RESUMEN
OBJECTIVE: Differentiating forms of autoimmune encephalitis (AE) from other causes of seizures helps expedite immunotherapies in AE patients and informs studies regarding their contrasting pathophysiology. We aimed to investigate whether and how Nuclear Magnetic Resonance (NMR)-based metabolomics could differentiate AE from drug-resistant epilepsy (DRE), and stratify AE subtypes. METHODS: This study recruited 238 patients: 162 with DRE and 76 AE, including 27 with contactin-associated protein-like 2 (CASPR2), 29 with leucine-rich glioma inactivated 1 (LGI1) and 20 with N-methyl-d-aspartate receptor (NMDAR) antibodies. Plasma samples across the groups were analyzed using NMR spectroscopy and compared with multivariate statistical techniques, such as orthogonal partial least squares discriminant analysis (OPLS-DA). RESULTS: The OPLS-DA model successfully distinguished AE from DRE patients with a high predictive accuracy of 87.0 ± 3.1% (87.9 ± 3.4% sensitivity and 86.3 ± 3.6% specificity). Further, pairwise OPLS-DA models were able to stratify the three AE subtypes. Plasma metabolomic signatures of AE included decreased high-density lipoprotein (HDL, -(CH2)n-, -CH3), phosphatidylcholine and albumin (lysyl moiety). AE subtype-specific metabolomic signatures were also observed, with increased lactate in CASPR2, increased lactate, glucose, and decreased unsaturated fatty acids (UFA, -CH2CH=) in LGI1, and increased glycoprotein A (GlycA) in NMDAR-antibody patients. INTERPRETATION: This study presents the first non-antibody-based biomarker for differentiating DRE, AE and AE subtypes. These metabolomics signatures underscore the potential relevance of lipid metabolism and glucose regulation in these neurological disorders, offering a promising adjunct to facilitate the diagnosis and therapeutics.
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Epilepsia Refractaria , Encefalitis , Humanos , Femenino , Epilepsia Refractaria/sangre , Epilepsia Refractaria/diagnóstico , Masculino , Adulto , Encefalitis/sangre , Encefalitis/diagnóstico , Persona de Mediana Edad , Diagnóstico Diferencial , Adulto Joven , Autoanticuerpos/sangre , Enfermedad de Hashimoto/sangre , Enfermedad de Hashimoto/diagnóstico , Metabolómica , Proteínas del Tejido Nervioso/sangre , Adolescente , Proteínas de la Membrana/sangre , Espectroscopía de Resonancia Magnética , Péptidos y Proteínas de Señalización Intracelular/sangre , Biomarcadores/sangre , Receptores de N-Metil-D-Aspartato/inmunología , Enfermedades Autoinmunes del Sistema Nervioso/sangre , Enfermedades Autoinmunes del Sistema Nervioso/diagnóstico , Enfermedades Autoinmunes del Sistema Nervioso/inmunologíaRESUMEN
Serological tests are important to detect autoantibodies (autoAbs) in patients with autoimmune neuropathies (AN) and myasthenia gravis (MG) as they are biomarkers for diagnosis, stratification, treatment selection, and monitoring. However, tests to detect autoAbs frequently lack proper standardization and results differ across diagnostic laboratories. We compared results for tests routinely performed in Spanish diagnostic laboratories to detect AN and MG autoAbs. In the Spanish Society of Immunology Autoimmunity Group national workshop, serum samples from 13 patients with AN or MG were tested for anti-ganglioside, anti-myelin-associated glycoprotein (MAG), anti-nicotinic acetylcholine receptor (AChR), and anti-muscle-specific kinase (MuSK) autoAbs using reference methods and were distributed for analysis to 27 participating laboratories using their routine methods. Overserved were inter-laboratory variability and worryingly low sensitivity, especially for anti-ganglioside immunoglobulin G and anti-MAG autoAb detection. This pilot study reflects autoAbs detection state of the art in AN and MG testing in leading diagnostic laboratories in Spain, highlighting the need for standardization prior to clinical use.
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Autoanticuerpos , Miastenia Gravis , Humanos , Miastenia Gravis/diagnóstico , Miastenia Gravis/sangre , Miastenia Gravis/inmunología , Autoanticuerpos/sangre , Proyectos Piloto , España , Masculino , Femenino , Enfermedades Autoinmunes del Sistema Nervioso/diagnóstico , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Enfermedades Autoinmunes del Sistema Nervioso/sangre , Persona de Mediana Edad , Receptores Colinérgicos/inmunología , Adulto , AncianoRESUMEN
BACKGROUND AND PURPOSE: Paraneoplastic neurological autoimmunity is well described with small-cell lung cancer, but information is limited for other neuroendocrine neoplasms (NENs). METHODS: Adult patients with histopathologically confirmed non-pulmonary NENs, neurological autoimmunity within 5 years of NEN diagnosis, and neural antibody testing performed at the Mayo Clinic Neuroimmunology Laboratory (January 2008 to March 2023) were retrospectively identified. Control sera were available from patients with NENs without neurological autoimmunity (116). RESULTS: Thirty-four patients were identified (median age 68 years, range 31-87). The most common primary tumor sites were pancreas (nine), skin (Merkel cell, eight), small bowel/duodenum (seven), and unknown (seven). Five patients received immune checkpoint inhibitor (ICI) therapy before symptom onset; symptoms preceded cancer diagnosis in 62.1% of non-ICI-treated patients. The most frequent neurological phenotypes (non-ICI-treated) were movement disorders (12; cerebellar ataxia in 10), dysautonomia (six), peripheral neuropathy (eight), encephalitis (four), and neuromuscular junction disorders (four). Neural antibodies were detected in 55.9% of patients studied (most common specificities: P/Q-type voltage-gated calcium channel [seven], muscle-type acetylcholine receptor [three], anti-neuronal nuclear antibody type 1 [three], and neuronal intermediate filaments [two]), but in only 6.9% of controls. Amongst patients receiving cancer or immunosuppressive therapy, 51.6% had partial or complete recovery. Outcomes were unfavorable in 48.3% (non-ICI-treated) and neural autoantibody positivity was associated with poor neurological outcome. DISCUSSION: Neurological autoimmunity associated with non-pulmonary NENs is often multifocal and can be treatment responsive, underscoring the importance of rapid recognition and early treatment.
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Autoanticuerpos , Tumores Neuroendocrinos , Humanos , Masculino , Femenino , Anciano , Persona de Mediana Edad , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Tumores Neuroendocrinos/inmunología , Tumores Neuroendocrinos/complicaciones , Adulto , Anciano de 80 o más Años , Estudios Retrospectivos , Autoinmunidad/inmunología , Síndromes Paraneoplásicos del Sistema Nervioso/inmunología , Síndromes Paraneoplásicos del Sistema Nervioso/sangre , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Enfermedades Autoinmunes del Sistema Nervioso/sangreRESUMEN
An 83-year-old man with hepatocellular carcinoma developed muscle weakness, ptosis, and dyspnea 3 weeks after receiving atezolizumab. Soon after, mechanical ventilation was initiated, which was followed by marked blood pressure spikes. The levels of creatine kinase and troponin-I were significantly elevated, and acetylcholine receptor antibodies were positive. The patient was diagnosed with immune checkpoint inhibitor (ICI)-induced myositis, myasthenia gravis (MG), myocarditis, and suspected autoimmune autonomic ganglionopathy (AAG). After immunotherapy, the serum markers and blood pressure normalized, and he was weaned from the ventilator after five months. To our knowledge, this is the first reported case of AAG secondary to ICI-induced myositis, MG, and myocarditis.
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Anticuerpos Monoclonales Humanizados , Neoplasias Hepáticas , Miastenia Gravis , Miocarditis , Miositis , Humanos , Masculino , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Miositis/inducido químicamente , Miositis/inmunología , Miositis/sangre , Miositis/diagnóstico , Miastenia Gravis/inducido químicamente , Miastenia Gravis/sangre , Miastenia Gravis/diagnóstico , Miastenia Gravis/inmunología , Miastenia Gravis/tratamiento farmacológico , Miocarditis/inducido químicamente , Miocarditis/diagnóstico , Miocarditis/sangre , Anciano de 80 o más Años , Neoplasias Hepáticas/tratamiento farmacológico , Carcinoma Hepatocelular/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Enfermedades del Sistema Nervioso Autónomo/inducido químicamente , Ganglios Autónomos/inmunología , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Enfermedades Autoinmunes del Sistema Nervioso/tratamiento farmacológico , Enfermedades Autoinmunes del Sistema Nervioso/inducido químicamente , Enfermedades Autoinmunes del Sistema Nervioso/diagnóstico , Enfermedades Autoinmunes del Sistema Nervioso/sangreRESUMEN
BACKGROUND AND OBJECTIVES: Despite detection of autoantibodies, anti-IgLON5 disease was historically considered a tau-associated neurodegenerative disease, with limited treatment options and detrimental consequences for the patients. Observations in increasing case numbers hint toward underlying inflammatory mechanisms that, early detection provided, open a valuable window of opportunity for therapeutic intervention. We aimed to further substantiate this view by studying the CSF of patients with anti-IgLON5. METHODS: We identified 11 patients with anti-IgLON5 from our database and compared clinical, MRI, and CSF findings with a cohort of 20 patients with progressive supranuclear palsy (PSP) (as a noninflammatory tauopathy) and 22 patients with functional neurologic disorder. RESULTS: Patients with anti-IgLON5 show inflammatory changes in routine CSF analysis, an increase in B-lymphocyte frequency, and the presence of plasma cells in comparison to the PSP-control group and functional neurologic disease controls. Patients with intrathecal plasma cells showed a clinical response to rituximab. DISCUSSION: Our findings indicate the importance of inflammatory mechanisms, in particular in early and acute anti-IgLON5 cases, which may support the use of immune-suppressive treatments in these cases. The main limitation of the study is the small number of cases due to the rarity of the disease.
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Enfermedades Autoinmunes del Sistema Nervioso , Linfocitos B , Moléculas de Adhesión Celular Neuronal/inmunología , Células Plasmáticas , Anciano , Anciano de 80 o más Años , Autoanticuerpos , Enfermedades Autoinmunes del Sistema Nervioso/sangre , Enfermedades Autoinmunes del Sistema Nervioso/líquido cefalorraquídeo , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Enfermedades Autoinmunes del Sistema Nervioso/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Neuroinflamatorias/sangre , Enfermedades Neuroinflamatorias/líquido cefalorraquídeo , Enfermedades Neuroinflamatorias/inmunología , Enfermedades Neuroinflamatorias/fisiopatología , Estudios RetrospectivosRESUMEN
OBJECTIVE: The study was undertaken to assess the impact of B cell depletion on humoral and cellular immune responses to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vaccination in patients with various neuroimmunologic disorders on anti-CD20 therapy. This included an analysis of the T cell vaccine response to the SARS-CoV-2 Delta variant. METHODS: We investigated prospectively humoral and cellular responses to SARS-CoV-2 mRNA vaccination in 82 patients with neuroimmunologic disorders on anti-CD20 therapy and 82 age- and sex-matched healthy controls. For quantification of antibodies, the Elecsys anti-SARS-CoV-2 viral spike (S) immunoassay against the receptor-binding domain (RBD) was used. IFN-gamma enzyme-linked immunosorbent spot assays were performed to assess T cell responses against the SARS-CoV-2 Wuhan strain and the Delta variant. RESULTS: SARS-CoV-2-specific antibodies were found less frequently in patients (70% [57/82]) compared with controls (82/82 [100%], p < 0.001). In patients without detectable B cells (<1 B cell/mcl), seroconversion rates and antibody levels were lower compared to nondepleted (≥1 B cell/mcl) patients (p < 0.001). B cell levels ≥1 cell/mcl were sufficient to induce seroconversion in our cohort of anti-CD20 treated patients. In contrast to the antibody response, the T-cell response against the Wuhan strain and the Delta variant was more pronounced in frequency (p < 0.05) and magnitude (p < 0.01) in B-cell depleted compared to nondepleted patients. INTERPRETATION: Antibody responses to SARS-CoV-2 mRNA vaccinnation can be attained in patients on anti-CD20 therapy by the onset of B cell repopulation. In the absence of B cells, a strong T cell response is generated which may help to protect against severe coronavirus disease 2019 (COVID-19) in this high-risk population. ANN NEUROL 2022;91:342-352.
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Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Linfocitos B/inmunología , Vacunas contra la COVID-19/administración & dosificación , Inmunidad Celular/inmunología , Inmunidad Humoral/inmunología , SARS-CoV-2/inmunología , Adulto , Enfermedades Autoinmunes del Sistema Nervioso/sangre , Enfermedades Autoinmunes del Sistema Nervioso/epidemiología , Linfocitos B/metabolismo , COVID-19/epidemiología , COVID-19/prevención & control , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neuroinmunomodulación/inmunología , Estudios Prospectivos , SARS-CoV-2/metabolismoRESUMEN
BACKGROUND AND OBJECTIVES: Progranulin (PGRN) is an important immune regulatory molecule in several immune-mediated diseases. The objective of this study is to investigate the role of PGRN in uveitis and its counterpart, experimental autoimmune uveitis (EAU), and experimental autoimmune encephalomyelitis (EAE). METHODS: Serum PGRN levels in patients with Behcet disease (BD) or Vogt-Koyanagi-Harada (VKH) disease and normal controls were measured by ELISA. EAE and EAU were induced in B10RIII, wild-type, and PGRN-/- mice to evaluate the effect of PGRN on the development of these 2 immune-mediated disease models. The local and systemic immunologic alterations were detected by ELISA, flow cytometry, and real-time PCR. RNA sequencing was performed to identify the hub genes and key signaling pathway. RESULTS: A significantly decreased PGRN expression was observed in patients with active BD and active VKH. Recombinant PGRN significantly reduced EAU severity in association with a decreased frequency of Th17 and Th1 cells. PGRN-/- mice developed an exacerbated EAU and EAE in association with strikingly increased frequency of Th1 and Th17 cells and reduced frequency of regulatory T (Treg) cells. In vitro studies revealed that rPGRN could inhibit IRBP161-180-specific Th1 and Th17 cell response and promote Treg cell expansion. It promoted non-antigen-specific Treg cell polarization from naive CD4+ T cells in association with increased STAT5 phosphorylation. Using RAN sequencing, we identified 5 shared hub genes including Tnf, Il6, Il1b, Cxcl2, and Ccl2 and the most significantly enriched MAPK and tumor necrosis factor signaling pathway in PGRN-/- EAU mice. The aggravated EAE activity in PGRN-/- mice was associated with a skew from M2 to M1 macrophages. DISCUSSION: Our results collectively reveal an important protective role of PGRN in EAU and EAE. These studies suggest that PGRN could serve as an immunoregulatory target in the study of prevention and treatment for the Th1/Th17-mediated diseases.
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Enfermedades Autoinmunes del Sistema Nervioso , Síndrome de Behçet , Encefalomielitis Autoinmune Experimental , Macrófagos , Progranulinas/sangre , Linfocitos T Reguladores , Células TH1 , Células Th17 , Uveítis , Animales , Enfermedades Autoinmunes del Sistema Nervioso/sangre , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Síndrome de Behçet/sangre , Síndrome de Behçet/inmunología , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/metabolismo , Humanos , Uveítis/sangre , Uveítis/inmunología , Síndrome Uveomeningoencefálico/sangre , Síndrome Uveomeningoencefálico/inmunologíaRESUMEN
BACKGROUND AND OBJECTIVES: The objective of the retrospective analysis was to test the hypothesis that changes in serum anti-myelin-associated glycoprotein (MAG) autoantibodies are associated with clinical response to immunotherapy in patients with anti-MAG neuropathy. METHODS: As of January 29, 2020, we used anti-myelin-associated glycoprotein-related search strings in the Medline database to identify studies that provided information on anti-MAG immunoglobulin M (IgM) autoantibodies and clinical outcomes during immunotherapies. The relative change in anti-MAG IgM titers, paraprotein levels, or total IgM was determined before, during, or posttreatment, and the patients were assigned to "responder," "nonresponder,"' or "acute deteriorating" category depending on their clinical response to treatment. The studies were qualified as "supportive" or "not supportive" depending on the percentage of patients exhibiting an association between relative change of anti-MAG antibody titers or levels and change in clinical outcomes. RESULTS: Fifty studies with 410 patients with anti-MAG neuropathy were included in the analysis. Forty studies with 303 patients supported the hypothesis that a "responder" patient had a relative reduction of anti-MAG antibody titers or levels that is associated with clinical improvements and "nonresponder" patients exhibited no significant change in anti-MAG IgM antibodies. Six studies with 93 patients partly supported, and 4 studies with 26 patients did not support the hypothesis. DISCUSSION: The retrospective analysis confirmed the hypothesis that a relative reduction in serum anti-MAG IgM antibodies is associated with a clinical response to immunotherapies; a sustained reduction of at least 50% compared with pretreatment titers or levels could be a valuable indicator for therapeutic response.
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Autoanticuerpos/sangre , Enfermedades Autoinmunes del Sistema Nervioso/sangre , Enfermedades Autoinmunes del Sistema Nervioso/tratamiento farmacológico , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Factores Inmunológicos/farmacología , Glicoproteína Asociada a Mielina/inmunología , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
BACKGROUND AND OBJECTIVES: To study the clinical and laboratory features of antineurofascin-155 (NF155)-positive autoimmune nodopathy (AN). METHODS: Patients with anti-NF155 antibodies detected on routine immunologic testing were included. Clinical characteristics, treatment response, and functional scales (modified Rankin Scale [mRS] and Inflammatory Rasch-built Overall Disability Scale [I-RODS]) were retrospectively collected at baseline and at the follow-up. Autoantibody and neurofilament light (NfL) chain levels were analyzed at baseline and at the follow-up. RESULTS: Forty NF155+ patients with AN were included. Mean age at onset was 42.4 years. Patients presented with a progressive (75%), sensory motor (87.5%), and symmetric distal-predominant weakness in upper (97.2%) and lower extremities (94.5%), with tremor and ataxia (75%). Patients received a median of 3 (2-4) different treatments in 46 months of median follow-up. Response to IV immunoglobulin (86.8%) or steroids (72.2%) was poor in most patients, whereas 77.3% responded to rituximab. HLA-DRB1*15 was detected in 91.3% of patients. IgG4 anti-NF155 antibodies were predominant in all patients; anti-NF155 titers correlated with mRS within the same patient (r = 0.41, p = 0.004). Serum NfL (sNfL) levels were higher in anti-NF155+ AN than in healthy controls (36.47 vs 7.56 pg/mL, p < 0.001) and correlated with anti-NF155 titers (r = 0.43, p = 0.001), with I-RODS at baseline (r = -0.88, p < 0.001) and with maximum I-RODS achieved (r = -0.58, p = 0.01). Anti-NF155 titers and sNfL levels decreased in all rituximab-treated patients. DISCUSSION: Anti-NF155 AN presents a distinct clinical profile and good response to rituximab. Autoantibody titers and sNfL are useful to monitor disease status in these patients. The use of untagged-NF155 plasmids minimizes the detection of false anti-NF155+ cases. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that anti-NF155 antibodies associate with a specific phenotype and response to rituximab.
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Autoanticuerpos/sangre , Enfermedades Autoinmunes del Sistema Nervioso , Moléculas de Adhesión Celular/inmunología , Factores Inmunológicos/farmacología , Factores de Crecimiento Nervioso/inmunología , Nódulos de Ranvier/inmunología , Rituximab/farmacología , Adulto , Anciano , Enfermedades Autoinmunes del Sistema Nervioso/sangre , Enfermedades Autoinmunes del Sistema Nervioso/tratamiento farmacológico , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Enfermedades Autoinmunes del Sistema Nervioso/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND AND OBJECTIVES: To analyze (1) the effect of immunoglobulin G (IgG) from patients with anti-myelin oligodendrocyte glycoprotein antibody (MOG-Ab)-associated disorder on the blood-brain barrier (BBB) endothelial cells and (2) the positivity of glucose-regulated protein 78 (GRP78) antibodies in MOG-Ab-associated disorders. METHODS: IgG was purified from sera with patients with MOG-Ab-associated disorder in the acute phase (acute MOG, n = 15), in the stable stage (stable MOG, n = 14), healthy controls (HCs, n = 9), and disease controls (DCs, n = 27). Human brain microvascular endothelial cells (BMECs) were incubated with IgG, and the number of nuclear NF-κB p65-positive cells in BMECs using high-content imaging system and the quantitative messenger RNA change in gene expression over the whole transcriptome using RNA-seq were analyzed. GRP78 antibodies from patient IgGs were detected by Western blotting. RESULTS: IgG in the acute MOG group significantly induced the nuclear translocation of NF-κB and increased the vascular cell adhesion molecule 1/intercellular adhesion molecule 1 expression/permeability of 10-kDa dextran compared with that from the stable MOG and HC/DC groups. RNA-seq and pathway analysis revealed that NF-κB signaling and oxidative stress (NQO1) play key roles. The NQO1 and Nrf2 protein amounts were significantly decreased after exposure to IgG in the acute MOG group. The rate of GRP78 antibody positivity in the acute MOG group (10/15, 67% [95% confidence interval, 38%-88%]) was significantly higher than that in the stable MOG group (5/14, 36% [13%-65%]), multiple sclerosis group (4/29, 14% [4%-32%]), the DCs (3/27, 11% [2%-29%]), or HCs (0/9, 0%). Removal of GRP78 antibodies from MOG-IgG reduced the effect on NF-κB nuclear translocation and increased permeability. DISCUSSION: GRP78 antibodies may be associated with BBB dysfunction in MOG-Ab-associated disorder.
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Autoanticuerpos/sangre , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Enfermedades Autoinmunes del Sistema Nervioso/fisiopatología , Barrera Hematoencefálica/fisiopatología , Chaperón BiP del Retículo Endoplásmico/inmunología , Glicoproteína Mielina-Oligodendrócito/inmunología , Adolescente , Adulto , Anciano , Enfermedades Autoinmunes del Sistema Nervioso/sangre , Preescolar , Células Endoteliales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Objective: To analyze the clinical manifestations, imaging, electroencephalography, treatment, and prognosis of 35 cases of autoimmune glial fibrillary acidic protein astrocytopathy (GFAP-A) in children. Methods: Children hospitalized in the Department of Neurology, Hunan Children's Hospital, China, between January 2015 and June 2021, owing to autoimmune diseases of the central nervous system were subjected to a cell-based assay (CBA). The assay identified 40 children positive for GFAP-immunoglobulin (Ig)G antibodies in the serum and/or the cerebrospinal fluid. Based on clinical manifestations and imaging characteristics, five children who were only positive for GFAP-IgG antibodies in serum were excluded, and the remaining 35 children were diagnosed with autoimmune GFAP-A. The clinical data derived from the 35 children were retrospectively analyzed. Results: A total of 35 children, including 23 males and 12 females with a mean age of 6.3 ± 0.6 years, manifested clinical symptoms of fever (62.9%), headache (42.9%), convulsions (42.9%), abnormal mental behavior (51.4%), disorders of consciousness (54.3%), visual disturbance (22.9%), ataxia (11.4%), paralysis (40%), and autonomic dysfunction (25.7%). One child exhibited only the clinical symptom of peripheral facial nerve palsy. Eleven out of 35 children were also positive for other antibodies. In addition to the common overlapping autoimmune syndromes, one case of autoimmune GFAP-A also manifested as Bickerstaff's brainstem encephalitis. Linear periventricular enhancement upon MRI was significantly less frequent in children (8.5%) than in adults. In pediatric patients, MRI contrast enhancement was principally seen in the meninges and brain lobes. Although repeated relapse (17.1%) and sequelae symptoms (20%) occurred in some cases, most children showed a favorable prognosis. Spearman's rank correlation showed that the antibody titer was not significantly associated with the severity of the initial disease conditions. Conclusions: The disease diagnosis in children seropositive for GFAP antibodies only should receive a comprehensive diagnosis based on their clinical symptoms, imaging, electroencephalographic characteristics, and treatment responses. Some patients with relapses should receive repeated gamma globulin and corticosteroid therapy or the addition of immunosuppressants to their therapeutic regimen, and slow-dose tapering of corticosteroids and extended treatment are recommended for patients with overlapping autoimmune syndromes.
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Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Proteína Ácida Fibrilar de la Glía/inmunología , Inmunoglobulina G/inmunología , Adolescente , Enfermedades Autoinmunes del Sistema Nervioso/sangre , Enfermedades Autoinmunes del Sistema Nervioso/líquido cefalorraquídeo , Enfermedades Autoinmunes del Sistema Nervioso/fisiopatología , Niño , Preescolar , Electroencefalografía , Encefalomielitis/sangre , Encefalomielitis/líquido cefalorraquídeo , Encefalomielitis/inmunología , Encefalomielitis/fisiopatología , Femenino , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina G/líquido cefalorraquídeo , Lactante , Masculino , Meningoencefalitis/sangre , Meningoencefalitis/líquido cefalorraquídeo , Meningoencefalitis/inmunología , Meningoencefalitis/fisiopatología , Mielitis/sangre , Mielitis/líquido cefalorraquídeo , Mielitis/inmunología , Mielitis/fisiopatología , Estudios RetrospectivosRESUMEN
We aimed to determine whether Alemtuzumab-induced immune reconstitution affects immunoglobulin and complement levels in the serum of Relapsing-Remitting Multiple Sclerosis (RRMS) patients. IgG4-levels were increased 24-months after treatment initiation compared to baseline levels in twenty-nine patients. Alemtuzumab-treated patients with the highest IgG4-levels were more prone to thyroid-related autoimmune manifestations and specific autoimmune adverse events such as Crohn's disease, Graves' disease, and hemolytic anemia. Compared to baseline, total IgG-levels showed a trend towards reduced levels following two-courses of Alemtuzumab, but no significant change of C3 and/or C4-levels was observed. In conclusion, monitoring of IgG4-levels can serve as a marker for secondary autoimmunity risk in multiple sclerosis patients treated with Alemtuzumab.
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Alemtuzumab/uso terapéutico , Autoanticuerpos/inmunología , Enfermedades Autoinmunes del Sistema Nervioso/inducido químicamente , Reconstitución Inmune , Inmunoglobulina G/inmunología , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Adulto , Alemtuzumab/efectos adversos , Enfermedades Autoinmunes del Sistema Nervioso/sangre , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Biomarcadores , Proteínas del Sistema Complemento/análisis , Femenino , Enfermedad de Graves/inducido químicamente , Enfermedad de Graves/inmunología , Humanos , Infecciones/etiología , Recuento de Linfocitos , Masculino , Esclerosis Múltiple Recurrente-Remitente/inmunología , Estudios Retrospectivos , Adulto JovenRESUMEN
In the past 5 years, the positivity rate of autoimmune encephalitis antibody panels has significantly decreased in patients with clinically suspected encephalitis in an encephalitis center in China. Furthermore, the spectrum of patients with autoantibodies related to autoimmune encephalitis has changed significantly, exhibiting a decreased percentage of patients with anti-N-methyl-d-aspartate receptor antibodies and an increased percentage of patients with infrequently observed autoantibodies. Meanwhile, a small but non-negligible proportion of patients with autoantibodies against cell surface and synaptic proteins exhibited positivity for more than one autoantibody.
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Autoanticuerpos/inmunología , Enfermedades Autoinmunes del Sistema Nervioso/epidemiología , Encefalitis/epidemiología , Adolescente , Adulto , Distribución por Edad , Anciano , Anciano de 80 o más Años , Encefalitis Antirreceptor N-Metil-D-Aspartato/sangre , Encefalitis Antirreceptor N-Metil-D-Aspartato/líquido cefalorraquídeo , Encefalitis Antirreceptor N-Metil-D-Aspartato/epidemiología , Encefalitis Antirreceptor N-Metil-D-Aspartato/inmunología , Autoanticuerpos/sangre , Autoanticuerpos/líquido cefalorraquídeo , Autoantígenos/inmunología , Enfermedades Autoinmunes del Sistema Nervioso/sangre , Enfermedades Autoinmunes del Sistema Nervioso/líquido cefalorraquídeo , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Niño , Preescolar , China/epidemiología , Encefalitis/sangre , Encefalitis/líquido cefalorraquídeo , Encefalitis/inmunología , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Morbilidad/tendencias , Proteínas del Tejido Nervioso/inmunología , Adulto JovenRESUMEN
BACKGROUND AND OBJECTIVES: Neurotropic viruses are suspected to play a role in the pathogenesis of autoimmune diseases of the CNS such as the association between the Epstein-Barr virus (EBV) and multiple sclerosis (MS). A group of autoimmune encephalitis (AE) is linked to antibodies against neuronal cell surface proteins. Because CNS infection with the herpes simplex virus can trigger anti-NMDA receptor (NMDAR) encephalitis, a similar mechanism for EBV and other neurotropic viruses could be postulated. To investigate for previous viral infections of the CNS, intrathecally produced virus-specific antibody synthesis was determined in patients with AE. METHODS: Antibody-specific indices (AIs) against EBV and measles, rubella, varicella zoster, herpes simplex virus, and cytomegalovirus were determined in 27 patients having AE (anti-NMDAR encephalitis, n = 21, and LGI1 encephalitis, n = 6) and in 2 control groups comprising of 30 patients with MS and 21 patients with noninflammatory CNS diseases (NIND), which were sex and age matched. RESULTS: An intrathecal synthesis of antibodies against EBV was found in 5/27 (19%) patients with AE and 2/30 (7%) of the patients with MS. All these patients had also at least 1 additional elevated virus-specific AI. In contrast, in none of the patients with NIND, an elevated virus-specific AI was detected. DISCUSSION: Intrathecally produced antibodies against EBV can be found in patients with AE and MS but only together with antibodies against different neurotropic viruses. Evidence of these antibodies is the result of a polyspecific immune response similar yet distinct from MS response rather than an elapsed infection of the CNS.
Asunto(s)
Anticuerpos Antivirales/líquido cefalorraquídeo , Enfermedades Autoinmunes del Sistema Nervioso/líquido cefalorraquídeo , Encefalitis Viral/líquido cefalorraquídeo , Herpesvirus Humano 4/inmunología , Simplexvirus/inmunología , Adolescente , Adulto , Anciano , Anticuerpos Antivirales/sangre , Enfermedades Autoinmunes del Sistema Nervioso/sangre , Encefalitis Viral/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Autoimmune Autonomic Ganglionopathy (AAG) is an uncommon immune-mediated neurological disease that results in failure of autonomic function and is associated with autoantibodies directed against the ganglionic acetylcholine receptor (gnACHR). The antibodies are routinely detected by immunoprecipitation assays, such as radioimmunoassays (RIA), although these assays do not detect all patients with AAG and may yield false positive results. Autoantibodies against the gnACHR exert pathology by receptor modulation. Flow cytometric analysis is able to determine if this has occurred, in contrast to the assays in current use that rely on immunoprecipitation. Here, we describe the first high-throughput, non-radioactive flow cytometric assay to determine autoantibody mediated gnACHR immunomodulation. Previously identified gnACHR antibody seronegative and seropositive sera samples (RIA confirmed) were blinded and obtained from the Oxford Neuroimmunology group along with samples collected locally from patients with or without AAG. All samples were assessed for the ability to cause gnACHR immunomodulation utilizing the prototypical gnACHR expressing cell line, IMR-32. Decision limits were calculated from healthy controls, and Receiver Operating Characteristic (ROC) curves were constructed after unblinding all samples. One hundred and ninety serum samples were analyzed; all 182 expected negative samples (from healthy controls, autonomic disorders not thought to be AAG, other neurological disorders without autonomic dysfunction and patients with Systemic Lupus Erythematosus) were negative for immunomodulation (<18%), as were the RIA negative AAG and unconfirmed AAG samples. All RIA positive samples displayed significant immunomodulation. There were no false positive or negative samples. There was perfect qualitative concordance as compared to RIA, with an Area Under ROC of 1. Detection of Immunomodulation by flow cytometry for the identification of gnACHR autoantibodies offers excellent concordance with the gnACHR antibody RIA, and overcomes many of the shortcomings of immunoprecipitation assays by directly measuring the pathological effects of these autoantibodies at the cellular level. Further work is needed to determine the correlation between the degree of immunomodulation and disease severity.
Asunto(s)
Autoanticuerpos/sangre , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Enfermedades del Sistema Nervioso Autónomo/inmunología , Citometría de Flujo/métodos , Ganglios Autónomos/inmunología , Receptores Colinérgicos/inmunología , Área Bajo la Curva , Autoanticuerpos/inmunología , Enfermedades Autoinmunes del Sistema Nervioso/sangre , Enfermedades del Sistema Nervioso Autónomo/sangre , Línea Celular Tumoral , Humanos , Inmunomodulación , Plasma , Curva ROC , Suero , Método Simple CiegoRESUMEN
OBJECTIVE: To identify and characterize autoantibodies (Abs) as novel biomarkers for an autoimmune context in patients with central and peripheral neurologic diseases. METHODS: Two distinct approaches (immunoprecipitation/mass spectrometry-based proteomics and protein microarrays) and patients' sera and CSF were used. The specificity of the identified target was confirmed by cell-based assay (CBA) in 856 control samples. RESULTS: Using the 2 methods as well as sera and CSF of patients with central and peripheral neurologic involvement, we identified Abs against the family of Argonaute proteins (mainly AGO1 and AGO2), which were already reported in systemic autoimmunity. AGO-Abs were mostly of immunoglobulin G 1 subclass and conformation dependent. Using CBA, AGO-Abs were detected in 21 patients with a high suspicion of autoimmune neurologic diseases (71.4% were women; median age 57 years) and only in 4/856 (0.5%) controls analyzed by CBA (1 diagnosed with small-cell lung cancer and the other 3 with Sjögren syndrome). Among the 21 neurologic patients identified, the main clinical presentations were sensory neuronopathy (8/21, 38.1%) and limbic encephalitis (6/21, 28.6%). Fourteen patients (66.7%) had autoimmune comorbidities and/or co-occurring Abs, whereas AGO-Abs were the only autoimmune biomarker for the remaining 7/21 (33.3%). Thirteen (61.9%) patients were treated with immunotherapy; 8/13 (61.5%) improved, and 3/13 (23.1%) remained stable, suggesting an efficacy of these treatments. CONCLUSIONS: AGO-Abs might be potential biomarkers of autoimmunity in patients with central and peripheral nonparaneoplastic neurologic diseases. In 7 patients, AGO-Abs were the only biomarkers; thus, their identification may be useful to suspect the autoimmune character of the neurologic disorder. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that AGO-Abs are more frequent in patients with autoimmune neurologic diseases than controls.
Asunto(s)
Proteínas Argonautas/sangre , Proteínas Argonautas/líquido cefalorraquídeo , Autoanticuerpos/sangre , Autoanticuerpos/líquido cefalorraquídeo , Enfermedades Autoinmunes del Sistema Nervioso/sangre , Enfermedades Autoinmunes del Sistema Nervioso/líquido cefalorraquídeo , Proteínas Argonautas/inmunología , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , HumanosRESUMEN
Human antibodies against Myelin Oligodendrocyte Glycoprotein (MOG) from immunoglobulin-G subclasses (MOG-IgG) have been recently associated with a new subgroup of neurological autoimmune diseases with distinct clinical characteristics from multiple sclerosis and neuromyelitis optica spectrum disorders. The use of MOG-IgG as a biomarker is an essential tool to assist in the diagnosis and clinical prognosis. The cell-based assay (CBA) is a methodology that expresses high levels of natively folded human MOG protein in the cell membrane being the methodology most used for clinical MOG-IgG diagnosis. However, there is still no consensus about the best approach to perform CBA to improve the results. The CBA using flow cytometry (CBA-FC) is an automated technique with objective quantification, reducing the subject of human bias that occurred at CBA using immunofluorescence (CBA-IF). In this study, we compared the performance of CBA-IF and CBA-FC as an acquisition tool analysis. The sera of 104 patients diagnosed with inflammatory Central Nervous System diseases were tested in both CBA-IF and CBA-FC. We used the dilution of 1:128 for CBA-IF and three different dilutions (1:20, 1:100, and 1:640) for CBA-FC. The CBA-FC and CBA-IF results had 88.5% agreement between assays and the CBA-IF titers by endpoint-dilution correlated with the CBA-FC titers. The highest serum dilution resulted in an increased CBA-FC specificity, but there was a reduction in the CBA-FC sensitivity. Our study showed that CBA-FC can be used in clinical practice as a diagnostic technique for MOG-IgG. In addition, in some specific cases, the combination of both techniques could be used as a tool to discriminate unspecific binding and overcome single assay limitations.
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Autoanticuerpos/sangre , Enfermedades Autoinmunes del Sistema Nervioso/diagnóstico , Citometría de Flujo/métodos , Inmunoglobulina G/sangre , Microscopía Fluorescente/métodos , Glicoproteína Mielina-Oligodendrócito/inmunología , Adulto , Autoantígenos/inmunología , Enfermedades Autoinmunes del Sistema Nervioso/sangre , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Tissue-based assay (TBA) is a widely-used method to detect neural autoantibodies, but the diagnostic accuracy for autoimmune encephalitis (AE) has not yet been adequately measured. We retrospectively evaluated the sensitivity and specificity of an indirect immunofluorescence TBA (IIF-TBA) in 159 patients with suspected AE. Serum and cerebrospinal fluid (CSF) specimens were collected and tested from December 2012 to September 2020. In the paired sample analysis, serum testing showed higher sensitivity than CSF, while the latter had higher specificity. Based on these results, we clarify the advantages of using a TBA as the principal screening method for patients with suspected AE.
Asunto(s)
Algoritmos , Enfermedades Autoinmunes del Sistema Nervioso/sangre , Enfermedades Autoinmunes del Sistema Nervioso/líquido cefalorraquídeo , Bioensayo/métodos , Encefalitis/sangre , Encefalitis/líquido cefalorraquídeo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Autoanticuerpos/sangre , Autoanticuerpos/líquido cefalorraquídeo , Enfermedades Autoinmunes del Sistema Nervioso/diagnóstico , Niño , Preescolar , Encefalitis/diagnóstico , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto JovenRESUMEN
We report three unrelated probands, two male and one female, diagnosed with Aicardi-Goutières syndrome (AGS) after screening positive on California newborn screening (CA NBS) for X-linked adrenoleukodystrophy (X-ALD) due to elevated C26:0 lysophosphatidylcholine (C26:0-LPC). Follow-up evaluation was notable for elevated C26:0, C26:1, and C26:0/C22:0 ratio, and normal red blood cell plasmalogens levels in all three probands. Diagnoses were confirmed by molecular sequencing prior to 12 months of age after clinical evaluation was inconsistent with X-ALD or suggestive of AGS. For at least one proband, the early diagnosis of AGS enabled candidacy for enrollment into a therapeutic clinical trial. This report demonstrates the importance of including AGS on the differential diagnosis for individuals who screen positive for X-ALD, particularly infants with abnormal neurological features, as this age of onset would be highly unusual for X-ALD. While AGS is not included on the Recommended Universal Screening Panel, affected individuals can be identified early through state NBS programs so long as providers are aware of a broader differential that includes AGS. This report is timely, as state NBS algorithms for X-ALD are actively being established, implemented, and refined.
Asunto(s)
Adrenoleucodistrofia/sangre , Enfermedades Autoinmunes del Sistema Nervioso/sangre , Enfermedades Genéticas Ligadas al Cromosoma X/sangre , Tamizaje Neonatal , Malformaciones del Sistema Nervioso/sangre , Adrenoleucodistrofia/complicaciones , Adrenoleucodistrofia/genética , Adrenoleucodistrofia/patología , Enfermedades Autoinmunes del Sistema Nervioso/complicaciones , Enfermedades Autoinmunes del Sistema Nervioso/genética , Enfermedades Autoinmunes del Sistema Nervioso/patología , Pruebas con Sangre Seca , Femenino , Enfermedades Genéticas Ligadas al Cromosoma X/complicaciones , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/patología , Humanos , Lactante , Recién Nacido , Lisofosfatidilcolinas/sangre , Masculino , Malformaciones del Sistema Nervioso/complicaciones , Malformaciones del Sistema Nervioso/genética , Malformaciones del Sistema Nervioso/patología , Espectrometría de Masas en TándemRESUMEN
OBJECTIVE: Patients with acquired autonomic dysfunction may have antibodies specific to the ganglionic nicotinic acetylcholine receptor (gAChR). However, the clinical features of children and adolescents with acquired autonomic dysfunction (AAD) remain unclear. This study aimed to determine the clinical features of pediatric patients with acquired autonomic dysfunction. METHODS: This study retrospectively examined a series of patients of AAD with serum gAChR antibodies who were referred to our laboratory for antibody testing between January 2012 and April 2019. The study included 200 patients (<20 years, 20 cases; ≥20 years, 175 cases) with clinical features of AAD. RESULTS: Upon comparing pediatric and adult patients, we found that antecedent infection and autonomic symptoms at onset with gastrointestinal symptoms occurred more frequently in children with AAD. We confirmed that four children (20.0%) met the diagnostic criteria for postural orthostatic tachycardia syndrome (POTS). A significantly higher number of children than adults had POTS (P = 0.002). In addition, upper GI dysfunction was more prevalent in children than in adults (P = 0.042). In particular, nausea and vomiting occurred in 60.0% of children with AAD and in 21.1% of adults (P < 0.001). The frequency of paralytic ileus was significantly higher in children with AAD (20.0%) relative to adults (6.3%) (P = 0.030). Regarding extra-autonomic manifestations, encephalopathy was more frequent in children (15.0%) than in adults (1.1%) (P < 0.001). INTERPRETATION: Pediatric AAD patients have their own clinical characteristics, and these features may be unique to children and adolescents.