Neurology® Neuroimmunology & Neuroinflammation最新文献

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.

Objectives: To evaluate the sensitivity of fluorescein angiography (FA) in detecting disease activity in Susac syndrome.

Methods: We conducted a blinded analysis of all FA, brain MRI, and audiogram examinations performed throughout the follow-up of patients with Susac syndrome.

Results: A total of 79 FA examinations, 85 brain MRI scans, and 49 audiograms were analyzed from 9 patients followed for a mean (SD) period of 6 (4) years. Disease activity was detected in 41.5% of FA examinations, 10.5% of MRI scans, and 25% of audiograms (FA vs MRI, p < 0.0001; FA vs audiogram, p = 0.06; audiogram vs MRI, p < 0.05). Within 3 months of clinical relapses, activity was observed in 57%, 24%, and 27% of FA, MRI, and audiogram examinations, respectively (FA vs MRI, p < 0.05; FA vs audiogram, p = 0.09; audiogram vs MRI, p = 1). Quantitative analysis of FA showed a mean (SD) of 2.5 (2.5) leakages (both eyes) during relapses compared with 1.2 (1.4) during remission (p < 0.05).

Discussion: FA, particularly arterial leakage, demonstrated the highest sensitivity in detecting disease activity and may be a valuable tool for treatment management in Susac syndrome. Future studies with larger samples should aim to identify the optimal threshold of FA changes associated with an increased risk of relapse.

We present a case of myelitis in a 63-year-old woman with breast adenocarcinoma treated with pembrolizumab. MRI showed multiple T2-hyperintense lesions throughout the spinal cord, and CSF demonstrated lymphocytic pleocytosis. We discuss the differential diagnosis of myelitis in the setting of cancer and immune checkpoint inhibitors.