Cerebrospinal fluid eosinophils in pediatric myelin oligodendrocyte glycoprotein antibody-associated disease.

BACKGROUND: Eosinophils in cerebrospinal fluid (CSF) are an uncommon finding most often associated with parasitic infections, but have also been described in some neuroinflammatory disorders. Eosinophilic infiltration is not thought to be a typical feature of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). We aim to describe the rate of CSF eosinophil positivity in a cohort of pediatric MOGAD patients. METHODS: Single-center retrospective chart review of pediatric MOGAD patients. Clinical and laboratory data was collected from the electronic medical record and analyzed. RESULTS: Of 46 pediatric patients with positive serum myelin oligodendrocyte glycoprotein antibody (MOG-IgG) identified, 38 patients fulfilling internationally proposed MOGAD diagnostic criteria were included for analysis. 6 patients with MOGAD were excluded as no CSF data was available, and 2 patients with positive MOG-IgG but diagnosis more consistent with MS were excluded. Median age was 7.3 years, and 19/38 (50 %) were female. Acute disseminated encephalomyelitis (ADEM) was the most common presenting phenotype (23/38, 61 %), and other phenotypes included optic neuritis (10/38, 26 %), transverse myelitis (3/38, 8 %), and neuromyelitis optica spectrum disorder (NMOSD) (2/38, 5 %). 12 of 36 (33 %) patients with all lumbar puncture (LP) data available had CSF eosinophils present, with eosinophil mean of 3 % and range from 1 % to 18 % of CSF while blood cells. CONCLUSION: CSF eosinophils were present in one third of pediatric MOGAD patients, which is a higher rate than previously reported in either MOGAD or aquaporin-4 antibody positive NMOSD cohorts. Understanding the CSF composition of pediatric MOGAD patients helps to facilitate more prompt diagnosis and treatment and may shed light onto underlying pathologic mechanisms of disease with the goal to inform future therapeutic targets.

Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease and Varicella Zoster Virus Infection - Frequency of an Association.

To determine whether there is a correlation between myelin oligodendrocyte glycoprotein (MOG) antibody-associated diseases and varicella zoster virus (VZV) infection. We provide a case report and performed a study to determine the frequency of MOG antibodies (MOG-IgG) in neurological VZV infections. Patients admitted to the Medical University of Innsbruck from 2008-2020 with a diagnosis of a neurological manifestation of VZV infection (n=59) were included in this study; patients with neuroborreliosis (n=34) served as control group. MOG-IgG was detected using live cell-based assays. In addition, we performed a literature review focusing on MOG and aquaporin-4 (AQP4) antibodies and their association with VZV infection. Our case presented with VZV-associated longitudinally extensive transverse myelitis and had MOG-IgG at a titer of 1:1280. In the study, we did not detect MOG-IgG in any other patient neither in the VZV group (including 15 with VZV encephalitis/myelitis) nor in the neuroborreliosis group. In the review of the literature, 3 cases with MOG-IgG and additional 9 cases with AQP4 IgG associated disorders in association with a VZV infection were identified. MOG-IgG are rarely detected in patients with VZV infections associated with neurological diseases.

Longitudinally extensive transverse myelitis with anti-myelin oligodendrocyte glycoprotein antibodies following SARS-CoV-2 infection.

We report the case of a patient with symptoms of myelopathy following acute SARS-CoV-2 infection. MRI documented a longitudinally extensive transverse myelitis and further investigation was unremarkable with the exception of positivity for MOG-IgG in serum. This report extends the spectrum of post-COVID-19 neurological syndromes, and documents a very significant improvement to long-term oral corticosteroid therapy in this setting. Further prospective studies are needed to establish the risk of recurrence in this subset of patients.

Anti-Interleukin-6 and Janus Kinase Inhibitors for Severe Neurologic Toxicity of Checkpoint Inhibitors.

BACKGROUND AND OBJECTIVES: To describe the marked clinical and biological responses of a targeted treatment with anti-interleukin-6 (IL-6)-receptor antibody and Janus kinase (JAK) inhibitors in a patient with a severe, corticoresistant CNS toxicity of immune-checkpoint inhibitor (ICI) therapy. METHODS: A 58-year-old man was admitted for subacute paraparesis, urinary retention, and ascending paresthesia. He was under treatment with ipilimumab and nivolumab for metastatic melanoma. Spine MRI disclosed multiple T2-hyperintense, contrast-enhancing longitudinally extensive lesions. A diagnosis of ICI-related acute transverse myelitis was made. RESULTS: ICIs were immediately discontinued, and the patient received high-dose glucocorticoids plus 1 session of plasma exchange, but he did not improve. Based on the marked elevation of CSF IL-6 (505 pg/mL), a second-line targeted therapy with anti-IL-6-receptor tocilizumab (8 mg/kg/mo for 3 infusions) plus JAK inhibitor ruxolitinib (50 mg/d) was administered. Patient neurologic status started to improve shortly after, with corresponding radiologic resolution. At 9 months, the patient was able to walk independently, presenting only slight residual disability while remaining in oncologic partial response. DISCUSSION: Our case suggests that some patients with severe, corticoresistant CNS immune-related toxicities of ICIs may benefit from cytokine blockade. Cytokine measurement in serum and CSF might help in selecting patients for personalized treatment strategies.

Modern Look at Transverse Myelitis and Inflammatory Myelopathy: Epidemiology of the National Veterans Health Administration Population.

BACKGROUND AND OBJECTIVES: To characterize population-level data associated with transverse myelitis (TM) within the US Veterans Health Administration (VHA). METHODS: This retrospective review used VHA electronic medical record from 1999 to 2015. We analyzed prevalence, disease characteristics, modified Rankin Scale (mRS) scores, and mortality data in patients with TM based on the 2002 Diagnostic Criteria. RESULTS: We identified 4,084 patients with an International Classification of Diseases (ICD) code consistent with TM and confirmed the diagnosis in 1,001 individuals (90.7% males, median age 64.2, 67.7% Caucasian, and 31.4% smokers). The point prevalence was 7.86 cases per 100,000 people. Less than half of the cohort underwent a lumbar puncture, whereas only 31.8% had a final, disease-associated TM diagnosis. The median mRS score at symptom onset was 3 (interquartile range 2-4), which remained unchanged at follow-up, although less than half (43.2%) of the patients received corticosteroids, IVIg, or plasma exchange. Approximately one-quarter of patients (24.3%) had longitudinal extensive TM, which was associated with poorer outcomes (p = 0.002). A total of 108 patients (10.8%) died during our review (94.4% males, median age 66.5%, and 70.4% Caucasian). Mortality was associated with a higher mRS score at follow-up (OR 1.94, 95% CI, 1.57-2.40) and tobacco use (OR 1.87, 95% CI, 1.17-2.99). DISCUSSION: This national TM review highlights the relatively high prevalence of TM in a modern cohort. It also underscores the importance of a precise and thorough workup in this disabling disorder to ensure diagnostic precision and ensure optimal management for patients with TM in the future.

Concurrent Longitudinally Extensive Transverse Myelitis and Guillain-Barré Syndrome in a Child Secondary to COVID-19 Infection: A Severe Neuroimmunologic Complication of COVID-19.

Neurologic manifestation of coronavirus disease 2019 (COVID-19) in children is evolving with time. We are reporting a young girl who presented to us with acute febrile illness followed by acute onset severe flaccid paralysis requiring prolonged intensive care unit stay and ventilator support. She was evaluated extensively and found to be positive for COVID serology, and neuroimaging revealed features of longitudinally extensive transverse myelitis (LETM) with enhancing cauda equina nerve roots, suggesting Guillain-Barré Syndrome (GBS). She failed to respond to immune suppressive therapy and needed plasma exchange for recovery. Like other common viral illnesses, COVID-19 can also act as a trigger for GBS-like illness and LETM, and we need to suspect these diagnoses in the cases with COVID-19 infection in compatible cases. This is probably the first pediatric case with concurrent GBS and LETM secondary to COVID-19 infection.

Case Report: Anti-MOG Antibody Seroconversion Accompanied by Dimethyl Fumarate Treatment.

Here we report three cases of anti-myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) mimicking multiple sclerosis in which seropositivity for anti-MOG antibodies occurred during disease-modifying drug dimethyl fumarate (DMF) treatment. These patients developed relapses with anti-MOG antibody seroconversion after switching from fingolimod or steroid pulse therapy to DMF, which was associated with peripheral lymphocyte recovery. MOGAD is considered a humoral immune disease, and DMF reportedly enhances Th2-skewed humoral immune activity. Therefore, we suggest that DMF, but not fingolimod, may exacerbate humoral immune imbalance and enhance autoantibody production, leading to aggravation of MOGAD.

COVID-19, HHV6 and MOG antibody: A perfect storm.

BACKGROUND: Serious neurological complications of SARS-CoV-2 are increasingly being recognized. CASE: We report a novel case of HHV6 myelitis with parainfectious MOG-IgG in the setting of COVID-19-induced lymphopenia and hypogammaglobulinemia. The patient experienced complete neurological recovery with gancyclovir, high dose corticosteroids, and plasma exchange. To our knowledge, this is the first case of HHV6 reactivation in the central nervous system in the setting of COVID19 infection and the first case of MOG-IgG myelitis in the setting of SARS-CoV-2 and HHV6 coinfection. CONCLUSION: Patients with neurological manifestations in the setting of COVID19-related immunodeficiency should be tested for opportunistic infections including HHV6. Viral infection is a known trigger for MOG-IgG and therefore this antibody should be checked in patients with SARS-CoV-2 associated demyelination.

Neuromyelitis optica spectrum disorder (NMOSD) presenting as acute transverse myelitis with positive aquaporin 4 antibodies.

An 80-year-old, previously healthy patient presents with acute transverse myelitis with sensory level at T8. The MRI scan of the spinal cord showed longitudinal extensive transverse myelitis, and she tested positive for aquaporin 4 antibodies in serum. She received treatment with intravenous and oral steroids, with no improvement and then underwent plasma exchange. She was then started on azathioprine for prevention of relapses, while continuing physiotherapy and occupational therapy. Eventually, she was transferred to a specialised spinal cord centre for long-term rehabilitation.

Overlapping central and peripheral nervous system syndromes in MOG antibody-associated disorders.

OBJECTIVE: Antibodies to myelin oligodendrocyte glycoprotein (MOG) are associated with CNS demyelination inclusive of optic neuritis (ON) and transverse myelitis (TM). To examine whether peripheral nervous system (PNS) involvement is associated with MOG antibody-associated disorders (MOGAD), we performed detailed characterization of an Australasian MOGAD cohort. METHODS: Using a live cell-based assay, we diagnosed 271 adults with MOGAD (2013-2018) and performed detailed clinical and immunologic characterization on those with likely PNS involvement. RESULTS: We identified 19 adults with MOGAD and PNS involvement without prior TM. All patients had CNS involvement including ON (bilateral [n = 3], unilateral [n = 3], and recurrent [n = 7]), a cortical lesion (n = 1), meningoencephalitis (n = 1), and subsequent TM (n = 4). Clinical phenotyping and neurophysiology were consistent with acute inflammatory demyelinating polyneuropathy (n = 1), myeloradiculitis (n = 3), multifocal motor neuropathy (n = 1), brachial neuritis (n = 2), migrant sensory neuritis (n = 3), and paresthesia and/or radicular limb pain (n = 10). Onset MRI spine was consistent with myeloradiculitis with nerve root enhancement in 3/19 and normal in 16/19. Immunotherapy resulted in partial/complete PNS symptom resolution in 12/15 (80%) (steroids and/or IV immunoglobulin n = 9, rituximab n = 2, and plasmapheresis n = 1). We identified serum antibodies targeting neurofascin 155, contactin-associated protein 2, or GM1 in 4/16 patients with MOGAD PNS compared with 0/30 controls (p = 0.01). There was no binding to novel cell surface antigens using an in vitro myelinating sensory neuronal coculture model. CONCLUSIONS: Myeloradiculitis, combined central and peripheral demyelination syndromes, and inflammatory neuropathies may be associated with MOGAD and may be immunotherapy responsive. We identified a subgroup who may have pathology mediated by coexistent autoantibodies.

Mycophenolate mofetil-induced liver injury in a patient with aquaporin-4 antibody positive transverse myelitis.

We present a case of a 49-year-old woman diagnosed with aquaporin-4 antibody-positive transverse myelitis, who developed a significant transaminitis 2 months after commencing mycophenolate mofetil (MMF) as a steroid-sparing agent. No other risk factors were identified, a blood liver panel was negative and liver biopsy showed features compatible with drug-induced liver injury (DILI). MMF was stopped with a corresponding normalisation of serum alanine aminotransferase over the next 2 months. This case highlights MMF as a rare cause of DILI and provides justification for monitoring of liver biochemistry on therapy.

Características clínicas del espectro de la enfermedad asociada a los anticuerpos contra la glucoproteína del oligodendrocito asociada a la mielina / Clinical presentation of the spectrum of myelin oligodendocryte glycoprotein antibody disease

INTRODUCCIÓN: La enfermedad asociada a anticuerpos contra la glucoproteína del oligodendrocito asociado a la mielina (MOG) es una entidad infrecuente y prácticamente nueva en la medicina. En países en desarrollo, aún hay importantes limitaciones para la detección de los anticuerpos anti-MOG mediante ensayo basado en células, por lo que conocer las características clínicas de los diferentes fenotipos y sus diferencias con otras patologías desmielinizantes del sistema nervioso es fundamental, y con ello realizar un abordaje diagnóstico y terapéutico adecuado de los pacientes. OBJETIVO: Presentar una actualización en cuanto a las características clínicas del espectro de la enfermedad. Éste es el primer artículo en castellano que reúne los fenotipos más frecuentes y brinda una descripción clara de lo que se debe tener en cuenta en cada uno de ellos. DESARROLLO: Esta entidad se caracteriza por tener un curso monofásico o recurrente. La neuritis óptica es el fenotipo de presentación más frecuente en la población general, y la encefalomielitis aguda diseminada, la más frecuente en los niños. Otros fenotipos que se describen en la presente revisión son la mielitis transversa, la encefalitis cortical y los síndromes de tallo cerebral, así como los criterios propuestos para el diagnóstico de la enfermedad asociada a anticuerpos anti-MOG. CONCLUSIONES: En la actualidad no existen estudios que busquen caracterizar a la población hispanoparlante con esta enfermedad ni artículos de revisión en lengua castellana, por lo que es importante difundir conocimiento y desarrollar investigación en esta área

INTRODUCTION: Myelin oligodendrocyte glycoprotein (MOG) antibody disease is a rare and practically new entity in medicine. In developing countries, there are still important limitations for the detection of anti-MOG antibodies by cell-based assay, so knowing the clinical characteristics of the different phenotypes and their differences with other demyelinating pathologies of the central nervous system is essential in order to make a proper diagnostic and therapeutic approach of the patients. AIM: To present an update regarding the clinical characteristics of the disease spectrum, being the first article in Spanish that gathers the most frequent phenotypes and provides a clear description of what should be considered to identify each of these phenotypes. DEVELOPMENT: This disease is characterized by having a monophasic or recurrent course, with optic neuritis being the most frequent presentation phenotype in general population and disseminated acute encephalomyelitis the most frequent in children. Other phenotypes described in this review are transverse myelitis, focal cortical encephalitis and cerebral stem syndromes, as well as the proposed criteria for the diagnosis of the disease associated with MOG antibody disease. CONCLUSION: Currently there are no studies that seek to characterize the Spanish-speaking population with this disease, or review articles in Spanish, so it is important to disseminate knowledge and develop research in this area

A comparative study on clinical characterizations between acute myelitis onset of neuromyelitis optica spectrum disease and idiopathic transverse myelitis.

BACKGROUND/AIMS: Both of neuromyelitis optica spectrum disease (NMOSDs) and idiopathic transverse myelitis (ITM) could present as acute transverse myelitis. However, long-term immunological treatment and prognosis are different for high recurrence of NMOSDs. In this study, we summarized clinical differences between acute attack myelitis of NMOSDs and ITM, we further screened serum auto-antibodies to help understand the two distinct clinical entities. METHODS: This is a retrospective study on 48 NMOSD patients and 49 ITM patients in neurological department of Nanjing Drum Tower Hospital from 2013 to 2019. Clinical, CSF and MRI profiles on the acute episode were also compared between NMOSD patients and ITM patients. Serum AQP4 and auto-antibodies were tested. Clinical parameters were further compared between NMOSD patients with and without auto-antibodies. RESULTS: Compared with ITM patients, NMOSD patients manifested with longer vertebral segments (5.42 ± 3.17 segments vs. 2.31 ± 2.36 segments, p < 0.001), higher female/male ratio (13:3 vs. 20:29, p < 0.001), higher IgG index (30.30% vs. 9.09%, p < 0.05). Positive rates of anti-Ro-52 (47.92% vs. 14.29%, p < 0.001), anti-ANAs (50.00% vs.10.20%, p < 0.001) and anti-SSA (35.42% vs. 6.12%, p = 0.001) were significantly higher in the NMOSD patients than the ITM patients. Seropositive Ro-52 and SSA were associated with longer injured spinal cord segments. However, Ro-52 antibody may not be associated with NMOSD relapsing during our follow up. CONCLUSIONS: NMOSD patients manifested with longer vertebral segments, higher female/male ratio, IgG index, anti-ANAs, anti-Ro-52 and anti-SSA seroprevalence than ITM patients. These features may help clinicians better distinguish NMOSD from ITM and provide long-term immunotherapy reasonably.

Outcome and risk of recurrence in a large cohort of idiopathic longitudinally extensive transverse myelitis without AQP4/MOG antibodies.

BACKGROUND: Longitudinally extensive transverse myelitis (LETM) is classically related to aquaporin (AQP4)-antibodies (Ab) neuromyelitis optica spectrum disorders (NMOSD) or more recently to myelin oligodendrocyte glycoprotein (MOG)-Ab associated disease. However, some patients remain negative for any diagnosis, despite a large work-up including AQP4-Ab and MOG-Ab. Data about natural history, disability outcome, and treatment are limited in this group of patients. We aimed to (1) describe clinical, biological, and radiological features of double seronegative LETM patients; (2) assess the clinical course and identify prognostic factors; and (3) assess the risk of recurrence, according to maintenance immunosuppressive therapy. METHODS: Retrospective evaluation of patients with a first episode of LETM, tested negative for AQP-Ab and MOG-Ab, from the French nationwide observatory study NOMADMUS. RESULTS: Fifty-three patients (median age 38 years (range 16-80)) with double seronegative LETM were included. Median nadir EDSS at onset was 6.0 (1-8.5), associated to a median EDSS at last follow-up of 4.0 (0-8). Recurrence was observed in 24.5% of patients in the 18 following months, with a median time to first relapse of 5.7 months. The risk of recurrence was lower in the group of patients treated early with an immunosuppressive drug (2/22, 9%), in comparison with untreated patients (10/31, 32%). CONCLUSIONS: A first episode of a double seronegative LETM is associated to a severe outcome and a high rate of relapse in the following 18 months, suggesting that an early immunosuppressive treatment may be beneficial in that condition.

Aquaporin-4 neuromyelitis optica spectrum disorder in a 2-year-old girl: Diagnostic and treatment considerations.

We describe a case of an unusually early and severe manifestation of Aquaporin-4 (AQP-4) positive Neuromyelitis Optica Spectrum Disorder (NMOSD) in a two-year-old girl. We discuss learning points from her clinical presentation and highlight differences between pediatric and adult presentations of the disease. We argue that AQP-4 NMOSD should always be considered in the differential diagnosis for any child presenting with an acute neuroimmunological process given the morbidity associated with the condition and the importance of early diagnosis and treatment.

MOG encephalomyelitis: distinct clinical, MRI and CSF features in patients with longitudinal extensive transverse myelitis as first clinical presentation.

BACKGROUND: Based on clinical, immunological and histopathological evidence, MOG-IgG-associated encephalomyelitis (MOG-EM) has emerged as a distinct disease entity different from multiple sclerosis (MS) and aquaporin-4-antibody-positive neuromyelitis optica spectrum disorder (NMOSD). MOG-EM is associated with a broader clinical phenotype including optic neuritis, myelitis, brainstem lesions and acute disseminated encephalomyelitis with a substantial clinical and radiological overlap to other demyelinating CNS disorders. OBJECTIVE: To evaluate common clinical, MRI and CSF findings, as well as therapy responses in patients with longitudinal extensive transverse myelitis (LETM) as initial clinical presentation of MOG-EM. METHODS: After excluding patients with a known diagnosis of MS, we identified 153 patients with myelitis of which 7 fulfilled the inclusion criteria and were investigated for MRI, CSF and clinical parameters. RESULTS: Patients with LETM as first clinical presentation of MOG-EM display similar characteristics, namely a lack of gadolinium-enhancement in spinal cord MRI, marked pleocytosis, negative oligoclonal bands, a previous history of infections/vaccinations and response to antibody-depleting treatments for acute attacks and long-term treatment. CONCLUSIONS: We identify common pathological findings in patients with LETM as first clinical presentation of MOG-EM which distinguishes it from other forms of LETM and should lead to testing for MOG-IgG in these cases.

MOG-IgG myelitis coexisting with systemic lupus erythematosus in the post-partum setting.

BACKGROUND: Longitudinally extensive transverse myelitis (LETM) accompanying systemic lupus erythematosus (SLE) is often due to coexisting aquaporin-4-IgG seropositive neuromyelitis optica spectrum disorder but has not been associated with myelin oligodendrocyte glycoprotein-IgG (MOG-IgG). OBJECTIVE AND METHODS: Case report at an academic medical center. RESULTS: A 32-year-old woman developed severe transverse myelitis (paraplegia) shortly after SLE onset in the post-partum period. Magnetic resonance imaging (MRI) revealed an LETM, cerebrospinal fluid showed marked inflammation, and testing for infections was negative. Serum live-cell-based assay for MOG-IgG was positive but aquaporin-4-IgG was negative. CONCLUSION: In patients with SLE and LETM, MOG-IgG testing should be considered, in addition to AQP4-IgG.

The frequency of longitudinally extensive transverse myelitis in MS: A population-based study.

BACKGROUND: Determining the frequency of longitudinally-extensive transverse myelitis (LETM: T2-lesion ≥3 vertebral segments) in multiple sclerosis (MS) is essential to assess its utility in differentiating from aquaporin-4-IgG (AQP4-IgG) positive neuromyelitis optica spectrum disorder (NMOSD) and myelin-oligodendrocyte-glycoprotein-IgG (MOG-IgG) myelitis. We sought to determine the frequency of LETM in MS during a myelitis attack. METHODS: We identified Olmsted County (MN, USA) residents on 12/31/2011 with inflammatory demyelinating disease. Inclusion criteria were: 1) Clinical myelitis episode accompanied by a new spinal magnetic resonance imaging (MRI) lesion (≤6 weeks from onset); 2) MS diagnosis by 2010 McDonald criteria; 3) Seronegative for AQP4-IgG and MOG-IgG. MRI characteristics were determined. RESULTS: Sixty-seven patients (median age at myelitis: 41 years [range, 16-65]; 76% females) with 92 myelitis attacks accompanied by a new MRI spinal cord lesion were identified. The frequency of LETM was 0%. The median T2-hyperintense lesion length in vertebral segments was 1.0 (range, 0.5-2.5) and 82/92 (89%) were peripheral in location on axial sequences; 58% had associated gadolinium enhancement. Two patients (2% of attacks) had multiple short lesions resembling LETM on sagittal images but axial sequences confirmed multiple non-contiguous short lesions. CONCLUSION: LETM is rare in adult MS myelitis and its presence should prompt evaluation for AQP4-IgG, MOG-IgG or other etiologies. Careful scrutiny of axial images is important as coalescence of multiple short lesions may lead to the artifactual appearance of an LETM.

GRP 78 antibodies are associated with clinical phenotype in neuromyelitis optica.

BACKGROUND: We previously reported the association between blood-brain barrier (BBB) dysfunction and glucose-regulated protein 78 (GRP 78) autoantibodies in neuromyelitis optica (NMO). OBJECTIVE: We clarify whether the BBB-endothelial cell activation induced by immunoglobulin G (IgG) is associated with the clinical phenotype, disease activity, and markers of BBB disruption. METHODS: We purified serum IgG from 24 serum samples from patients with NMO spectrum disorder (NMOSD), who were positive for anti-AQP4 antibodies (longitudinally extensive transverse myelitis [LETM], n = 14; optic neuritis [ON], n = 6; other phenotype, n = 4) and nine healthy controls. IgG was exposed to human brain microvascular endothelial cells (TY10) and the number of nuclear NF-κB p65-positive cells, as a marker of endothelial cell activation, was analyzed using a high-content imaging system. Change in BBB permeability was also measured. The presence of GRP78 autoantibodies was detected by Western blotting. RESULTS: In the LETM group, IgG significantly induced the nuclear translocation of NF-κB p65 in comparison to the ON and healthy control groups. A significant correlation was observed between the number of NF-κB nuclear-positive cells and clinical markers of BBB disruption, including Gd enhancement in spinal MRI and the cerebrospinal fluid/serum albumin ratio. This effect was significantly reduced at the remission phase in the individual NMOSD patients. Furthermore, GRP78 antibody positivity was associated with the LETM phenotype and disease severity in NMOSD patients. CONCLUSION: Endothelial cell activation was associated with the LETM phenotype, clinical markers of BBB disruption and disease activity. These observations may explain the phenotypic differences between the NMOSD subtypes, LETM, and isolated ON.