Neurology® Neuroimmunology & Neuroinflammation最新文献

Background and objectives: Aquaporin (AQP)-4 (AQP4)-seropositive neuromyelitis optica (NMO) frequently coexists with rheumatologic autoimmune conditions, including Sjögren syndrome and systemic lupus erythematosus, 2 conditions that share a common HLA-DRB1 (HLA-DRB1*03:01) association with NMO. AQP4 is a member of a family of ubiquitously expressed water channels. Its immunodominant pathogenic T-cell epitope, which binds MHC II with exceptionally high affinity, is homologous to sequences in other AQPs, including AQP5, a candidate target autoantigen in Sjögren syndrome. Thus, we hypothesized that self-antigen molecular mimicry exists between AQPs and contributes to autoimmunity.

Methods: Previously, we examined binding of AQP4 T-cell epitopes to MHC II (I-A^b) by biochemical assays; we now evaluate interaction of I-A^b and AQPs by molecular modeling. T cells from mice immunized with the immunodominant AQP4 epitope or its homologous AQP5 sequence were examined for proliferation and cross-recognition between AQPs. T-cell receptor (TCR) engagement of individual T cells with AQP-MHC II complexes was examined using AQP4 and AQP5 peptide/MHC II tetramers. The pathogenic potential of AQP4-primed and AQP5-primed T cells was examined by T-cell adoptive transfer into naïve mice.

Results: The immunodominant AQP4 T-cell epitope was predicted to make optimal contacts within the pockets of the MHC II antigen-binding cleft. Like AQP4, the corresponding homologous AQP5 amino acid sequence was predicted to bind MHC II, albeit with modest affinity. In a reciprocal manner, T cells were detected that proliferated to both AQP4 and AQP5. Multi-tetramer analysis of individual T cells demonstrated that the same TCR could engage both AQP4 and AQP5. T cells from mice immunized with AQP4 or AQP5 caused paralysis and CNS inflammation in recipient mice, but not in AQP4-deficient mice, demonstrating that AQP4 expression is obligately required in this model of aquaporin CNS autoimmunity.

Discussion: T cells can express TCRs that recognize multiple AQPs. Autoimmunity can be initiated through molecular mimicry between distinct self-antigens such as AQP4 and AQP5 that are expressed in separate organs. These findings suggest that T-cell self-antigen mimicry may contribute to coexistence of NMO with other autoimmune conditions, such as Sjögren syndrome.

Background and objectives: Autoimmune nodopathy with anti-contactin1 (CNTN1) autoantibodies is a rare sensory-motor neuropathy characterized by subacute-onset sensory ataxia and variable disease courses. Comorbidities such as glomerulonephritis and diabetes mellitus are observed in some patients. The diversity in clinical presentation may reflect differences in the targeted CNTN1 epitopes.

Methods: To investigate the relationship between clinical features and the underlying epitopes, we analyzed serum samples from 16 anti-CNTN1-positive patients. Binding epitopes were assessed using cell-based assays with recombinant CNTN1 variants and peptide microarrays.

Results: Epitope mapping in 16 patients revealed that 13 harbored antibodies targeting CNTN1 immunoglobulin (Ig) domains while 3 recognized fibronectin (Fn) domains. Glomerulonephritis was exclusively observed in patients with autoantibodies binding to the Ig domain, whereas diabetes mellitus and a chronic course of disease were more prevalent in patients with binding to the fibronectin domain.

Discussion: Our findings highlight the heterogeneity of anti-contactin1 nodopathies, suggesting that distinct epitope-binding patterns may underlie different clinical manifestations and may be associated with different pathogenic mechanisms and comorbidities.

Background and objectives: Multifocal motor neuropathy (MMN) is an asymmetric motor neuropathy driven by IgM autoantibodies targeting gangliosides, particularly GM1. In this study, we investigated the relationship between IgM seropositivity, complement activation, and clinical parameters using an induced pluripotent stem cell (iPSC)-derived motor neuron (MN) model of MMN.

Methods: We used serum samples from 137 patients with MMN to assess IgM binding and subsequent C3 fixation to iPSC MNs and their correlation with clinical parameters, including muscle strength expressed as MRC sum scores, obtained from patient records. In addition, we tested the efficacy of IV immunoglobulin (IVIg) and specific complement inhibitors to prevent C3 fixation to MNs.

Results: We observed increased IgM binding to iPSC MNs using serum samples from patients with MMN compared with those from healthy controls, which correlated with IgM anti-ganglioside antibody titers. Higher antibody binding correlated with levels of C3 fixation, more severe weakness, and the need for higher IVIg doses. Complement activation, but not IgM binding, also correlated with vibration sense abnormalities, brachial plexus MRI abnormalities, and the degree of axonal damage. At therapeutic concentrations, IVIg moderately inhibited complement activation (34%-54%) while specific complement inhibitors were highly effective (89.1%-98.7%) in the iPSC MN model.

Discussion: This study demonstrates that IgM antibodies in serum samples from patients with MMN induce complement activation on iPSC MNs, which correlates significantly with clinical outcomes. In addition, our findings indicate that complement inhibitors offer a potentially targeted novel therapeutic strategy for MMN and that our iPSC MN model is a viable preclinical screening platform.

Background and objectives: Anti-contactin-associated protein-like 2 (CASPR2) disease-previously considered a subtype of anti-voltage-gated potassium channel (VGKC-complex) encephalitis-is a relatively new disease entity, and information on long-term outcomes and relapses is limited. We investigated long-term clinical outcomes and factors associated with higher relapse rates. In addition, we compared different treatment strategies.

Methods: In this nationwide observational cohort study, patients with anti-CASPR2 disease were included. Clinical data were collected at diagnosis and during follow-up, both retrospectively and prospectively.

Results: Forty-four patients with anti-CASPR2 disease were included (42 male patients [96%]; median age at onset 66 years [interquartile range (IQR) 61-71; range 40-86]). The median follow-up time was 55 months (IQR 38-78; range 8-200). Sixty percent of the patients experienced at least one relapse. Most patients experienced similar but fewer symptoms during relapse(s). However, new symptoms could occur during a relapse episode, mainly involving the peripheral nervous system. The median time to relapse was 10.5 months (IQR 6-14; range 3-58). Twelve of the 44 patients were diagnosed with cancer, with 3 cancers identified only at relapse. We found significantly higher anti-VGKC-complex concentrations at diagnosis (p = 0.043) and a higher occurrence of seizures (p = 0.041) in relapsing patients. In 94%, a clear correlation was observed between anti-VGKC-complex concentrations and the clinical status (59% decrease from diagnosis to post-treatment stage, 122.5% increase during the first relapse). In our total cohort, tapering with oral steroids seemed effective in reducing relapses during administration (annual relapse rate [ARR] 0.12) but did not prevent relapses beyond the taper. Second-line therapy also appeared effective (ARR 0.09) while steroid-sparing agents provided limited benefits (ARR 0.22). In patients prone to relapse, repeated courses of rituximab seem necessary to prevent further relapses (hazard ratio 26.33, p < 0.0005 in post-second-line treatment group; ARR 0.09 vs 0.81).

Discussion: The relapse rate in anti-CASPR2 disease is much higher than previously reported. In patients prone to relapse, (repeated) courses of rituximab appear to be most effective in preventing future relapses beyond acute therapy and tapering with oral steroids. Anti-VGKC-complex concentrations in serum can aid in monitoring of relapses and disease course in most of the patients. It is recommended to repeat tumor screening when patients relapse.

Classification of evidence: This study provides Class IV evidence that, in anti-CASPR2 disease, prolonged immunotherapy is associated with reduced relapse rates.

Objectives: This report details a pediatric case of myelin oligodendrocyte glycoprotein antibody disease (MOGAD) characterized by isolated MOG-IgG3 positivity and IgG1 deficiency, highlighting a unique serologic profile and exploring its immunologic significance. In addition, a review of MOGAD cases with isolated MOG-IgG3 antibodies is included.

Methods: A 12-year-old boy presenting with a progressive neurologic syndrome underwent clinical, radiologic, and laboratory evaluation.

Results: MRI showed extensive brain and spinal lesions. MOG-IgG3 antibodies were identified in serum and CSF by live cell-based assay, while other MOG-IgG subclasses were not detected. Serum IgG1 was low at baseline and throughout follow-up. First-line immunotherapy treatment led to significant improvement, with no relapses at 2-year follow-up.

Discussion: This case highlights the potential role of subclinical IgG1 deficiency in shaping the predominance or selective detection of MOG-IgG3 in MOGAD. While most MOG antibodies are predominantly of the IgG1 isotype, our review identified a few cases with isolated MOG-IgG3 antibodies. A possible contribution to pathogenesis cannot be excluded, and the patient's inability to produce a balanced IgG subclass profile could have favored a sustained IgG3 response. Larger studies are needed to clarify the clinical significance of MOG-IgG3 in MOGAD.

Objectives: Progressive multifocal leukoencephalopathy (PML) is a rare, often fatal CNS infection caused by reactivation of JC virus, typically in immunocompromised patients. No effective antiviral therapy has been established. We report a case of PML in a patient with multiple sclerosis (MS) treated with fingolimod, who received oral tenofovir alafenamide fumarate (TAF).

Methods: This is a single-patient case report from Stavanger University Hospital, Norway. A 67-year-old woman with secondary progressive MS developed progressive neurologic symptoms during fingolimod treatment. MRI and CSF analyses confirmed PML with detectable JCV DNA. Fingolimod was discontinued, and oral TAF 50 mg/d was initiated. Clinical course, MRI changes, and CSF biomarkers were monitored over 6 months.

Results: At baseline, JCV DNA was 4,940 international units [IU]/mL in CSF and the Expanded Disability Status Scale (EDSS) score was 8.5. Four days after TAF initiation, partial radiologic improvement was observed. After 3 and 6 months, JCV DNA was undetectable (<1,000 IU/mL). The patient remained clinically stable with unchanged EDSS score and tolerated TAF without adverse effects. MRI showed regression of PML lesions but development of new MS activity after fingolimod withdrawal.

Discussion: This case demonstrates temporal association between TAF initiation and virologic clearance of JCV, suggesting potential antiviral activity.

Classification of evidence: As a single case without controls, this report provides Class IV evidence that oral TAF might stabilize the clinical course in patients with PML.

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.