Neurology® Neuroimmunology & Neuroinflammation最新文献

Objectives: The aim of this study was to analyze changes in hospital incidence cases and disease severity of autoantibody-associated autoimmune encephalitis (AE) during the COVID-19 pandemic compared with the prepandemic period.

Methods: A retrospective multicenter study analyzed data from 24 centers within the German Network for Research on Autoimmune Encephalitis (GENERATE). Patients with a new diagnosis of definite antibody-positive autoimmune encephalitis from 2017 to 2022 were included and divided into prepandemic (2017-2019) and pandemic (2020-2022) periods.

Results: Among 392 patients, 227 were diagnosed before and 165 during the pandemic (mean 9.5 vs 6.9 per site, p = 0.04). A reduction was observed in cases with antibodies to neuronal surface antigens (174 vs 122 cases; mean 7.3 vs 5.1 per site, p = 0.02), while cases with antibodies against intracellular antigens remained stable (p = 0.40). No differences were observed in disease severity, age, or sex distribution between periods.

Discussion: This study provides clinical data on antibody-positive AE before and during the COVID-19 pandemic. The findings do not support the hypothesis that SARS-CoV-2 infection triggers autoantibody-associated AE or increases disease severity.

Objectives: Amyloid β-related angiitis (ABRA) is a rare, inflammatory vasculopathy resulting from intravascular amyloid deposition. We describe a refractory presentation of ABRA and its response to tocilizumab.

Methods: Single-patient, biopsy-confirmed ABRA with serial MRI and clinical outcomes. Treatments included high-dose IV methylprednisolone, hyperosmolar therapy, cyclophosphamide, and escalation to tocilizumab.

Results: A 70-year-old woman presented with seizure and focal deficits. Initial MRI showed multifocal subcortical T2/FLAIR hyperintensities with cortical microhemorrhages without enhancement. Despite steroids, interval imaging showed progressive vasogenic edema, new leptomeningeal enhancement, and rising microhemorrhage burden. She developed severe headache and worsening hemiparesis; CT/MRI demonstrated marked edema with subfalcine/uncal herniation. Biopsy confirmed ABRA. Edema did not improve with steroids, maximal hyperosmolar therapy, or cyclophosphamide. After tocilizumab, MRI within 48 hours showed reduced edema and midline shift with near-resolution of sulcal enhancement; hemiparesis markedly improved without hemicraniectomy.

Discussion: We expand the phenotypic spectrum of ABRA by presenting a herniation syndrome associated with fulminant disease and a clear clinicoradiographic natural history. The precipitous progression of microhemorrhage accrual suggests a pathophysiologically distinct mechanism of disease from cerebral amyloid angiopathy-related inflammation. IL-6 receptor blockade was associated with rapid clinical and radiographic improvement and stabilization, supporting prospective evaluation of tocilizumab in amyloid-related neuroinflammatory disorders.

Background and objectives: Multiple sclerosis (MS) is a chronic progressive, demyelinating autoimmune CNS disease. Autoantibodies to the motif P-(SA)-x-(SGA)-R-(SN)-(LRKH) are a class of predictive markers specific to MS that could add to emerging diagnostic criteria for MS. In this study, we describe the discovery of an MS patient-derived monoclonal antibody (mAb) specific to this motif from memory B cells, and we develop a proof-of-principle autoantibody test to report the prevalence of seropositivity, predict MS early in disease, and identify underlying tolerance-breaking antigens in Epstein-Barr virus (EBV) and the CNS.

Methods: Peptide tetramers containing the motif were used to screen activated memory B cells, collected from a patient with MS, on the Beacon Optofluidic system. A mAb to the motif and serum samples from clinically diagnosed patients with MS and healthy controls were used to qualify a Luminex xMAP autoantibody serologic test. Antigen discovery methods included phage-immunoprecipitation sequencing (PhIP-Seq), biolayer interferometry, human protein microarrays, isoelectric focusing gels and blots, and immunofluorescence staining of mouse brain cell cultures.

Results: A mAb cloned from an MS patient's memory B cells binds diverse peptides containing the MS signature motif with affinities ranging from 2 to 25 nM. Consensus peptides defined by alanine scanning PhIP-Seq were used to develop an autoimmune IgG test with a sensitivity equivalent to 0.5 ng/mL mAb, a precision of <11%, and a positivity rate of 11% among a cohort of 179 patients with MS (n = 91 healthy and n = 49 unrelated neurologic disease serum samples were negative). Utility of the assay for prodromal MS was demonstrated using retrospective, longitudinal samples from cases in the Department of Defense Serum Repository. The mAb identified EBV tegument protein BRRF2 as a tolerance-breaking antigen with nanomolar affinity, containing the motif with reactivity to oligoclonal bands in CSF from MS signature-positive patients. Immunocytochemical staining of mixed mouse neuronal cells showed the dominant cross-reactive human antigen to be vimentin.

Discussion: We describe a test for MS signature autoantibodies that could be used to support MS diagnosis, prodromal research, and early interventions. The integration of this assay with other emerging biomarkers will advance progress toward a combined predictive risk score for MS.

Background and objectives: JC virus (JCV) reactivation causing progressive multifocal leukoencephalopathy (PML) is a complication in patients with multiple sclerosis (MS) treated with disease-modifying therapies (DMTs). Although natalizumab (NTZ) is most frequently involved, PML also occurs less commonly with sphingosine-1-phosphate receptor modulators (S1P-RM), dimethyl fumarate (DMF), and ocrelizumab. This study aimed to identify factors predicting worse outcomes, focusing on the influence of PML-immune reconstitution inflammatory syndrome (PML-IRIS), plasma exchange (PlEx), corticosteroids, and DMT reintroduction.

Methods: This retrospective multicenter cohort study analyzed patients with MS who had JCV-associated pathology (PML or granule cell neuronopathy) from 42 centers (2009-2022). The primary outcome was disability at 12 months, measured by the modified Rankin Scale (mRS). Multivariable analyses identified predictors of poor outcomes, PML-IRIS development, and recurrent MS activity.

Results: Of 96 identified patients, 94 were analyzed. Most cases occurred under NTZ (77%), followed by S1P-RM (22%) and DMF (1%). Twelve-month survival was 91.5%, with a median mRS of 3 [IQR: 2-4]. Multivariable analysis showed that higher pre-PML disability (OR: 1.95 [95% CI 1.46-2.60], p < 0.001), elevated CSF JCV viral load (OR: 2.45 [95% CI 1.55-3.87], p < 0.001), and symptomatic presentation at onset (OR: 3.93 [95% CI 1.23-12.55], p = 0.021) were associated with worse outcomes. Conversely, PML-IRIS was associated with better outcomes (OR: 0.28 [95% CI 0.09-0.86], p = 0.025). PlEx and corticosteroid use had no negative effect.

Discussion: This study provides valuable insights into the management of iatrogenic PML in patients with MS. The findings may guide clinicians in making informed decisions, particularly regarding the use of PlEx, corticosteroids, and the management of PML-IRIS.

Background and objectives: A subset of patients with NMDAR encephalitis is resistant to first-line and second-line immunotherapy and requires prolonged intensive care. The clinical definition of refractory, intensive care-dependent NMDARE (RI-NMDARE) is lacking, and its frequency, risk factors, and outcomes are unknown. The aim of this study was to define RI-NMDARE and compare its clinical and biomarker characteristics with those of severe NMDARE.

Methods: This was a retrospective cohort study including patients with nonherpetic NMDARE admitted to intensive care units (ICUs) and diagnosed at the French National Reference Center, from 2005 to 2023. Favorable outcome was defined as a modified Rankin Scale (mRS) score < 2 at 24 months from onset.

Results: The study included 216 ICU-admitted patients with NMDARE (81% female, median age 21 years). Nearly 90% of patients were discharged from ICU within 3 months after initiation of second-line therapy; the remainder were defined as patients with RI-NMDARE (26/216 patients, 12%; 92% female; median age, 24 years-none younger than 15 years; median ICU stay, 5.7 months). Compared with the rest of the cohort, patients with RI-NMDARE were more frequently of non-White ethnicity (14/25, 56%, vs 55/156, 35%; p = 0.047) and had more frequent mechanical ventilation (26/26, 100%, vs 116/183, 63%; p < 0.001); ovarian teratoma (62% vs 22%, p < 0.001); and combination of seizures, hyperkinetic movement disorders, and dysautonomia (85% vs 33%, p < 0.001). They also had shorter times from onset to ICU admission (median 7 vs 14 days; p = 0.002) and significantly higher median CSF cell counts (72 vs 25/mm³, p < 0.001), CSF antibody titers (1,280 vs 60, p < 0.001), and serum neurofilament levels (230 vs 144 pg/mL, p = 0.028). Despite increased use of the cyclophosphamide-rituximab combination (85% vs 17%, p < 0.001) and earlier immunotherapy (median 10 days, range 1-82 vs 19 days, range 1-304; p = 0.001), patients with RI-NMDARE had poorer outcomes (mRS score ≥ 2 at 24 months, 72% vs 39%; p = 0.004) and higher mortality (19% vs 6.7%, p = 0.046) compared with non-RI-NMDARE patients.

Discussion: RI-NMDARE represents a distinct, high-risk subgroup with a severe clinical profile marked by rapid disease progression; the triad of seizures, movement disorders, and dysautonomia; and elevated biomarkers. RI-NMDARE is associated with poorer outcomes, underscoring the need for early recognition and tailored therapeutic strategies.

Background and objectives: Myasthenia gravis (MG) is an autoimmune disorder primarily caused by antibodies targeting neuromuscular junction proteins, particularly the acetylcholine receptor and the muscle-specific tyrosine kinase. However, 10%-20% of patients with MG are double-seronegative (dsMG). Antibodies against low-density lipoprotein receptor-related protein 4 (LRP4-IgG) have been found in a variable proportion of dsMG cases, but their frequency and clinical relevance remain unclear because of differences in assay methodologies and study populations. In this study, we assessed the frequency of LRP4-IgG in patients with suspected MG using different cell-based assay (CBA) protocols.

Methods: In this multicenter observational study, we enrolled consecutive patients presenting with symptoms suggestive of MG. LRP4-IgG was tested by 2 centers using 3 different CBAs: live (l-CBA), methanol-fixed (mf-CBA), and paraformaldehyde-fixed (pf-CBA). Patients were classified as having MG or other disorders (ODs). Positive samples were cross-tested between centers.

Results: Among 684 patients (302 with MG, 382 with ODs), LRP4-IgG was detected by mf-CBA in 2% (6/302) of MG cases and in 0.52% (2/382) of OD cases. Among patients with MG, 3.9% (4/102) of dsMG and 1% (2/200) of seropositive patients tested positive. Only 50% of mf-CBA-positive cases were confirmed by pf-CBA, and none were detected by l-CBA. Cross-center testing showed partial reproducibility.

Discussion: LRP4-IgG detection in suspected MG is rare and inconsistent across assays, suggesting that routine testing is not currently warranted and that these antibodies are at present of limited diagnostic value. These findings highlight the need for standardized, validated LRP4-IgG assays. Future studies should focus on direct comparison and harmonization of testing protocols to clarify the clinical utility of LRP4-IgG testing.

Background and objectives: Multiple sclerosis (MS) is characterized by CXCR3⁺ memory B cells that infiltrate the CNS to mature into antibody-secreting cells (ASCs). It remains elusive how to benefit from this disease hallmark as a prognostic tool. We aimed to uncover markers that reflect B-cell entry and maturation in the CNS and, on that basis, explore associations with response to high-efficacy MS therapies.

Methods: Ex vivo single-cell technologies were applied to blood samples and postmortem CNS suspensions from MS and control donors, either treated or untreated. In addition, in vitro assays were performed on blood samples from healthy individuals to functionally asses B-cell activation, differentiation, and transmigration.

Results: Single-cell RNA sequencing revealed ITGB1 (integrin β1/CD29) as a major discriminator of CXCR3⁺ memory B cells in blood, which was validated using spectral flow cytometry. CD29⁺CXCR3⁺ memory B cells preferentially crossed a brain microvascular endothelial layer and were highly receptive to T-cell help to become ASCs in vitro. In contrast to blood, CD29 and CXCR3 coexpression was restricted to ex vivo ASCs derived from CSF, meninges, and brain tissue of people with MS, which was supported by enhanced CD29 upregulation on in vitro-differentiated ASCs. While CD29 was downregulated on CXCR3⁺ memory B cells that accumulated in the blood of natalizumab-treated patients, CD29 levels were only reduced on CXCR3⁺ memory B cells that repopulated in cladribine-treated patients without early disease activity.

Discussion: These findings put forward CD29 as a putative marker on CXCR3⁺ precursors of CNS-residing ASCs for predicting treatment responses in MS.

Background and objectives: Chronic immune activation is a hallmark of latent viral infections and autoimmune disorders, profoundly shaping immune cell phenotypes, including CD4⁺ cytotoxic T lymphocytes (CD4 CTL). The mechanisms underlying CD4 CTL development remain elusive, although antigenic triggers and the local microenvironment are thought to influence their phenotype. In this study, it was investigated if CD4 CTL induced under different circumstances exhibit phenotypic differences.

Methods: Using single cell multiomics, we analyzed CD4 CTL from healthy cytomegalovirus (CMV)-seropositive donors, patients with CMV-seronegative relapsing-remitting multiple sclerosis (RR-MS) (autoimmune trigger), and patients with CMV-seropositive RR-MS (combination of viral and autoimmune trigger).

Results: Our findings reveal that the heterogeneous pool of CD4 CTL encompasses distinct subsets with divergent expression of proinflammatory, cytotoxic, and migratory markers. Moreover, we identified a pathogenic CD4 CTL subset coexpressing the MS-associated transcription factor eomesodermin (EOMES) and the migratory receptor class I-restricted T-cell-associated molecule, which accumulates in MS lesions and demonstrates resistance to natalizumab treatment.

Discussion: CMV was implicated as a dominant driver of development of highly cytotoxic CD4⁺ T cells, as these cells were markedly enriched in CMV-seropositive individuals. This comprehensive phenotypic atlas of CD4 CTL advances our understanding of their development and highlights potential targets for diagnosing, treating, and preventing MS progression.