Neurology® Neuroimmunology & Neuroinflammation最新文献

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.

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.