Neurology® Neuroimmunology & Neuroinflammation最新文献

Background and objectives: In this study, we examine the long-term changes in chronic lesion tissue (CLT) among patients with relapsing-remitting MS (RRMS), focusing on its impact on clinical and radiologic disease progression indicators.

Methods: The study involved 72 patients with multiple sclerosis with at least a 5-year follow-up. Annual assessments used 3D fluid-attenuated inversion recovery (FLAIR), precontrast and postcontrast 3D T1, and diffusion-weighted MRI. Lesion segmentation was conducted using iQ-MS software, while brain structures were segmented using AssemblyNet. Volumetric changes in CLT were tracked using a novel custom-designed pipeline that estimates longitudinal volumetric changes in CLT using serial MRI data.

Results: Throughout the follow-up period, the volume of CLT in the entire cohort increased continuously and steadily, averaging 7.75% ± 8.2% or 315 ± 465 mm³ per year. Patients with expanding CLT experienced significantly faster brain atrophy, affecting both white and gray matter, particularly in the brain's central area. Expanded CLT was also associated with higher and worsening Expanded Disability Status Scale (EDSS) scores, in contrast to the stable CLT group, where EDSS remained unchanged. Sample size calculation for a clinical trial investigating the effect of treatment on slow expansion of chronic lesions demonstrated that a relatively small cohort of patients with RRMS, ranging from 24 to 69 patients per arm, would be required.

Discussion: This study demonstrates that, over a period of up to 5 years, patient-specific enlargement of CLT, when present, progresses at a constant rate and significantly influences brain atrophy and disease progression. In addition, the study underscores CLT as a promising biomarker for RRMS progression and suggests the feasibility of smaller, targeted clinical trials to evaluate treatments aimed at reducing chronic lesion expansion.

A 46-year-old man presented with progressive painful monocular vision loss and left leg paresthesias. Workup demonstrated multifocal demyelinating lesions and CSF-restricted oligoclonal bands. He was diagnosed with multiple sclerosis (MS), but follow-up testing was notable for positive myelin oligodendrocyte glycoprotein-immunoglobulin G (MOG-IgG). We discuss implications and clinical considerations for MOG-IgG positivity in MS.

Background and objectives: A simple, quick, and reproducible procedure for distinguishing multiple sclerosis (MS), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), and neuromyelitis optica spectrum disorder (NMOSD) at inaugural optic neuritis (ION) could be highly valuable in guiding early management.

Methods: We included all adults admitted to the MS center of Marseille for ION between March 2016 and April 2024, with CSF analysis including the kappa free light chain (K-FLC) index. Receiver operating characteristic curves were used to measure the diagnostic ability of the K-FLC index.

Results: Two hundred twenty-seven adults were admitted for ION; 210 (93%) had a K-FLC index measurement. MS was diagnosed in 84 (40%); clinically isolated syndrome suggestive of MS in 77 (36.5%), including 20 with future conversion to MS (CISwc); MOGAD in 26 (12.5%); NMOSD in 13 (6%); and other inflammatory disorders in 10 (5%). A K-FLC index ≥6.7 differentiated MS/CISwc from other diagnoses with specificity 86% and sensitivity 95% (area under the curve [AUC] 0.94). A K-FLC index <4.9 differentiated MOGAD from other diagnoses with specificity 63% and sensitivity 92% (AUC 0.78) and MOGAD from MS/CISwc with specificity 96% and sensitivity 92% (AUC 0.97). Among all patients, 93 (44%) had a K-FLC index <4.9: 24 of these (26%) had MOGAD and 5 (5.5%) MS/CISwc. Among the remaining patients with a K-FLC index ≥4.9 (n = 117), 2 (1.7%) had MOGAD (K-FLC index of 7.9 and 16.2) and 99 (85%) MS/CISwc. Among patients with normal MRI (n = 96), 73 (76%) had a K-FLC index <4.9: 22 of these (30%) had MOGAD, and none showed conversion to MS. Among the remaining patients with a K-FLC index ≥4.9 (n = 23), 2 (8.5%) had MOGAD and 7 (30.5%) showed conversion to MS. The K-FLC index did not differentiate NMOSD from other diagnoses and only moderately differentiated NMO from MS/CISwc (AUC 0.80).

Discussion: The K-FLC index is an accessible biomarker to guide early diagnosis in patients with ION. The probability of MOGAD in patients with ION and a K-FLC index ≥4.9 is low even in case of normal brain/spinal cord MRI.

Classification of evidence: This study provides Class II evidence that for patients with ION, the K-FLC index can distinguish between MS/CISwc and MOGAD.

Background and objectives: Association of human leukocyte antigen (HLA) with anti-aquaporin-4 immunoglobulin G-positive neuromyelitis optica spectrum disorder (AQP4-IgG NMOSD) has been reported. However, this association in the Korean population has not been previously investigated. We aimed to evaluate whether specific HLA subtypes were associated with Korean patients with AQP4-IgG NMOSD and whether the HLA genotype is associated with specific clinical features.

Methods: We compared the HLA subtypes of 122 patients with AQP4-IgG NMOSD with those of 485 (HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1) and 173 (HLA-DPB1) healthy controls. In addition, we compared the clinical features of patients with and without specific HLA genotypes.

Results: The most significant risk allele for AQP4-IgG NMOSD was HLA-DRB1*03:01 (24 patients [19.67%], odds ratio [OR]: 3.997, p_c value = 0.0001). Susceptibility of AQP4-IgG NMOSD was significantly associated with the HLA-DRB1*03:01-DQB1*02:01 (23 patients [18.85%], OR: 3.792, p_c value = 0.0002) and DRB1*12:02-DQB1*03:01 (23 patients [18.85%], OR: 3.402, p_c value = 0.0009) haplotypes. Patients with the DRB1*12:02-DQB1*03:01 haplotype showed more frequent spinal involvement, a higher Expanded Disability Status Scale score at disease-onset nadir, and a shorter time to second attack than patients without this haplotype.

Discussion: In a Korean cohort of patients withAQP4-IgG NMOSD, the HLA-DRB1*12:02-DQB1*03:01 haplotype was associated with disease severity at onset. HLA-DRB1*03:01, broadly reported as a significant susceptibility allele across diverse ethnic groups, showed a significant risk association in Korean patients with AQP4-IgG NMOSD.

Background and objectives: Pediatric onset multiple sclerosis (POMS) leads to optic nerve and retinal damage from optic neuritis (ON) and potential subclinical disease activity. Neuroaxonal retinal damage manifests in peripapillary retinal nerve fiber layer (pRNFL) and macular ganglion cell and inner plexiform layer (GCIP) thinning. Inner nuclear layer (INL) thickness has been suggested to increase with inflammatory activity or after acute ON, and decrease from chronic neurodegeneration. Macular microcysts in the INL have been described in patients with adult MS. The objective of this study was to investigate the INL in a large cohort of POMS as a potential biomarker for evaluation of disease course and therapeutic success.

Methods: For this cross-sectional case-control study, we prospectively recruited 153 patients with POMS and 92 controls, including asymptomatic healthy volunteers and children admitted to the hospital with nonretinal disorders. Optical coherence tomography was performed including intraretinal segmentation. Visual function was determined as best corrected visual acuity (BCVA).

Results: Eyes of children with POMS with prior ON had increased INL thickness (44.31 µm) compared with control eyes (42.96 µm, p = 0.014), whereas pRNFL (83 µm, p < 0.001) and GCIP thickness (68.42 µm, p < 0.001) were reduced compared with control eyes (pRNFL 97 µm, GCIP 78.53 µm). In eyes without history of ON, INL and other layer thicknesses were not different from controls. pRNFL (B = -2, p < 0.001) and GCIP loss (B = -1.6, p < 0.001), but not INL, were associated with worse BCVA. We found macular microcysts in 1 eye of 1 patient with a history of severe ON (0.3%). INL thickness was not associated with age, sex, disease duration, immunotherapy, disability or the MRI parameters T2 lesion count, T2 lesion volume, contrast-enhancing lesions, or contrast-enhancing lesion volume.

Discussion: The INL in POMS shows changes similar to what has been reported in adults, with macular microcysts being much rarer. A lack of cross-sectional association between INL thickness and disease severity may represent the early disease stage with neuroinflammation instead of neurodegeneration being in focus.

Background and objectives: DNA variations in the NF-kappa-B essential modulator (NEMO) gene are linked to incontinentia pigmenti (IP) and also immunodeficiency and autoinflammatory conditions. Some patients with IP present with neonatal vasculitis-like brain changes, although pathogenesis is unclear. We investigated cell-specific gene expression in a neonate with IP, who had encephalopathy, seizures, and vasculitis-like brain changes, and responded to steroid treatment.

Methods: Single-cell RNA (ribonucleic acid) sequencing (scRNAseq), using the HIVE single-cell system, was performed on a neonate with IP, before and after steroid treatment, compared with a sex-matched healthy control toddler.

Results: A total of 20,411 cells were sequenced and clustered into 10 cell types. In IP compared with control, upregulated significant gene set enrichment analysis gene ontology pathways (FDR <0.05) included defense response, complement activation, humoral immune response, and phagocytosis across all cell types. After steroid treatment, these pathways were predominantly downregulated in monocytes and neutrophils. The upregulated genes in IP that became downregulated after steroid treatment were interferon-related genes, oligoadenylate synthases, and immunoglobulin genes.

Discussion: IP-associated loss of NEMO function is associated with a proinflammatory phenotype, that is moderated by steroids. scRNAseq provides a rationale for immune modulation in an n = 1 setting and valuable insights into the pathogenesis and therapeutics of this rare disease.

Background and objectives: Myasthenia gravis (MG) is an autoimmune disease most frequently caused by autoantibodies (auto-Abs) against the acetylcholine receptor (AChR) located at the neuromuscular junction. Thymic follicular hyperplasia is present in most of the patients with early-onset AChR-Ab⁺ MG (EOMG), but its cellular and molecular drivers and development remain poorly understood.

Methods: We constructed a single cell-based transcriptional profile of lymphoid cell types in thymi from 11 immunotherapy-naïve patients with EOMG. Multiplex histology and ELISA were used to determine migration inhibitory factor (MIF) levels.

Results: Within EOMG thymi, we consistently observed 6 distinct clusters of B-cell populations maturing toward germinal center (GC)-associated and Ab-secreting cells, featuring prominent GC activity, as indicated by substantial clonal expansions and cycling B-cell subsets. Cell-cell interactome predictions identified strong interactions between T cells and GC-associated and memory B cells, dominated by B-cell prosurvival signaling through the MIF-CD74 axis. Multiplex histology confirmed abundant expression of CD74 in MG thymic B cells. Circulating MIF levels in EOMG correlated with higher disease severity as assessed by Myasthenia Gravis Foundation of America status.

Discussion: Our data not only illustrate and define hyperplastic thymic niches in MG as favorable environments for pathogenic B-cell proliferation, maturation, and persistence but also suggest that the MIF-CD74 axis should be investigated for potential novel therapeutic targeting in EOMG.

Background and objectives: Abnormal brain MRI is associated with poor outcomes in anti-N-methyl-d-aspartate receptor encephalitis (NMDARE). We aimed to characterize the lesions on brain MRI in NMDARE and to assess the clinical and prognostic associations.

Methods: This retrospective cohort study included patients with NMDARE identified at the French Reference Center for Autoimmune Encephalitis, with at least a one-year follow-up, and with available brain MRI results. In case of brain extralimbic lesion, the image files were reviewed when available. Clinical data were collected from medical records. Multivariable logistic regression analysis was used to study the outcomes at 2-year follow-up; recovery was defined as modified Rankin Scale score ≤1.

Results: Among the 255 patients included, 37 (14.5%) had limbic hyperintensities and 41 (16.1%) had extralimbic lesions that included multiple sclerosis (MS)-like lesions (14/41, 34.1%); extensive lesions (5/41, 12.2%); and poorly demarcated fluffy lesions, either multifocal (10/41, 24.4%) or involving the cerebral cortex or cerebellum (6/41 each, 14.6%). Extralimbic lesions coexisting with limbic lesions (19/41 patients, 46.3%) were mostly fluffy lesions (11/19, 57.9%). Ten patients had overlapping demyelinating syndromes: 4 with MS, 4 with myelin oligodendrocyte glycoprotein-associated disorder, and 2 with neuromyelitis optica spectrum disorder; all had MS-like (7/10 patients) or extensive (3/10 patients) lesions, and none had fluffy lesions. Extralimbic lesions were associated with symptoms nontypical for NMDARE (23/41, 56.1%, p < 0.001), especially cerebellar ataxia (17/41, 41.5%) and motor impairment (12/41, 29.3%). At 2 years, patients with MS-like or extensive lesions had a lower recovery rate (5/12, 41.7%, and 1/4, 25%, respectively) compared with the patients without extralimbic lesions (124/162, 76.5%; p = 0.014 and p = 0.047, respectively). In multivariable analysis, MS-like lesions, but not hippocampal nor fluffy lesions, were associated with absence of recovery at 2 years (adjusted OR 0.1, 95% CI 0.03-0.42, p = 0.002; extensive lesions [n = 4] not included in the analysis).

Discussion: Brain MRI lesions in NMDARE include limbic hyperintensities and 3 patterns of extralimbic lesions, which are associated with nontypical NMDARE symptoms. Moreover, MS-like and extensive lesions, but not fluffy nor hippocampal lesions, are associated with overlapping demyelinating syndromes and poor clinical outcomes at 2 years. These findings can have practical implications on the monitoring of patients with NMDARE.

Objectives: Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) haploinsufficiency is a rare genetic condition characterized by development of immune cytopenia, hypogammaglobulinemia, and/or lymphoproliferative disorder, as well as multiple autoimmunity. Treatment with abatacept was shown to alleviate autoimmune conditions, yet its long-lasting impact on bone marrow function remains undetermined.

Methods: We here present the case of a now 39-year-old woman with CTLA-4 haploinsufficiency with predominant CNS affection, yet multiorgan autoimmunity and lymphopenia. We conducted single-cell RNA sequencing (scRNA-seq) of peripheral mononuclear blood cells before and after abatacept induction.

Results: After several high-efficacy immunosuppressive treatments with little-to-no response, she started abatacept in 2017 and experienced ongoing remission including resolution of pre-existing immune cytopenia and hypogammaglobulinemia. Using scRNA-seq, we were able to demonstrate reconstitution of peripheral B cells accompanied by reduction of CD8⁺ T cells. CD4⁺ and CD8⁺ T cells were characterized by downregulation of pathways involved in activation of innate immune cells.

Discussion: Our findings demonstrate long-lasting resolution of lymphopenia after abatacept treatment in CTLA-4 haploinsufficiency despite severity and duration of symptoms. Thus, abatacept should be considered throughout before stem cell transplantation also in CTLA-4 haploinsufficiency with severe symptoms.

Classification of evidence: As a single report without controls, this report provides class IV evidence that abatacept might revert lymphopenia in patients with CTLA-4 haploinsufficiency.