Neurology® Neuroimmunology & Neuroinflammation最新文献

Objectives: Immune effector cell-associated neurotoxicity syndrome (ICANS) is typically a monophasic condition with a variable onset after chimeric antigen receptor T-cell (CAR T-cell) therapy. We report an exceedingly rare case of late-onset ICANS relapse, highlighting challenges in its recognition and management.

Methods: A patient receiving CAR T-cell therapy for large B-cell lymphoma was monitored for neurotoxicity. Clinical, neuroimaging, and laboratory evaluations were performed to assess symptom progression and guide treatment.

Results: The first ICANS episode occurred 14 days after infusion, presenting as grade 4 ICANS with coma, requiring intubation and intensive care. The patient was treated with methylprednisolone and anakinra, resulting in full recovery. A second episode occurred on day 40, characterized by disorientation, confabulation, and focal seizures (grade 3 ICANS). Treatment with levetiracetam, anakinra, and dexamethasone led to resolution.

Discussion: This case highlights the potential for delayed ICANS relapse beyond typical time frames, underscoring the need for prolonged monitoring. These findings support a possible biphasic course of ICANS, warranting further research on its pathophysiology and optimal long-term management.

Astrocytes are the main structural cells of the brain and spinal cord. Tessellating throughout the entire tissue, these highly arborized cells form intimate connections with each other and with essentially all other cell types in the CNS, including neurons, other glia such as microglia and oligodendrocyte-lineage cells, blood vessel cells, pial epithelium, and peripheral immune cells, when present. However, far more than inert cells gluing the CNS together, astrocytes are diverse and dynamic. Through their connections, they adapt and respond to local tissue cues, influencing CNS homeostasis and pathology. Yet, astrocyte biology is only superficially appreciated in clinical spheres. In this article, we briefly review some of the major facets of astrocyte biology as relevant to various neuroinflammatory diseases, including multiple sclerosis, myelin oligodendrocyte glycoprotein antibody-associated disorders, neuromyelitis optica spectrum disorders, anti-glial fibrillary acidic protein autoimmune encephalitis, and other neuroimmune conditions, highlighting their clinical and biological significance.

Background and objectives: Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a progressive neurologic disorder characterized by chronic inflammation in the CNS. HTLV-1-specific cytotoxic CD8⁺ T lymphocytes (CTLs) play a crucial role in the pathogenesis of HAM/TSP; however, the dynamics of CTLs in the CSF remain poorly understood. The aim of this study was to investigate the accumulation of HTLV-1-specific CTLs in the CSF of patients with HAM/TSP and to evaluate their association with neuroinflammation and neural damage.

Methods: The frequency of HTLV-1-specific CTLs was compared between paired peripheral blood (PB) and CSF from patients with HAM/TSP and asymptomatic HTLV-1 carriers (ACs) using MHC/antigen tetramers. In addition, cytokine levels and neurofilament light chain (NfL) concentration were analyzed in the CSF of patients with HAM/TSP and ACs.

Results: The frequency of HTLV-1-specific CTLs in PB was significantly higher in patients with HAM/TSP compared with ACs (median [interquartile range (IQR)] = 3.0 [0.9-8.3] % vs 0.3 [0.2-3.1] %, p < 0.01). Notably, this difference was even more pronounced in CSF, where patients with HAM/TSP exhibited a significantly elevated frequency compared with ACs (19.1 [7.9-33.4] % vs 6.1 [0.9-15.7] %, p < 0.01). Furthermore, the frequency of HTLV-1-specific CTLs in the CSF was considerably higher than in the PB of patients with HAM/TSP (p < 0.0001). The lack of accumulation of cytomegalovirus-specific CTLs indicates that HTLV-1-specific CTLs selectively accumulate in the CSF of patients with HAM/TSP. These accumulated HTLV-1-specific CTLs in the CSF significantly correlated with increased levels of cytokines in patients with HAM/TSP. In addition, CSF NfL levels were significantly higher in patients with HAM/TSP than in ACs (696 [534-1,407] vs 429 [373-717] pg/mL, p < 0.05) and showed a positive correlation with HTLV-1 proviral load.

Discussion: HTLV-1-specific CTLs selectively accumulate in the CSF of patients with HAM/TSP. Chronic inflammation, primarily driven by the interaction between proliferating HTLV-1-infected cells and accumulated HTLV-1-specific CTLs, may contribute to neural damage in patients with HAM/TSP.

CNS involvement in hepatitis B virus (HBV) infection is rare. We report a 27-year-old woman with HBV infection presenting with headaches and seizures, whose imaging and brain biopsy confirmed acute hemorrhagic leukoencephalitis. She responded well to steroid and tenofovir therapy.

Background and objectives: Demyelinating diseases are neurologic disorders characterized by the loss of the myelin sheath and impaired regeneration. Retinoid X receptor γ (RXRγ) is a member of the nuclear receptor superfamily and plays a crucial role in oligodendrocyte biology and myelin formation. However, the clinical application of drugs targeting RXRγ for demyelinating diseases is limited. Selecting small-molecule drugs approved by the U.S. Food and Drug Administration (FDA) that have high binding activity to RXRγ may be an effective strategy for treating demyelinating disorders.

Methods: We used an online molecular docking tool to predict that spironolactone (SPIR), an FDA-approved drug, displays strong binding activity to RXRγ. Subsequently, we verified the impact of SPIR on oligodendrocyte precursor cell (OPC) differentiation and myelin sheath formation through in vitro OPC culture and pharmacologic experiments in mice. Furthermore, using genetic models with CRISPR-LSL-Cas9, we confirmed that the effect of SPIR on OPCs relies on RXRγ.

Results: In this study, we identified that SPIR, an FDA-approved drug, functions as an RXRγ agonist in OPCs. RXRγ was identified as a crucial factor of myelin production. Its activation promotes the differentiation of OPCs and enhances myelin generation. We confirmed the specificity of SPIR's target, demonstrating that SPIR facilitates OPC differentiation and myelin generation in a RXRγ-dependent manner. Our findings not only identify the RXRγ agonist to promote OPC differentiation but also provide new experimental evidence for expanding the clinical indications of SPIR.

Discussion: The promotion of OPC differentiation by SPIR in animal models suggests its potential for treating demyelinating diseases.

Background and objectives: Anti-IgLON5 disease manifests by various neurologic symptoms, the severity of which can be evaluated using the anti-IgLON5 composite score (ICS). This study assessed the correlation of neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) with the ICS and investigated these biomarkers as predictors of long-term clinical severity and mortality in anti-IgLON5 disease.

Methods: Patients diagnosed with anti-IgLON5 disease at a national reference center (2016-2024) with available serum and CSF samples were included. NfL and GFAP concentrations were measured in these samples using Simoa assay Neurology 2-Plex B Kit. The severity of symptoms was classified according to the ICS, which was retrospectively evaluated at diagnosis, at last clinical evaluation, and at any other timepoint when samples were collected.

Results: Thirty patients (60% male, median age 72 years) were included. Serum NfL concentration was significantly correlated with the total ICS (rho = 0.38, p = 0.025) and its partial bulbar score (rho = 0.39, p = 0.020); serum GFAP concentration was significantly correlated only with the bulbar ICS (rho = 0.34, p = 0.044). CSF NfL and GFAP concentrations were not significantly correlated with the total ICS nor any of its partial scores. Anti-IgLON5 antibody CSF titers, but not serum titers, showed a significant inverse correlation with the total ICS (rho = -0.44, p = 0.04). In 26 patients sampled <4 months after diagnosis, neither NfL nor GFAP predicted the total or partial ICS at last clinical evaluation (median 18 months after diagnosis), but serum NfL increased the risk of 1-year mortality independently of age (hazard ratio for each 10 pg/mL increase: 2.05, 95% CI [1.21-3.45], p = 0.007). In patients with bulbar involvement (n = 22), serum NfL concentration was lower than in 10 controls with bulbar amyotrophic lateral sclerosis (median interquartile range [IQR] 26 pg/mL [21-51] vs 158 pg/mL [100-340], p < 0.001) and higher than in 10 controls with bulbar myasthenia gravis (median [IQR] 15 pg/mL [8-26], p = 0.040).

Discussion: In anti-IgLON5 disease, serum NfL and GFAP are elevated and correlate with the clinical severity, especially of bulbar symptoms. In clinical practice, serum NfL could be useful for disease monitoring and to predict the risk of death.

Objectives: Complement factor I (CFI) deficiency is a rare condition that can present with fulminant relapsing CNS autoinflammation. In this report, we highlight the utility of genetic testing in unexplained CNS autoinflammation.

Methods: This case report describes a young adult with partial CFI deficiency, presenting with acute hemorrhagic leukoencephalitis and longitudinally extensive transverse myelitis.

Results: In this case of unexplained CNS autoinflammation, in-hospital whole-genome sequencing and complement testing revealed partial CFI deficiency. CSF profiling during flares showed increased neutrophils and proinflammatory cytokines. CSF gene expression profiling more closely aligned with cases of bacterial meningitis than autoimmune encephalitis, consistent with innate immune system hyperactivity. Emergent IL-1 receptor antagonism led to sustained suppression of further immunologic attacks.

Discussion: Our case describes a presentation of CFI deficiency with fulminant and relapsing CNS autoinflammation. These flares were temporally associated with infections, which we hypothesize triggered innate immune overactivity due to CFI deficiency. Treatment with an IL-1 receptor antagonist, anakinra, suppressed further attacks and enabled neurologic recovery in a syndrome that is almost uniformly fatal. This case highlights the diagnostic value of inpatient genetic testing in cases of unexplained neuroinflammation and proposes targeted suppressive treatment to reduce neurologic deterioration.

Background and objectives: In the 2023 diagnostic criteria, supporting clinical/MRI features are required to diagnose myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) in patients at high risk of false MOG-IgG positivity (low/unavailable titer, cerebrospinal fluid-restricted), to help differentiation from multiple sclerosis (MS). However, overlap is possible and determining the frequency of the MOGAD supporting features at MS onset may help prevent misdiagnosis. We assessed the frequency of the MOGAD supporting features and potential risk of misdiagnosis at first attack of MS/clinically isolated syndrome (CIS).

Methods: In this observational study, we retrospectively identified consecutive patients hospitalized between 2021 and 2024 at 2 Italian centers, with: (1) relapsing-remitting MS/CIS, and (2) first attack MRI available. The frequency of the MOGAD supporting features was assessed at MS/CIS presentation, and potential risk of misdiagnosis determined based on the probability of concurrent false MOG-IgG positivity. Other clinical-MRI features typical of MOGAD but not included in the 2023 diagnostic criteria were also evaluated.

Results: A total of 244 patients with MS/CIS were included (median age, 34 [range, 13-78] years; 66% were female). Overall, 65/244 (27%) patients with MS/CIS showed at least 1 MOGAD supporting feature during the presenting attack. "Central cord lesion" (27/82 [33%]) and "deep gray nuclei involvement" (24/86 [28%]) were more represented than other supporting features (0%-7%); p < 0.001. MOG-IgG was tested in 207/244 (85%) patients, showing false positivity in 3 (1.4%) patients. The combined probability of detecting a false MOG-IgG positivity and meeting 1 of the MOGAD supporting features was 0.4%. Among other typical MOGAD features not included in the diagnostic criteria, the following had a 0% frequency at MS/CIS presentation: (1) encephalopathy, (2) marked CSF pleocytosis (>50 cells/mm³), (3) wheelchair need during myelitis, and (4) MRI T2-lesion resolution postattack.

Discussion: Although the MOGAD supporting features can be met in one-fourth of patients at MS/CIS presentation, the risk of misdiagnosis in similar unselected cohorts remains low. Future refinements of the MOGAD supporting features should take into account their relative frequency in MS/CIS and possible integration with additional clinical-MRI features that are more specific for MOGAD.

Objectives: The gut microbiota and altered intestinal physiology have been implicated in multiple sclerosis (MS). Enteric glial cells regulate enteric nervous and immune function and express glial fibrillary acidic protein (GFAP) and S100β. Serum GFAP and neurofilament light chain can predict disease worsening; however, no clear markers differentiate relapsing from progressive disease.

Methods: To investigate enteric glial function in MS, we measured stool GFAP (st-GFAP) using an enzyme-linked immunosorbent assay in 31 healthy controls (HCs), 77 patients with relapsing remitting MS (RRMS), and 53 patients with progressive MS (ProgMS). Participants underwent clinical follow-up at 2 and 5 years after stool donation.

Results: We found higher st-GFAP levels in patients with ProgMS compared with those with RRMS and HCs. St-GFAP was positively correlated with baseline Expanded Disability Status Scale (EDSS) score, 25-foot walk time, and an increased EDSS score at 2 and 5 years. We found enteric glial hyperplasia in the colonic mucosa of a patient with primary progressive MS, as indicated by GFAP and S100β immunoreactivity, an effect not observed in duodenum tissue in patients with RRMS from our Milan cohort. St-GFAP in patients with ProgMS was negatively associated with Eubacterium hallii.

Discussion: These exploratory data indicate an altered enteric glial phenotype in patients with ProgMS and suggest that st-GFAP may be a prognostic biomarker.

Objectives: The aim of this study was to characterize inflammatory cytokine profiles in women diagnosed with episodic migraine, endometriosis, or both conditions and to determine how these cytokine patterns relate to symptom severity and functional impact, to identify potential biological markers distinguishing comorbid cases from single-diagnosis cases.

Methods: Female patients with only episodic migraine, only endometriosis, or both conditions were enrolled. Plasma levels of proinflammatory cytokines were measured, and correlations with clinical parameters were analyzed.

Results: Women with episodic migraine had elevated levels of IL-1β, IL-6, and TNF-α compared with healthy controls, with even higher levels in those with both migraine and endometriosis, indicating a synergistic effect on systemic inflammation. IL-1β correlated with headache frequency and disability while IL-6 and TNF-α were linked to migraine severity and pain. Women with endometriosis alone did not show similar cytokine elevations, suggesting that inflammation is particularly amplified in comorbidity. Changes in leukocyte distribution further supported a unique immune activation profile in the comorbid group.

Discussion: These findings reveal novel biological evidence of a shared inflammatory endotype in women suffering from both conditions, which may contribute to the increased burden and comorbidity, highlighting the need for integrative diagnostic and management approaches.