Neurology® Neuroimmunology & Neuroinflammation最新文献

Chimeric antigen receptor (CAR) T cells are genetically modified T cells expressing CARs, initially developed to recognize tumor antigens and kill cancer cells that evade T-cell recognition. Because of their impressive success in hemato-oncologic malignancies, CAR T cells are being repurposed with redesigned constructs for safety and sustained efficacy to target refractory systemic autoimmune or neurologic diseases. The CD19 CAR T cells-targeting those CD19-positive, antibody-secreting, long-lived plasma cells, and plasmablasts-are now extensively explored in refractory neuroautoimmunities with promising benefits based on case series in patients with myasthenia gravis (MG), stiff person syndrome (SPS), neuromyelitis, myositis, and multiple sclerosis; some patients with MG and SPS with steadily progressive and disabling disease refractory to all available therapies, including rituximab and new biologics, exhibit impressive clinical improvements with long-lasting benefits. The review, triggered by these early results and ongoing trials, addresses what these cells are and why they show effectiveness not only in antibody-mediated B-cell neurologic diseases unresponsive to available anti-B-cell agents but also in patients with nonpathogenic antibodies, implying effects even beyond B cells; points out that CARs are "living cells" penetrating physiologic barriers, such as the blood-brain barrier, expanding within tissues to memory cells ensuring sustained effects; describes the process and challenges of preparing and administering CAR T cells and their safety profile stressing the differences in toxicities when treating autoimmunites vs malignancies; and highlights that CD19 CAR T cells can successfully target even 2 different autoimmune diseases in the same patient, such as SPS and MG, offering promising prospects of changing the therapeutic algorithm in all neuroautoimmunities with potential for achieving even an immune reset shifting immunity to a healthy state.

Background and objectives: Antibody-associated neurologic diseases often present with movement disorders (MDs). The frequency and clinical course of specific MDs in most antibody-associated disease subtypes remain largely unknown.

Methods: We performed a retrospective nationwide observational study on a large cohort of Dutch patients with antibody-associated neurologic diseases between January 2000 and April 2024 to describe associated MDs.

Results: We identified 1,140 patients (56% female; 58/1,140 [5%] aged < 18 years; mean age 56 years [range 1-87]). The most common antibody targets were HuD (n = 212, 19%), NMDA receptor (NMDAR; n = 189, 17%), leucine-rich glioma inactivated 1 (LGI1; n = 187, 16%), and high-concentration glutamic acid decarboxylase 65-kilodalton isoform (GAD65; n = 135, 12%). MDs were present in 459 patients (42%) and represented the predominant and/or first symptom in 56% and 50% of cases, respectively. Cerebellar ataxia was by far the most common MD symptom (n = 235, mainly represented by Yo and GAD65), followed by dyskinesia (n = 61, mainly NMDAR), myoclonus (n = 51, mainly NMDAR), and stiff-person syndrome (n = 51, mainly GAD65). Syndromes associated with Yo- and delta/notch-like epidermal growth factor-related receptor (DNER/Tr) antibodies presented (almost) exclusively with MD (cerebellar ataxia) while the lowest MD frequency was observed in anti-gamma-aminobutyric acid B receptor (GABA_BR; 6/56, 11%) and anti-LGI1 encephalitis (19/181, 10%; excluding faciobrachial dystonic seizures). Furthermore, we identified MD associations that have not been previously reported, including chorea/dystonia (n = 1) and catatonia (n = 1) in anti-kelch like protein 11-associated brainstem encephalitis, chorea (n = 2) in anti-glycine receptor encephalitis, and episodic ataxia in anti-LGI1 and anti-GAD65-associated neurologic syndrome (both n = 1).

Discussion: MDs are common in antibody-associated neurologic diseases, occurring in 42% of patients, with varying frequencies depending on the specific subtype and antibody. MDs can be the first, predominant, and even only manifestation of these diseases. In addition, we also describe some novel antibody-MD associations. Antibody-associated neurologic diseases should be in the differential diagnosis of new-onset MDs, and we provide recommendations for rational antibody testing in different phenotypes.

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.

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.

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.

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.