the mechanism underlying sarcoid neuropathy. [ABSTRACT FROM AUTHOR]

Vasculitic neuropathy can present associated with both primary and secondary systemic vasculitis as a result from underlying diseases such as rheumatic diseases and infections, Moreover, confined vasculitis in the peripheral nervous system may be present. Thus, the diagnosis and management of vasculitic neuropathy require multidisciplinary approaches. Current views as well as relevant clinical research on the diagnosis, assessment, and management of vasculitic neuropathy are reviewed to suggest appropriate treatment strategies. We searched PubMed and Google Scholar for reports published between July 2017 and July 2022. For the treatment of vasculitic neuropathy, determining the causative primary disease is important and often requires diagnosis by tissue biopsy. Due to the scarce research on the treatment of vasculitic neuropathy, treatment is empirically based on findings from studies of systemic vasculitides involving other organs, particularly antineutrophil cytoplasmic antibody-associated vasculitis. In addition to conventional glucocorticoids and immunosuppressive agents, complement-targeted therapy, anti-B-cell therapy, and disease-specific molecular targeted therapies have recently gained relevance. Future research is needed to develop new patient-specific therapeutic options. [ABSTRACT FROM AUTHOR]

This study aims to describe electron microscopic findings of vasculitis associated with anti‐neutrophil cytoplasmic antibody (ANCA) and complement. Sural nerve biopsy specimens were obtained from 10 patients with microscopic polyangiitis (MPA), a representative ANCA‐associated vasculitis, and six patients with nonsystemic vasculitic neuropathy (NSVN), who were negative for ANCA but positive for complement deposition. In patients with MPA, attachment of neutrophils to epineurial vascular endothelial cells, migration of neutrophils to the extravascular space via the penetration of the endothelial layer, and release of neutrophil components to the extracellular space were observed. Such neutrophil‐associated lesions were not observed in patients with NSVN. Nonetheless, morphological changes in epineurial vascular endothelial cells, such as increases in cytoplasmic organelles and cytoplasmic protrusions into the vascular lumen, were observed in patients with NSVN. Since these findings were observed where light microscopy‐based findings suggestive of vasculitis (e.g., the disruption of vascular structures and fibrinoid necrosis) were absent, they were considered early lesions that preceded the formation of the so‐called necrotizing vasculitis. In conclusion, this study enabled the visualization of distinctive early ultrastructural lesions associated with ANCA and complement. Further studies are needed to elucidate the molecular basis of the induction of these fine structural changes, which will contribute to the development of targeted therapies based on specific mechanisms of vasculitis. [ABSTRACT FROM AUTHOR]