Neurology® Neuroimmunology & Neuroinflammation最新文献

Background and objectives: Fc receptor-like 5 (FCRL5) is an IgG-binding receptor frequently reported to be highly expressed on double-negative and atypical memory B cells, both of which are frequently expanded in inflammatory conditions. However, its expression profile in multiple sclerosis (MS) remains unclear. This study aims to characterize FCRL5 expression in CSF, serum, and peripheral blood mononuclear cells (PBMC) of patients with MS and to define the phenotypic and transcriptional features of FCRL5⁺ B cells in MS.

Methods: A proximity extension assay-based proteomic analysis was conducted on the CSF of patients with relapsing-remitting MS (RRMS, n = 59) and controls (n = 29). The observed FCRL5 upregulation was validated using single-molecule array analysis in a cohort comprising patients with RRMS (n = 40), controls (n = 30), and individuals with other inflammatory neurologic diseases (OIND, n = 20). Serum FCRL5 levels were also assessed in a cohort of patients with MS characterized by 3T MRI (n = 58). In addition, flow cytometry-based techniques and RNA sequencing were performed on PBMC from patients with RRMS and controls to investigate the phenotype and transcriptional profiles of FCRL5⁺ B cells. Finally, the effect of Bruton tyrosine kinase inhibitors (BTKi) on FCRL5 regulation was also evaluated in vitro.

Results: FCRL5 was significantly upregulated in the CSF of patients with RRMS compared with that in controls and OIND. Elevated CSF FCRL5 levels were associated with an increased risk of new brain lesions within 24 months. Serum FCRL5 levels were not correlated with CSF measurements but were inversely correlated with the cortical and juxtacortical lesion burdens. Moreover, flow cytometry analysis revealed that peripheral CD19⁺FCRL5⁺ B cells of patients with RRMS differed from those of controls by their strong CD11c expression. The transcriptional profiles of CD19⁺CD11c⁺FCRL5⁺ cells also differed significantly between the 2 groups, characterized by reduced expression of humoral response genes and enhanced inflammatory signaling. In addition, FCRL5 regulation was found to be BTK-dependent.

Discussion: The soluble form of FCRL5 can be measured in the CSF and could serve as a promising biomarker for MS diagnosis and disease activity prediction. In addition, this study highlights that CD19⁺CD11c⁺FCRL5⁺ B cells in MS display a distinct transcriptional profile compared with controls.

Background and objectives: The aim of this study was to elucidate the clinical spectrum and mechanisms of autoimmune nodopathy (AN) with autoantibodies against leucine-rich repeat leucin-rich glioma inactivated 1 (LGI) family member 4 (LGI4) localized at juxtaparanodes and satellite glia in the dorsal root ganglion.

Methods: We developed a live cell-based assay for LGI4-immunoglobulin (Ig) G and surveyed 131 patients with chronic inflammatory demyelinating polyneuropathy. LGI4-IgG, anti-LGI4 antibody-negative CIDP-IgG, or healthy control (HC)-IgG were applied to Schwann cells, and cell proliferation was assayed using 5-bromo-2'-deoxyuridine labeling. Quantitative real-time PCR was used to assess the expression of Krox20 and Prx, both of which independently control peripheral nerve myelination. LGI4-IgG or HC-IgG was intraneurally injected into mouse sciatic nerves, and the effects were immunohistochemically and morphometrically assessed.

Results: Eight anti-LGI4 antibody-positive (LGI4⁺) patients were identified; dominant tissue-binding IgG subclasses were IgG4 in 4 patients and IgG2 and IgG3 in 2 patients each. Patients had a relatively old onset age (median 72 years, range 41-90 years). Four patients had acute/subacute monophasic courses, and 4 had chronic progressive/relapsing courses. Predominant symptoms/signs were motor weakness (8 cases), muscle atrophy (4), deep and superficial sensory impairment (8 and 7, respectively), Romberg sign (4), and hand/finger tremor (5). CSF showed extremely high protein levels (median 253 mg/dL). Three chronic cases had nerve hypertrophy. IVIg and efgartigimod were partially (7/7 patients) and markedly (1/1 patient) effective, respectively. Notably, 1 chronic patient with predominant tissue-binding LGI4-IgG2 but without LGI4-IgG4 showed a moderate reduction in myelinated fibers with endoneurial edema, numerous onion bulbs, and few inflammatory cell infiltrates in the biopsied sural nerve. Electron microscopy demonstrated onion bulb formations around the axons and subtle detachment of myelin terminal loops from axonal membranes in the paranodes. In Schwann cell culture, proliferation was significantly higher, and Krox20 but not Prx mRNA levels were lower after incubation with LGI4-IgG from chronic (but not acute-onset) cases compared with HC-IgG incubation. With intraneural injection, both LGI4-IgG4 and LGI4-IgG2 deposited mainly at the nodes extending toward the paranodes and caused nodal/paranodal alterations.

Discussion: LGI4⁺ AN manifests as acute/subacute monophasic and chronic progressive/relapsing diseases, sometimes exhibiting nerve hypertrophy with onion bulbs through nonmyelinating Schwann cell proliferation.

Background and objectives: Intrathecal synthesis of immunoglobulin G (IgG) is a key feature of multiple sclerosis (MS) and a prognostic marker for the disease course. Although previous studies identified 2 genetic regions-the major histocompatibility complex (MHC) region on chromosome 6 and the immunoglobulin heavy chain constant (IGHC) locus on chromosome 14-associated with intrathecal IgG synthesis in MS, the genetic underpinnings remain insufficiently understood.

Methods: We conducted a genome-wide association study on intrathecal IgG synthesis using the IgG index to identify individuals with (≥0.7) or without (<0.7) quantitative intrathecal synthesis. We used logistic regression models adjusting for sex, age, and population structure. We performed secondary analyses to examine associations between identified loci and the extent of intrathecal IgG synthesis and the presence and extent of intrathecal immunoglobulin A and M synthesis. We further conducted association analyses for imputed human leukocyte antigen alleles and analyzed whether a higher genetic burden for MS risk-quantified through polygenic risk scores-is associated with intrathecal IgG synthesis.

Results: In the discovery cohort (n = 3,934), we identified a novel genome-wide significant association of the intronic variant rs844586 (p = 1.48 × 10^-8) in the sterile alpha motif domain containing 5 (SAMD5) gene on chromosome 6, with intrathecal IgG synthesis. We could confirm this association in a replication cohort (n = 1,094) and demonstrated that it is independent of a previously described association signal at the MHC region. In a subset (n = 1,413), we further identified rs1407 as a potential causal variant (p = 3.80 × 10^-11, posterior inclusion probability = 0.92) for the previously reported association signal at the IGHC locus with the extent of intrathecal IgG synthesis. In addition, we demonstrated that a higher genetic burden for MS susceptibility, both within and outside of the MHC region, is associated with a higher likelihood of and a more pronounced intrathecal IgG synthesis.

Discussion: Our study revealed a previously unknown association between an intronic variant in SAMD5 with intrathecal IgG synthesis and identified a potential causal variant within the IGHC locus. It further provides evidence for possible effects of known MS risk variants on disease severity through their effect on the intrathecal humoral immune response, a prognostic marker for the disease course.

Background and objectives: Anti-Ma2 encephalitis is a rare autoimmune paraneoplastic syndrome that can present as secondary narcolepsy due to hypothalamic involvement.

Methods: We present a case of anti-Ma2 encephalitis in which polysomnography was key to suspect the final diagnosis.

Results: A 72-year-old man presented with progressive hypersomnia and recurrent falls, initially misinterpreted as secondary to obstructive sleep apnea and cardiogenic syncope, respectively. Symptoms continued to worsen, prompting hospital admission. Video-polysomnography revealed a previously unreported sleep pattern, characterized by an abnormally increased proportion of REM sleep (approximately 3 times the expected), with sleep-onset REM periods occurring every time sleep was resumed after nocturnal awakenings. In addition, non-REM sleep was undifferentiated, without sleep spindles, K complexes, or slow-wave sleep. The recurrent SOREMPs raised suspicion of secondary narcolepsy. MRI showed T2 hyperintensities in different brain regions, including the hypothalamus, and CSF analysis confirmed anti-Ma2 antibodies and decreased hypocretin-1 levels. Symptoms only partially improved after immunotherapy, and malignancy screening remained inconclusive.

Discussion: This case illustrates the diagnostic challenge of autoimmune encephalitis, especially in the older population, and adds to the growing evidence on the value of sleep studies in these conditions. We describe a unique polysomnography pattern in anti-Ma2 encephalitis that could guide the diagnosis of this entity.

Background and objectives: Myopathy is one of the most common neurologic immune-related adverse events (irAEs) reported after treatment with immune checkpoint inhibitor (ICI) cancer immunotherapies. Current knowledge on disease course relates to short-term outcomes, and long-term outcome data are lacking. The aim of this study was to evaluate the long-term outcomes of patients with ICI-related myopathy.

Methods: We reviewed Mayo Clinic patients diagnosed with ICI-related myopathy between 2013 and 2024 with at least 6 months of follow-up; we compared them with patients who died because of myopathy within 2 months from disease onset.

Results: Twenty-three patients were identified; the median follow-up duration was 13 months (range 6-76). The median age at presentation was 73 years (range 34-87), and 57% were male. The most common presentations were ocular involvement (78%, including oculomotor and ptosis), followed by proximal limb (74%), axial (61%), and bulbar (48%) weakness. Myocarditis was present in 35%. At disease nadir, 43% had an irAE grade >2. All patients were treated with corticosteroids; 61% received additional immunosuppressive/immunomodulatory treatment in the acute setting. The median treatment duration was 5 months (range 1-17). At the last follow-up, 87% of patients had a favorable outcome (irAE grade ≤2), yet residual symptoms/signs were common (48%). Gradual improvement was observed in most patients, even after immunosuppressive/immunomodulatory treatment was discontinued. The only patient with a truly refractory course had biopsy findings of nemaline rods. Compared with patients with long-term follow-up, patients who died within 2 months (N = 9) were more commonly men (57% vs 100%, p = 0.03) and more likely to have bulbar or axial involvement (p = 0.01 and p = 0.04, respectively).

Discussion: Approximately half of the patients with ICI-related myopathy and long-term follow-up had some residual symptoms/signs, despite good functional outcomes. Symptoms continue to improve over 12 months regardless of immunosuppressive/immunomodulatory treatment duration. Male sex and axial and bulbar symptoms/signs were all associated with a terminal disease course. A prolonged refractory disease course might suggest an atypical pathology.

Objectives: To report a case of paraneoplastic motor neuron disease (MND) with a favorable outcome after cancer treatment.

Methods: Clinical, electrophysiologic, radiologic, and serum/CSF study of a patient with brachial amyotrophic diplegia/flail-arm syndrome (BAS/FAS).

Results: A 68-year-old man presented with a subacute-onset upper limb weakness and atrophy evocative of BAD/FAS. Electrodiagnostic study (EDX) confirmed MND; CSF examination found oligoclonal bands and elevated neurofilament light chains (NfL). A prostate adenocarcinoma was concomitantly diagnosed in a context of dysuria and elevated prostate-specific antigen level. One month after onset of cancer treatment (double hormonotherapy), the patient's impairment started to improve. Subsequently, the muscle denervation signs on EDX disappeared and CSF NfL levels decreased. At last follow-up visit, 2 years after onset, he was asymptomatic and unimpaired. Anti-ankyrin-3 (Ank3) autoantibodies were detected in the CSF by tissue-based immunofluorescence and confirmed by cell-based assay.

Discussion: We herein describe an original case of subacute-onset BAD/FAS with evidence of CSF inflammatory changes, autoantibodies of unknown significance, and simultaneous diagnosis of prostate cancer suggesting a possible paraneoplastic neurological syndrome (PNS). The outcome was remarkably favorable after hormonotherapy. Even in the absence of usual onconeural antibodies, MND may be encountered among PNS, and their prognosis is not always poor.

Background: Autologous chimeric antigen receptor (CAR) T-cell therapy has recently gained interest in the treatment of rheumatic and neuroimmunologic diseases.

Methods: We report a 62-year-old female patient with a 14-year history of treatment-refractory anti-GAD-positive stiff-person syndrome (SPS) and concomitant anti-AChR-positive myasthenia gravis. Despite a relatively stable disease course in the first 8 years, SPS dramatically progressed afterward. In 2023, she was able to walk less than 10-15 m and suffered from severe persistent stiffness in the left arm superimposed with painful muscle spasm attacks (MSAs). Numerous immunotherapies, including intravenous immunoglobulins, plasma exchange, steroids, azathioprine, and rituximab, were ineffective. Consequently, she was escalated to compassionate use of autologous anti-CD19 CAR T-cell therapy (KYV-101).

Results: From the third month post-CAR-T, we observed a substantial improvement in walking distance, pain, anxiety, and MSAs in the arm. By the sixth month, she was able to walk 500 m. The anti-GAD titers declined from 1:320 to 1:32. Side effects included grade 2 cytokine release syndrome and moderate leukopenia, without serious infections.

Discussion: CAR T-cell therapy was effective at mitigating SPS symptoms, despite the long history and severe refractory disease course in our patient. Controlled trials are needed to evaluate its potential in SPS.

Epstein-Barr virus (EBV) is a very common herpesvirus that infects more than 90% of the general population. Epidemiologic data indicate that EBV is a requisite risk factor for the development of multiple sclerosis (MS); however, the mechanisms by which EBV contributes to MS pathogenesis are unclear. In this review, we discuss how EBV alters the functions of B cells, its primary cellular reservoir, and the associated dysregulation of anti-EBV immunity in patients with MS. We comprehensively explore the evidence for different potential mechanisms by which EBV may lead to the development of MS, including the so-called driver and hit-and-run models. Finally, we discuss key outstanding scientific questions that must be addressed to advance not only our understanding of the role of EBV in MS pathology but also the development of novel disease therapies.

Background and objectives: Beta-synuclein (beta-syn), synaptosomal-associated protein 25 (SNAP-25), and neurogranin are CSF biomarkers of synaptic damage, which have been poorly investigated in non-neurodegenerative neurologic diseases. In this study, we examined the diagnostic and prognostic role of these markers compared with the neuroaxonal damage marker neurofilament light chain protein (NfL) in infectious and autoimmune inflammatory neurologic diseases (IINDs and AINDs).

Methods: This cohort study included CSF samples from patients with different etiologies of IIND (varicella-zoster virus, herpes simplex virus, tick-borne meningoencephalitis, bacterial meningitis/(meningo)encephalitis, neuroborreliosis, or other/unknown etiology) or AIND (autoimmune encephalitis or other etiology) as well as controls.

Results: A total of 123 patients with IINDs (mean age 55.23 ± 18.04 years, 43.2% female), 22 with AINDs (age 60.41 ± 16.03 years, 81.8% female), and 95 controls (age 52.39 ± 17.94 years, 56.9% female) were enrolled. Compared with the control group, participants with IINDs and AINDs showed higher concentrations of beta-syn (p < 0.001 and p = 0.038, respectively), neurogranin (p = 0.039 and p = 0.002, respectively), and NfL (p < 0.001 and p = 0.001, respectively), with no differences between the 2 latter groups. Overall, synaptic markers and NfL demonstrated poor-to-moderate diagnostic accuracy in discriminating between diagnostic groups (area under the curve 0.366-0.809). All synaptic biomarkers were elevated in participants with IINDs presenting with altered mental status (beta-syn, p < 0.001; SNAP-25, p = 0.002; and neurogranin, p = 0.008), seizures (beta-syn, p = 0.013; SNAP-25, p = 0.005; and neurogranin, p = 0.004), and inflammatory changes on neuroimaging (beta-syn, p = 0.016; SNAP-25, p = 0.029; and neurogranin, p = 0.007). Participants with AINDs requiring intensive care showed higher levels of beta-syn (p = 0.033) and NfL (p = 0.002). Participants with IINDs with a poor functional status (modified Rankin Scale [mRS] scores of 3-6) exhibited higher concentrations of beta-syn (p < 0.001), SNAP-25 (p = 0.022), neurogranin (p = 0.004), and NfL (p < 0.001) compared with those with mRS scores of 0-2. Accordingly, higher levels of synaptic markers were associated with poorer short-term outcomes in patients with IINDs, but not in those with AINDs.

Discussion: Elevated CSF levels of beta-syn, neurogranin, and NfL may suggest a common pattern of synaptic and neuroaxonal damage in both IINDs and AINDs. Although these biomarkers have limited value in distinguishing between different diseases, they are associated with clinical severity and with short-term outcome, particularly in patients with IINDs.