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.

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: 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: 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.

Background and objectives: Invasive procedures may delay the diagnostic process in multiple sclerosis (MS). We investigated the added value of serum neurofilament light chain (sNfL), glial fibrillary acidic protein (sGFAP), chitinase-3-like 1 (sCHI3L1), and the immune responses to the Epstein-Barr virus-encoded nuclear antigen 1 to current MS diagnostic criteria.

Methods: In this multicentric study, we selected patients from 2 prospective cohorts presenting a clinically isolated syndrome (CIS). Patients were classified as (1) not presenting dissemination in space (DIS) nor dissemination in time (DIT) (noDIS and noDIT); (2) presenting DIS without DIT (DIS and noDIT); and (3) presenting both (DIS and DIT), which were used as a reference. sNfL, sGFAP, and sCHI3L1 levels were measured with single-molecule array immunoassays and EBNA1-specific IgG levels with ELISA. Biomarker levels were compared between groups using linear regression models. Receiver operating characteristic curve analyses and Youden Index were used to determine cutoff values associated with MS diagnosis during follow-up.

Results: We included 181 patients (66.3% females, mean [SD] age of 35.0 [9.7] years). At baseline, 25 (13.8%) were classified as noDIS and noDIT, 62 (34.3%) as DIS and noDIT, and 94 (51.9%) as DIS and DIT. Only sNfL Z-scores discriminated between groups (DIS and DIT vs DIS and noDIT [p = 0.002], DIS and DIT vs noDIS and noDIT [p < 0.001], and DIS and noDIT vs noDIS and noDIT [p = 0.026]). In noDIS and noDIT patients (median interquartile range [IQR] follow-up of 8.1 [5.0-11.7] years), high sNfL Z-scores best predicted MS diagnosis (specificity [SP] and 95% CI of 93.3% [68.1-99.8] and positive predictive value [PPV] of 87.5% [47.3-99.7]). Among DIS and noDIT patients (median [IQR] follow-up of 6.8 [4.0-9.1] years), high sNfL Z-scores best predicted MS diagnosis (SP of 80% [28.4-99.5] and PPV of 97.3% [85.8-99.9]) without considering oligoclonal band (OB) status. In the subset of patients of this group with negative OBs, a combination of high sNfL Z-scores and sGFAP levels predicted MS diagnosis (SP of 100% [39.8-100] and PPV of 100% [54.1-100]).

Discussion: These results suggest that sNfL and sGFAP may be incorporated in particular scenarios to diagnose MS in patients with CIS not fulfilling current diagnostic criteria.

Background and objectives: Levels of activated complement proteins in the CSF are increased in people with multiple sclerosis (MS) and are associated with clinical disease severity. In this study, we determined whether complement activation profiles track with quantitative MRI metrics and liquid biomarkers indicative of disease activity and progression.

Methods: Complement components and activation products (Factor H and I, C1q, C3, C4, C5, Ba, Bb, C3a, C4a, C5a, and sC5b-9) and liquid biomarkers (neurofilament light chain, glial fibrillary acidic protein [GFAP], CXCL-13, CXCL-9, and IL-12b) were quantified in the CSF of 112 patients with clinically isolated syndromes and 127 patients with MS; longitudinal MRIs according to a standardized protocol of the Swiss MS cohort were assessed. We used multivariable models to analyze associations of the 12 complement parameters as individual independent variables and longitudinal brain volumes, T2-weighted (T2w) lesion volumes, contrast-enhancing (CELs) and paramagnetic rim lesions (PRLs), and molecular biomarkers as dependent variables, respectively.

Results: Strongest associations with accelerated brain atrophy were found for C4a: doubling of C4a CSF levels was associated with an additional brain volume loss of -0.24% (95% CI -0.31% to -0.16%; p < 0.0001) per year, followed by Ba and C3a (-0.22% [-0.29% to -0.15%]) and -0.13% ([-0.21 to -0.06]; both p < 0.001). Doubling of C3a, Ba, and C4a levels correlated with 2.2- (1.6-3.0; p < 0.0001), 2.0- (1.3-3.1; p = 0.0038), and 1.8-fold (1.2-2.6; p = 0.0029) increased longitudinal T2w lesion volumes; C3a and Ba were associated with 2.5- (1.4-4.6; p = 0.0022) and 3.3-fold (1.5-7.2; p = 0.0024) higher odds for CELs and 2.6- (1.7-4.0; p < 0.0001) and 2.3-fold (1.3-4.3; p = 0.006) increased PRL incidence rates. C1q, C3a, and C4a were associated with higher GFAP levels, and CXCL-13, CXCL-9, and IL-12b analyses showed consistent patterns with strongest associations for C1q, followed by Ba, C3a, and C4a.

Discussion: Intrathecal complement activation is consistently associated with MRI metrics and liquid biomarkers indicative for MS disease activity and progression. Our results demonstrate that aberrant complement activation is strongly associated with structural brain damage in MS. Therapeutic targeting of the complement system might limit disability accumulation due to MS.

Background and objectives: The optimal immunosuppressive treatment for autoimmune chronic intestinal pseudo-obstruction (CIPO) is unknown due to lack of clinical trials. Even less data exist on treatment recommendations for patients who do not respond to first-line immunotherapy.

Methods: We describe 4 patients with autoimmune CIPO treated with vedolizumab (3/4), a monoclonal antibody that interferes the lymphocyte trafficking to the gastrointestinal tract, or rituximab (1/4) who did not respond to steroids or IV immunoglobulins. We made a systematic review of previously published cases of CIPO treated with these biological agents.

Results: Vedolizumab was effective in 2 of 3 patients but failed in a child with nonparaneoplastic anti-Hu-associated CIPO, who had generalized dysautonomia. The 2 patients who responded to vedolizumab had an isolated CIPO, and they did not present neuronal antibodies. Rituximab was prescribed in a case of anti-Hu-associated, nonparaneoplastic CIPO, who showed a complete clinical response after this treatment. Our review of the literature retrieved 4 previous cases of autoimmune CIPO treated with rituximab but none treated with vedolizumab. All patients treated with rituximab had Hu antibodies. Two patients showed a clinical response to the treatment with rituximab.

Discussion: Our findings underscore the potential efficacy of rituximab and vedolizumab in the management of autoimmune CIPO refractory to first-line treatments.

A 28-year-old Black woman presented with both typical and atypical features of multiple sclerosis in the setting of multimorbidity including psychiatric history, complicating diagnosis and treatment. This case illustrates the importance of differential diagnosis and longitudinal follow-up before committing to disease-modifying therapy. Individualized treatment decision-making is highlighted.