AQP4 Antibody Research Articles

Tumefactive Acute Disseminated Encephalomyelitis after Recent Covid-19 Infection: A Case Report

Objective: To report a case of a patient with recent mild to moderate COVID-19 infection who developed tumefactive acute disseminated encephalomyelitis. Methods: Patient data were obtained from medical records from the University of Wisconsin – Madison Hospitals in Madison, WI, USA. Results: We report a 59-year-old man with past medical history notable for atrial fibrillation, biventricular pacemaker, end-stage renal disease secondary to idiopathic fibrillary glomerulonephritis, on hemodialysis awaiting transplantation, who presented with ongoing cognitive changes and pneumonia. He was repeatedly COVID-19 positive with minimal symptoms for 4 weeks prior to admission. He developed right sided hemiparesis and persistent, progressive encephalopathy manifesting primarily with disorientation, agitation, and aggression. CSF was notable for cell count of 7, protein of 48, and glucose of 65. Anti-MOG antibody and AQP-4 antibody were negative. A series of CT/CTA head imaging with and without contrast showed progressive multifocal supratentorial areas of white matter hypoattenuation and MRI head with and without contrast demonstrated progressive multi-focal large ovoid T2 FLAIR hyperintensities, partially ring enhancing on contrasted portion of study, consistent with tumefactive demyelinating disease. Significant improvement in mental status and right sided hemiparesis symptoms was observed with initiation of corticosteroids. Conclusion: This case study provides neuroimaging evidence and clinical correlation to support that SARS–CoV-2 and resultant COVID-19 infection can lead to tumefactive acute disseminated encephalomyelitis. This complication has not been previously documented associated with recent COVID-19 infection.

Clinical failure of natalizumab in multiple sclerosis: Specific causes and strategy

BackgroundNatalizumab is a very effective treatment of multiple sclerosis (MS). Failure is rare and should lead to consider some specific etiologies. The purpose of our study was to describe causes of subacute neurological events under natalizumab. MethodsObservational single-center retrospective study in the MS expert center of Lyon, France. Inclusion criteria: any patient with definite MS who received at least three infusions of natalizumab between April 2007 and February 2017. Clinical data were extracted from the Lyon EDMUS/OFSEP database. Events of interest: occurrence of a subacute neurological deficit, characterized by new clinical symptoms. We excluded pseudo-relapses and progression. FindingsA subacute neurological deficit occurred in 35 cases, for 607 patients treated with natalizumab. Ten patients presented natalizumab antibodies, nine had progressive multifocal leukoencephalopathy (PML), five presented an isolated subacute neurological deficit and two had AQP4 antibodies. No myelin oligodendrocyte glycoprotein (MOG) antibodies were found. InterpretationThe occurrence of an acute or subacute neurological deficit with natalizumab is rarely a MS relapse and should lead systematically to explore some important alternate etiologies, eliminating PML first.

A case of neuromyelitis optica spectrum disorder with coexisting systemic lupus erythematosus

ABSTRACT Neuromyelitis Optica or Devic disease is changed to Neuromyelitis Optica spectrum disorder to include more diverse neurological and autoimmune manifestations. This is a severe relapsing autoimmune demyelinating disorder commonly affecting the optic nerve and spinal cord. It has been reported as either the first manifestation of SLE or as a coexisting condition with other autoimmune disorders commonly included but not limited to SLE and SS. We discussed a case of a 49-year-old female patient who was initially presented with a left-sided weakness that rapidly progressed to quadriparesis and bladder dysfunction within a few days. She had positive autoimmune serology tests for SLE posing a diagnostic challenge as SLE is associated with neurological manifestations. Due to a lack of definitive diagnostic criteria for SLE, presence of AQP-4 antibodies in CSF, and evidence of longitudinal extensive transverse myelitis in MRI cervical spine, we conclude that she has Neuromyelitis Optica spectrum disorder with probable SLE. It is possible that she may develop more signs and symptoms of SLE with time and will need close follow up. Timely diagnosis and prompt treatment are vital to decrease morbidity and mortality, as done in our case. The patient was started on high-dose steroids with significant improvement in her symptoms. These patients may need early treatment with plasmapheresis and long-term follow-up with immunotherapy to prevent relapse. There are few case reports in the literature, and more information is needed to understand and better diagnose NMO with coexisting SLE.

Optic chiasm involvement in AQP-4 antibody–positive NMO and MOG antibody–associated disorder

Background: Optic neuritis (ON) is often the presenting symptom in inflammatory central nervous system demyelinating disorders. Objective: To compare the frequency and pattern of optic chiasm involvement in patients with aquaporin-4-immunoglobulin G (AQP4-IgG)-associated ON to patients with myelin oligodendrocyte glycoprotein-immunoglobulin G (MOG-IgG)-associated ON. Methods: Retrospective review of all patients evaluated at Mayo Clinic, Stanford University and Ramathibodi Hospital who were found to have: (1) ON, (2) either MOG-IgG or AQP4-IgG by cell-based assay, and (3) magnetic resonance imaging (MRI) at the time of ON. MRI was reviewed for contrast enhancement of the optic chiasm and the pattern of involvement. Results: One hundred and fifty-four patients (74 AQP4-IgG and 80 MOG-IgG) were included. Among patients with AQP4-IgG-ON, 20% had chiasmal involvement, compared with 16% of patients with MOG-IgG-ON (p = 0.66). In patients with chiasmal involvement, longitudinally extensive optic nerve enhancement (from orbit extending to chiasm) was identified in 54% of MOG-IgG-ON patients, compared with 7% of AQP4-IgG-ON patients (p = 0.01). Conclusion: Chiasmal involvement of MOG-IgG-ON and AQP4-IgG-ON occur at more similar frequencies than previously reported. Furthermore, MOG-IgG-ON chiasmal involvement is more likely to be part of a longitudinally extensive optic nerve lesion.

Clinical Characteristics of Chinese Male Patients with Aquaporin-4 Antibody-Positive Late-Onset Neuromyelitis Optica Spectrum Disorder

Background and Objective: Limited studies are available for male patients with anti-aquaporin-4 antibody (AQP4-Ab)-positive late-onset neuromyelitis optica spectrum disease (LONMOSD). The aim of this study was to investigate the clinical characteristics of Chinese male patients with AQP4-Ab-positive LONMOSD. Methods: We retrospectively reviewed the medical records of 12 male patients with LONMOSD, 16 male patients with early-onset NMOSD (EONMOSD), and 64 female patients with LONMOSD. These enrolled patients were classified according to the age of onset: LONMOSD (≥50 years of age at onset) versus EONMOSD (<50 years of age at onset). Clinical characteristics and magnetic resonance imaging (MRI) findings were collected. All included patients were positive for AQP4 antibody. Results: Compared with female LONMOSD patients, male LONMOSD patients had less frequent transverse myelitis (TM) at onset (8.33 vs. 53.13%, p = 0.004) and lower Expanded Disability Status Scale (EDSS) scores (median 1 vs. 4, p = 0.036). Compared with male EONMOSD patients, male LONMOSD patients had a shorter time from onset to diagnosis (0.85 months vs. 6.00 months, p = 0.04). Conclusion: Less common TM at onset, less disease severity, and shorter time from onset to diagnosis probably occur in male LONMOSD patients.

Neutrophil-to-Lymphocyte Ratio on Admission is an Independent Risk Factor for the Severity of Neurological Impairment at Disease Onset in Patients with a First Episode of Neuromyelitis Optica Spectrum Disorder.

PurposeTo investigate the relationship between the neutrophil-to-lymphocyte ratio (NLR) and the severity of neurological impairment at disease onset in patients with a first episode of neuromyelitis optica spectrum disorder (NMOSD).Patients and MethodsThis retrospective study included 259 patients with newly diagnosed NMOSD who were hospitalized at our institution between January 2013 and January 2020 (NMOSD group) and 169 healthy control subjects who underwent a physical examination at our hospital during the same period (control group). The clinical data collected included general information, past medical history, biochemical test results, imaging findings, NLR, AQP-4 antibody status, and initial Expanded Disability Status Scale score. A logistic regression model was used to analyze NLR as an independent risk factor for the severity of neurological impairment at disease onset in the NMOSD group. Receiver-operating characteristic curve analysis was used to evaluate the ability of the NLR to predict the severity of neurological impairment at disease onset in the NMOSD group and to determine its critical value.ResultsThe NLR was significantly higher in the NMOSD group than in the control group (P<0.001). In the NMOSD group, neurological impairment at disease onset was more severe in those with a high NLR than in those with a low NLR (P<0.001). At onset of disease, patients with severe neurological impairment had a more significant increase in NLR than those with mild-to-moderate neurological impairment (P<0.001). Both univariate (OR 1.180, 95% CI 1.046–1.331, P=0.007) and multivariate (OR 1.146, 95% CI 1.003–1.308, P=0.044) logistic regression analyses showed that the NLR was positively correlated with the severity of neurological impairment at onset of disease in the NMOSD group. The area under the receiver-operating characteristic curve was 0.687.ConclusionThe NLR is an independent risk factor for the severity of neurological impairment at disease onset in patients with a first episode of NMOSD.

Clinical and Prognostic Analysis of Autoantibody-Associated CNS Demyelinating Disorders in Children in Southwest China.

Objective: To analyze the positive and recurrence rates of different autoantibody-associated demyelination disorders in children in Southwest China, and describe the clinical, radiological, and prognostic features of the myelin oligodendrocyte glycoprotein antibody (MOG-ab) and aquaporin-4 antibody (AQP4-ab) associated disease. This study also summarizes steroid maintenance therapy approaches for MOG-ab-positive children.Methods: A total of 160 children presenting with acquired demyelinating syndromes (ADS) between January 2016 and December 2019 were tested for MOG-ab and AQP4-ab. Clinical data, MRI scans, and survival analyses were compared between MOG-ab-positive and AQP4-ab-positive children. Evolution of serologic status and treatment response to immunosuppressants were collected in MOG-ab-positive children.Results: Of the 160 included children, the MOG-ab positivity rate (47.4%) was significantly higher than the AQP4-ab (5%) positivity rate. The recurrence rate for AQP4-ab disease (71.4%) was higher than that of MOG-ab disease (30.1%). For 135 children with both MOG-ab and AQP4-ab tested, the median age at onset was 7 (interquartile range [IQR] 5–10) years, and the median follow-up period was 19 (IQR 13–27.5) months. MOG-ab-positive children more frequently presented with acute disseminated encephalomyelitis, had deep gray matter lesions on MRI, had a better clinical and radiological recovery, and were less likely to have sustained disability than AQP4-ab-positive children. In MOG-ab-positive and AQP4-ab-positive children, maintenance therapy was a protective factor for recurrence, but presenting optic neuritis was a predictor of earlier relapse. A high Expanded Disability Status Scale score at onset was associated with sustained disability. Steroid maintenance therapy longer than 6 months after the initial attack was associated with a lower risk of a second relapse in MOG-ab-positive children. On serial serum MOG antibody analysis, clinical relapse occurred in 34.6% of children with persistent seropositivity, but none of the children who converted to seronegative status experienced relapse.Conclusion: The MOG antibody is more common in children with ADS than the AQP4 antibody. MOG-ab-positive children are characterized by distinct clinical and radiological features. Although some MOG-ab-positive children experience relapsing courses or have persistently seropositive status, they still predict a better outcome than AQP4-ab-positive children.

Longitudinal Evaluation of Serum MOG-IgG and AQP4-IgG Antibodies in NMOSD by a Semiquantitative Ratiometric Method.

Background and purpose: Immunoadsorption (IA) is an antibody-depleting therapy used to treat neuromyelitis optica spectrum disorder (NMOSD) associated to antiaquaporin 4 (anti-AQP4-IgG) and antimyelin oligodendrocyte glycoprotein (anti-MOG-IgG) serum autoantibodies. Our aim was to evaluate longitudinal changes of serum MOG-IgG and AQP4-IgG antibody titer and to correlate it with the clinical status.Methods: Autoantibody titer and clinical features of two MOG-IgG+/AQP4-IgG– and two AQP4-IgG+/MOG-IgG– patients with NMOSD were collected at baseline (T0), after 6 IA courses (T1), and then 2 weeks (T2) and 6 months after treatment (T3). A fluorescent ratiometric assay was used for a quantitative detection of MOG and AQP4 antibodies, based on HEK-293 cells transfected with the full-length hMOG fused to GFP or h-AQP4-M23 isoform fused to m-cherry, respectively. We defined the antibody titer as MOG quantitative ratio (MOGqr) and AQP4 quantitative ratio (AQP4qr).Results: In Case 1, the MOGqr dropped from 0.98 at T0 to 0.14 at T3, and in Case 2, it decreased from 0.96 at T0 to undetectable at T3. In Case3, the AQP4qr remained high: 0.90 at T0 and 0.92 at T3. In Case 4, the AQP4qr decreased from 0.50 at T0 to undetectable at T3. Complete recovery was found in Cases 1, 2, and 4.Conclusions: Semiquantitative ratiometric method accurately detects even slight variation of MOG-IgG and AQP4-IgG titer, suggesting it may be useful to monitor the antibody titer during the disease course and maintenance immunotherapy.

A case of progressive multifocal leukoencephalopathy with HIV positivity

AbstractBackgroundWe report a case of progressive multifocal leukoencephalopathy with HIV positive. We analyzed her epidemiology, clinical manifestation, neuroimaging and laboratory test.MethodThe patient was a 36‐year‐old right‐handed man with 4 months of left upper limb numb, 2 months of left limbs weak. 4 months ago, he felt cold on her left upper limb without any reason.3 months agohe suddenly couldn’t recognize his routine home way for several minutes. 2 months ago, he felt dizzy and weak on his left upper limb. He was considered as cervical spondylosis without recover after massage. His brain MRI showed his right frontal and parietal cortex ischemic, right thalamus, corona radiata and callosum ischemic infarction (subacute stage), and posterior angel of bilateral ventricles demyelination. The focus weren’t enhanced on brain enhancement MRI. He got treatment according to cerebral infarction and didn’t relieve. His blood test results showed decreased white cells, red cells and platelet count. His CSF test was normal. His serum NMDA, AQP4 antibody were all negative.1 months ago, he began to have fever and could relieve after cortisone. He couldn’t get better after antiviral therapy according to viral encephalitis. His bilateral vision suddenly got blind. His PET‐CT scan was normal. He didn’t relieve after immune globulin. His nervous system examination showed his cognitive function deceased, left central facial paralysis and left limbs upper motor neuron paralysis. His bilateral light reflex was normal. However both of his eyes couldn’t react on light. His bone marrow aspiration was normal. Finally, he got HIV test and the result was positive. His CSF and urine of JC virus PCR test were 1000000copies/ml and 2000copies/ml.ResultHe was diagnosed as progressive multifocal leukoencephalopathy and HIV infection. 1 month later, he was dead.ConclusionThe syndromes of this case became worse and worse, but he couldn’t get right diagnose and treatment. His brain MRI image seems like ischemic stroke. The most important HIV test was done at the final stage. This case gave us a lesson and we should keep mind on HIV test.

Quantitative spinal cord MRI in MOG-antibody disease, neuromyelitis optica and multiple sclerosis.

Spinal cord involvement is a hallmark feature of multiple sclerosis, neuromyelitis optica with AQP4 antibodies and MOG-antibody disease. In this cross-sectional study we use quantitative spinal cord MRI to better understand these conditions, differentiate them and associate with relevant clinical outcomes. Eighty participants (20 in each disease group and 20 matched healthy volunteers) underwent spinal cord MRI (cervical cord: 3D T1, 3D T2, diffusion tensor imaging and magnetization transfer ratio; thoracic cord: 3D T2), together with disability, pain and fatigue scoring. All participants had documented spinal cord involvement and were at least 6 months post an acute event. MRI scans were analysed using publicly available software. Those with AQP4-antibody disease showed a significant reduction in cervical cord cross-sectional area (P = 0.038), thoracic cord cross-sectional area (P = 0.043), cervical cord grey matter (P = 0.011), magnetization transfer ratio (P ≤ 0.001), fractional anisotropy (P = 0.004) and increased mean diffusivity (P = 0.008). Those with multiple sclerosis showed significantly increased mean diffusivity (P = 0.001) and reduced fractional anisotropy (P = 0.013), grey matter volume (P = 0.002) and magnetization transfer ratio (P = 0.011). In AQP4-antibody disease the damage was localized to areas of the cord involved in the acute attack. In multiple sclerosis this relationship with lesions was absent. MOG-antibody disease did not show significant differences to healthy volunteers in any modality. However, when considering only areas involved at the time of the acute attack, a reduction in grey matter volume was found (P = 0.023). This suggests a predominant central grey matter component to MOG-antibody myelitis, which we hypothesize could be partially responsible for the significant residual sphincter dysfunction. Those with relapsing MOG-antibody disease showed a reduction in cord cross-sectional area compared to those with monophasic disease, even when relapses occurred elsewhere (P = 0.012). This suggests that relapsing MOG-antibody disease is a more severe phenotype. We then applied a principal component analysis, followed by an orthogonal partial least squares analysis. MOG-antibody disease was discriminated from both AQP4-antibody disease and multiple sclerosis with moderate predictive values. Finally, we assessed the clinical relevance of these metrics using a multiple regression model. Cervical cord cross-sectional area associated with disability scores (B = -0.07, P = 0.0440, R2 = 0.20) and cervical cord spinothalamic tract fractional anisotropy associated with pain scores (B = -19.57, P = 0.016, R2 = 0.55). No spinal cord metric captured fatigue. This work contributes to our understanding of myelitis in these conditions and highlights the clinical relevance of quantitative spinal cord MRI.

Paroxysmal symptoms in neuromyelitis optica spectrum disorder: Results from an online patient survey

BackgroundParoxysmal symptoms (PS), defined as short-lasting, recurrent, and stereotyped neurological symptoms, are frequently reported by patients with Neuromyelitis Optica Spectrum Disorder (NMOSD). Their prevalence and spectrum of presentations in NMOSD have not been fully characterized. MethodsPatients with NMOSD, who were members of a closed international Facebook Group, were recruited to complete an anonymous survey on REDCap. Participants were queried regarding demographic and NMOSD-related characteristics and PS history. ResultsThe sample consisted of 219 responders with self-reported NMOSD, of whom 134 (63.8%) reported testing positive for AQP4 Antibody. 156 responders (71.9%) reported ≥1 type of PS during the disease course. The most common PS were intermittent tingling/numbness sensation (N=106, 67.9%), followed by involuntary muscle contractions/abnormal posture (N=95, 60.9%), hot/cold/burning sensations (N=87, 55.8%), and shock-like sensations along the spine or limbs (N=77, 49.4%). 150 responders (96% of those with PS) reported that PS were painful; in 82 responders (54.6%), the pain intensity reached ≥ 8/10 and in 40 responders (26.0%) - 10/10 level. PS were most commonly aggravated by fatigue (105 responders, 70.0%), physical activity (N=86, 57.3%), and neck flexion (N=39 responders, 26.0%). 82 patients (52.5% of those with PS) reported having been prescribed one or more medications for PS. Less than 50% reported them to be 'very helpful.' ConclusionsThis survey highlights that PS occurs commonly in NMOSD patients. The symptomatology of PS is diverse. PS are often painful and not adequately treated. Our study represents a novel method to learn more about a rare disease from the patient's perspective. Given the fact that the study was conducted using an anonymous questionnaire and the diagnosis of NMOSD was self-reported by the survey participants, its’ results should be regarded as a first step towards the understanding of PS in NMOSD, which should be further validated in a larger, controlled study.

Relapsing Demyelinating Syndromes in Children: A Practical Review of Neuroradiological Mimics.

Relapsing demyelinating syndromes (RDS) in children encompass a diverse spectrum of entities including multiple sclerosis (MS) acute disseminated encephalomyelitis (ADEM), aquaporin-4 antibody associated neuromyelitis optica spectrum disorder (AQP4-NMOSD) and myelin oligodendrocyte glycoprotein antibody disease (MOG-AD). In addition to these, there are “antibody-negative” demyelinating syndromes which are yet to be fully characterized and defined. The paucity of specific biomarkers and overlap in clinical presentations makes the distinction between these disease entities difficult at initial presentation and, as such, there is a heavy reliance on magnetic resonance imaging (MRI) findings to satisfy the criteria for treatment initiation and optimization. Misdiagnosis is not uncommon and is usually related to the inaccurate application of criteria or failure to identify potential clinical and radiological mimics. It is also notable that there are instances where AQP4 and MOG antibody testing may be falsely negative during initial clinical episodes, further complicating the issue. This article illustrates the typical clinico-radiological phenotypes associated with the known pediatric RDS at presentation and describes the neuroimaging mimics of these using a pattern-based approach in the brain, optic nerves, and spinal cord. Practical guidance on key distinguishing features in the form of clinical and radiological red flags are incorporated. A subsection on clinical mimics with characteristic imaging patterns that assist in establishing alternative diagnoses is also included.

Effects of intravenous methylprednisolone pulse therapy on recurrent optic neuritis associated with aquaporin 4 antibody seropositive neuromyelitis optica

Objective: To observe the effects of intravenous methylprednisolone pulse (IVMP) therapy on the recovery of visual acuity and its influencing factors in patients with the relapse of aquaporin (AQP) 4 antibody positive neuromyelitis optica related optic neuritis (NMO-ON). Methods: Retrospective case series. Forty-eight eyes of 35 patients diagnosed as NMO-ON in the Neuro-ophthalmology Clinic of Beijing Tongren Hospital from September 2012 to April 2018 were included in this research. All patients were AQP4 antibody seropositive, and had clinical manifestations of acute optic neuritis, with a history of optic neuritis treated with glucocorticoids effectively. They received the treatment of IVMP 500 mg/d or 1 000 mg/d for 3 to 5 days. The post-treatment and pre-treatment visual acuities were compared. Improving four lines or more was considered as markedly effective, improving two or three lines as effective, and improving one line or no change or a decline as no effect. The impacts of age, visual acuity at onset, relapse rate and dosage on the acute exacerbation of NMO-ON were analyzed. Mann-Whitney U test and Kruskal-Wallis test were used for statistical analysis. Results: Among the 35 patients, there were 2 males and 33 females, aged from 15 to 73 years (median, 36 years). In the 48 eyes of recurrence, the treatment was effective 41.7% (20/48), effective 20.8% (10/48), and ineffective 37.5% (18/48). The IVMP therapy was effective in 25 of 34 eyes with one recurrence and 5 of 14 eyes with two or more recurrences, and the difference was statistically significant (Z=2.315, P=0.021). The efficacy in 13 eyes with preoperative visual acuity not lower than 0.05 (10/13) was better than 35 eyes with preoperative visual acuity lower than 0.05 (20/35), and the difference was statistically significant (Z=1.994, P=0.046). Different ages and doses (1 000 mg/d and 500 mg/d) made no significant difference in the efficacy (P=0.273,0.105). Conclusions: The IVMP therapy is effective for the NMO-ON relapse in patients who were AQP4 antibody seropositive. The effect of IVMP treatment at doses of 500 mg/d and 1 000 mg/d is similar. Furthermore, visual acuity less than 0.05 and more relapses reduce the efficacy in relapsed NMO-ON patients. (Chin J Ophthalmol, 2020, 56: 509-513).

Radiological characteristics of neuromyelitis optica spectrum disorder in Kuwait

BackgroundNeuromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelinating disorder of the central nervous system that predominantly targets optic nerves and spinal cord. Studies of NMOSD are scarce in the Middle East. ObjectiveTo evaluate the MRI characteristics of NMOSD patients in Kuwait. Patient and methodsThis is an observational, retrospective study on NMOSD patients who attended the MS clinic. Patients who fulfilled the 2015 diagnostic criteria of NMOSD were included. Patients` clinical, radiological and serological data were extracted from the medical records. The radiological variables were compared according to gender and AQP4 serostatus. ResultsForty-two patients fulfilling the NMOSD diagnostic criteria. The mean age and mean age of onset were 32.6 ± 11.4 and 28.9 ± 9.8 years respectively. Females represented 83.3 % of the cohort with female-to-male ratio of 5:1. Thirty-one patients (73.8 %) tested positive for AQP4 antibody. Nineteen patients (45.2 %) had bilateral optic nerve involvement, while chiasmal involvement was seen in 8 (19.0 %) patients. Spinal cord was involved in 36 (85.7 %) patients; of whom 27 (64.3 %) had LETM. The most common spinal segment involved was the cervical (72.2 %) followed by the dorsal (25.0 %) regions. The brain was involved in 39 (92.8 %) patients and the periventricular region around fourth and lateral ventricles was the most commonly involved site (n = 35; 83.3 %), along with periaqueductal (n = 25; 61.9 %) and corpus callosal (n = 24; 57.1 %) regions. Isolated area postrema involvement was observed in 9 (21.4 %) patients. ConclusionThis is the first study describing the radiological characteristics of NMOSD in Kuwait. Although our data is comparable with the previous international studies, a higher percentage of bilateral optic nerve, brain, and callosal involvement was observed. Further multicenter studies with a larger cohort are needed to confirm our results.

Myelin oligodendrocyte glycoprotein antibody-associated disease: an immunopathological study.

Conformation-sensitive antibodies against myelin oligodendrocyte glycoprotein (MOG) are detectable in patients with optic neuritis, myelitis, opticomyelitis, acute or multiphasic disseminated encephalomyelitis (ADEM/MDEM) and brainstem/cerebral cortical encephalitis, but are rarely detected in patients with prototypic multiple sclerosis. So far, there has been no systematic study on the pathological relationship between demyelinating lesions and cellular/humoral immunity in MOG antibody-associated disease. Furthermore, it is unclear whether the pathomechanisms of MOG antibody-mediated demyelination are similar to the demyelination patterns of multiple sclerosis, neuromyelitis optica spectrum disorders (NMOSD) with AQP4 antibody, or ADEM. In this study, we immunohistochemically analysed biopsied brain tissues from 11 patients with MOG antibody-associated disease and other inflammatory demyelinating diseases. Patient median onset age was 29 years (range 9-64), and the median interval from attack to biopsy was 1 month (range 0.5-96). The clinical diagnoses were ADEM (n = 2), MDEM (n = 1), multiple brain lesions without encephalopathy (n = 3), leukoencephalopathy (n = 3) and cortical encephalitis (n = 2). All these cases had multiple/extensive lesions on MRI and were oligoclonal IgG band-negative. Most demyelinating lesions in 10 of 11 cases showed a perivenous demyelinating pattern previously reported in ADEM (153/167 lesions) and a fusion pattern (11/167 lesions) mainly in the cortico-medullary junctions and white matter, and only three lesions in two cases showed confluent demyelinated plaques. In addition, 60 of 167 demyelinating lesions (mainly in the early phase) showed MOG-dominant myelin loss, but relatively preserved oligodendrocytes, which were distinct from those of AQP4 antibody-positive NMOSD exhibiting myelin-associated glycoprotein-dominant oligodendrogliopathy. In MOG antibody-associated diseases, MOG-laden macrophages were found in the perivascular spaces and demyelinating lesions, and infiltrated cells were abundant surrounding multiple blood vessels in and around the demyelinating lesions, mainly consisting of macrophages (CD68; 1814 ± 1188 cells/mm2), B cells (CD20; 468 ± 817 cells/mm2), and T cells (CD3; 2286 ± 1951 cells/mm2), with CD4-dominance (CD4+ versus CD8+; 1281 ± 1196 cells/mm2 versus 851 ± 762 cells/mm2, P < 0.01). Humoral immunity, evidenced by perivascular deposits of activated complements and immunoglobulins, was occasionally observed in some MOG antibody-associated demyelinating lesions, and the frequency was much lower than that in AQP4 antibody-positive NMOSD. Subpial lesions with perivenous demyelination were observed in both ADEM and cortical encephalitis. Our study suggests that ADEM-like perivenous inflammatory demyelination with MOG-dominant myelin loss is a characteristic finding of MOG antibody-associated disease regardless of whether the diagnostic criteria of ADEM are met. These pathological features are clearly different from those of multiple sclerosis and AQP4 antibody-positive NMOSD, suggesting an independent autoimmune demyelinating disease entity.

Antibody signatures in patients with histopathologically defined multiple sclerosis patterns

Early active multiple sclerosis (MS) lesions can be classified histologically into three main immunopathological patterns of demyelination (patterns I–III), which suggest pathogenic heterogeneity and may predict therapy response. Patterns I and II show signs of immune-mediated demyelination, but only pattern II is associated with antibody/complement deposition. In pattern III lesions, which include Baló’s concentric sclerosis, primary oligodendrocyte damage was proposed. Serum antibody reactivities could reflect disease pathogenesis and thus distinguish histopathologically defined MS patterns. We established a customized microarray with more than 700 peptides that represent human and viral antigens potentially relevant for inflammatory demyelinating CNS diseases, and tested sera from 66 patients (pattern I n = 12; II n = 29; III n = 25, including 8 with Baló’s), healthy controls, patients with Sjögren’s syndrome and stroke patients. Cell-based assays were performed for aquaporin 1 (AQP1) and AQP4 antibody detection. No single peptide showed differential binding among study cohorts. Because antibodies can react with different peptides from one protein, we also analyzed groups of peptides. Patients with pattern II showed significantly higher reactivities to Nogo-A peptides as compared to patterns I (p = 0.02) and III (p = 0.02). Pattern III patients showed higher reactivities to AQP1 (compared to pattern I p = 0.002, pattern II p = 0.001) and varicella zoster virus (VZV, compared to pattern II p = 0.05). In patients with Baló’s, AQP1 reactivity was also significantly higher compared to patients without Baló’s (p = 0.04), and the former revealed distinct antibody signatures. Histologically, Baló’s patients showed loss of AQP1 and AQP4 in demyelinating lesions, but no antibodies binding conformational AQP1 or AQP4 were detected. In summary, higher reactivities to Nogo-A peptides in pattern II patients could be relevant for enhanced axonal repair and remyelination. Higher reactivities to AQP1 peptides in pattern III patients and its subgroup of Baló’s patients possibly reflect astrocytic damage. Finally, latent VZV infection may cause peripheral immune activation.

MRI differences between MOG antibody disease and AQP4 NMOSD

Background: MOG antibody and AQP4 antibody seropositive diseases are immunologically distinct subtypes of neuromyelitis optica spectrum disorders (NMOSD) with similar clinical presentations. MRI findings can be instrumental in distinguishing MOG antibody disease from AQP4 antibody NMOSD. Objectives: The aim of this study is to characterize the neuroradiological differences between MOG antibody disease and AQP4 antibody NMOSD with the aim to distinguish between the two entities. Methods: This is a retrospective study of 26 MOG and 25 AQP4 seropositive patients in which MRI features of the brain, spinal cord, and orbit were compared. Results: The majority of the abnormal findings in the MOG cohort were located on orbital MRIs, while spinal cord magnetic resonance (MR) abnormalities were more common in the AQP4 cohort. Brain abnormalities showed some overlap, but cortical gray/juxtacortical white matter involvement was distinct to MOG patients, while area postrema involvement was a rare feature. Conclusion: Cortical gray/juxtacortical white matter lesions on brain MRI might help distinguish MOG antibody disease from AQP4-positive NMOSD. These findings could be of value in distinguishing the two entities as early as the first presentation.

Clinical Features, Gender Differences, Disease Course, and Outcome in Neuromyelitis Optica Spectrum Disorder.

Introduction:Neuromyelitis optica spectrum disorder (NMOSD) is an astrocytopathy with a predilection for the optic nerve, spinal cord, and brainstem. In this ambispective study, we evaluate clinical characteristics, responses to therapy, and disability outcomes in patients with NMOSD.Methods:Patients diagnosed as NMOSD and following up for at least 1 year at a tertiary care center in India were recruited. Patient data were collected ambispectively from January 2012 until December 2018.Results:A total of 106 patients (29M/77F) with NMOSD were evaluated. The mean age of onset was 29 (±11.6) years. About 77 patients (72.64%) were positive for the AQP4 antibody. Age of onset was higher for those presenting with an opticospinal syndrome (34.2 years) as compared to either isolated longitudinally extensive transverse myelitis (LETM) (30 years) or optic neuritis (ON) (25.3 years). The most common syndrome at onset was LETM in 57 patients (53.77%) followed by ON in 31 patients (29.24%). Azathioprine was the most common immunotherapy (83.96%) prescribed followed by rituximab (7.54%) and mycophenolate mofetil (1.88%). There was a significant decrease in the number of relapses post-azathioprine (P < 0.001). Out of 67 patients with ON, 21 (31.34%) had complete recovery while 17 (25.37%) patients had a severe deficit at a 3-month follow-up. Out of 92 patients with a motor deficit, 49 (53.26%) patients had a partial motor deficit at a 6-month follow-up. The severe visual deficit at baseline and female gender predicted poor visual and motor recovery, respectively.Conclusion:This is the largest descriptive study on patients with NMOSD from India. Relapse rates were similar irrespective of the clinical presentation, age, gender, and disease course. Treatment with immunosuppressive treatment significantly affected the disease course.

Effectiveness of subcutaneous tocilizumab in neuromyelitis optica spectrum disorders

BackgroundTocilizumab (TCZ), a humanized monoclonal antibody against the interleukin-6 receptor, is approved for treatment of rheumatoid arthritis and several other immune-mediated disorders. Off-label use of the intravenous formulation of tocilizumab for Neuromyelitis Optica Spectrum Disorder (NMOSD) decreased relapse rates in two small case series. However, treatment protocol that requires frequent intravenous infusions may adversely affect adherence to therapy, especially in the more disabled patients, thereby reducing effectiveness. A subcutaneous formulation of tocilizumab was shown to be noninferior to the IV formulation for approved rheumatologic diseases. The effectiveness of subcutaneous TCZ for NMOSD is unknown. MethodsWe retrospectively reviewed clinical, radiological and serological data on all NMOSD patients who received subcutaneous TCZ in two tertiary referral centers between 2014–2019. ResultsTwelve NMOSD patients who received at least 6 months of subcutaneous TCZ were identified. Eleven were female; mean age was 46.9 ± 14.5 years and mean disease duration was 6.6 ± 4.6 years. Seven patients were seropositive for AQP-4 antibodies, two – for MOG-IgG antibodies, and three were doubly seronegative. During subcutaneous TCZ treatment, eight patients (66.6%) were relapse-free, one patient (8.3%) experienced 1 relapse, two patients (16.6%) - 2 relapses, and one patient (8.3%) - 3 relapses. The median relapse rate within 1 year after starting subcutaneous TCZ - 0 (interquartile range =1.75–0) - was significantly lower than in the year prior to treatment initiation (2, interquartile range = 4.0–0.25; p = 0.04). Overall, the annual relapse rate (ARR) decreased from a median of 2 (interquartile range = 5.75–1.29) prior to subcutaneous TCZ to 0 (interquartile range= = 1.0–0) on treatment (p = 0.0015). One TCZ-treated patient died following a severe myelitis attack. ConclusionsEffectiveness of subcutaneous TCZ in NMOSD appears to be similar to that reported for the IV formulation and has an advantage of at-home administration. Prospective, comparative studies of subcutaneous TCZ for NMOSD are warranted.

Comparison of the low frequency fluctuation between AQP4 antibody positive and MOG antibody positive patients with optic neuritis

Objective To compare the changes of spontaneous brain activity in myelin oligodendrocyte glycoprotein antibody (MOG-Ab) positive and Aquaporin 4 antibody (AQP4-Ab) positive neuromyelitis optica spectrum disorder (NMOSD) by using resting-state functional magnetic resonance imaging (fMRI). Methods A case control study was designed.A total of 11 NMOSD patients with positive MOG-Ab and 21 NMOSD patients with positive AQP4-Ab were enrolled from October 2006 to May 2017 in PLA General Hospital.Thirty-four healthy controls closely matched in age, sex and education were recruited and underwent resting-state fMRI scans.The amplitude of low-frequency fluctuation (ALFF) was extracted to investigate the spontaneous brain activity.This study was approved by Ethics Committee of PLA General Hospital (S2019-111-01). All subjects enrolled signed informed consent. Results Two patients in the MOG-Ab positive group had seizure history, and no seizure history was observed in AQP4-Ab positive group and healthy control group.Compared with healthy control group, all patients in MOG-Ab positive group and AQP4-Ab positive group had significantly increased ALFF values of prefrontal gyrus.The ALFF values of bilateral anterior central gyrus and bilateral posterior central gyrus in AQP4-Ab positive group were 1.89±0.56 and 2.10±0.69, respectively, which were lower than 3.32±1.15 and 3.61±1.23 in MOG-Ab positive group, the differences were statistically significant (both at P<0.001, AlphaSim correction). Conclusions Resting-state fMRI could provide new evidence of possibly multi-focal disease mechanisms.Hyperactivity in prefrontal cortex, motor cortex and somatosensory cortex might reflect differences in pathological processes between MOG-Ab positive and AQP4-Ab positive NMOSD patients. Key words: Optic neuritis; Resting-state functional magnetic resonance imaging; Amplitude of low frequency fluctuation; Neuromyelitis optica spectrum disorder; Aquaporin 4 antibody; Myelin oligodendrocyte glycoprotein antibody