Objective Determine the utility of aquaporin 4 IgG (AQP4-IgG) testing (live cell-based assay) for Neuromyelitis Optica Spectrum Disorders (NMOSD). Methods We included Mayo Clinic patients (1/1/2018-12/31/2019) tested for serum AQP4-IgG by live cell-based flow-cytometric assay. Medical records were reviewed to assess if patients fulfilled 2015 NMOSD criteria. Results Of 1371 patients tested, 41 were positive (3%) and all fulfilled NMOSD criteria with AQP4-IgG (specificity = 100%). Only 10/1330 testing negative met NMOSD criteria without AQP4-IgG (sensitivity = 80%) and seven of these 10 were MOG-IgG positive. Conclusions AQP4-IgG by live cell-based assay was highly specific and without false positives in a high throughput setting.

Background and Objectives.Studies on tumefactive brain lesions in myelin-oligodendrocyte-glycoprotein-IgG-associated disease (MOGAD) are lacking. We sought to characterize the frequency, clinical, laboratory, and MRI features of these lesions in MOGAD and compare them to multiple sclerosis (MS) and aquaporin-4-IgG-positive-neuromyelitis-optica-spectrum-disorder (AQP4+NMOSD).Methods.We retrospectively searched 194 MOGAD and 359 AQP4+NMOSD patients with clinical/MRI details available from the Mayo Clinic databases and included those with ≥1 tumefactive brain lesion (maximum transverse diameter ≥2 cm) on MRI. Tumefactive MS patients were identified using the Mayo Clinic medical-record-linkage-system. Binary multivariable stepwise logistic regression identified independent predictors of MOGAD diagnosis; Cox proportional regression models were used to assess the risk of relapsing disease and gait aid in tumefactivevs. non-tumefactive MOGAD patients.Results.We included 108 patients with tumefactive demyelination (MOGAD=43; AQP4+NMOSD=16; MS=49). Tumefactive lesions were more frequent among MOGAD (43/194[22%]) than AQP4+NMOSD (16/359[5%]) (p<0.001). Risk of relapse and need for gait aid were similar in tumefactive and non-tumefactive MOGAD. Clinical features more frequent in MOGAD than MS included headache (18/43[42%]vs.10/49[20%]; p=0.03) and somnolence (12/43[28%]vs.2/49[4%]; p=0.003), the latter also more frequent than AQP4+NMOSD (0/16[0%]; p=0.02). The presence of: peripheral T2-hypointense rim, T1-hypointensity, diffusion restriction (particularly an arc pattern), ring enhancement, Balo’-like or cystic appearance favored MS over MOGAD (p<0.001). MRI features were broadly similar in MOGAD and AQP4+NMOSD, except for more frequent diffusion restriction in AQP4+NMOSD (10/15[67%]) than MOGAD (11/42[26%], p=0.005). Cerebrospinal fluid analysis revealed less frequent positive oligoclonal bands in MOGAD (2/37[5%]) than MS (30/43[70%]) (p<0.001) and higher median white cell count in MOGAD than MS (33vs.6 cells/µl, p<0.001). At baseline, independent predictors of MOGAD diagnosis were presence of somnolence/headache, absence of T2-hypointense rim, lack of T1-hypointensity, and no diffusion restriction (Nagelkerke R Squared=0.67). Tumefactive lesion resolution was more common in MOGAD than MS or AQP4+NMOSD and improved model performance.Discussion.Tumefactive lesions are frequent in MOGAD but are not associated with a worse prognosis. The clinical, MRI, and CSF attributes of tumefactive MOGAD differ from tumefactive MS, and are more similar to tumefactive AQP4+NMOSD with the exception of lesion resolution, which favors MOGAD.

Cerebral cortical encephalitis (CCE) is a recently described myelin oligodendrocyte glycoprotein antibodyassociated disease (MOGAD) phenotype. In this observational retrospective study, we characterized 19 CCE patients (6.7% of our MOGAD cohort). Headache (n = 15, 79%), seizures (n = 13, 68%), and encephalopathy (n = 12, 63%) were frequent. Magnetic resonance imaging revealed unilateral (n = 12, 63%) or bilateral (n = 7, 37%) cortical T2 hyperintensity and leptomeningeal enhancement (n = 17, 89%). N-Methyl-D-aspartate receptor autoantibodies coexisted in 2 of 15 tested (13%). CCE pathology (n = 2) showed extensive subpial cortical demyelination (n = 2), microglial reactivity (n = 2), and inflammatory infiltrates (perivascular, n = 1; meningeal, n = 1). Most received high-dose steroids (n = 17, 89%), and all improved, but 3 had CCE relapses. This study highlights the CCE spectrum and provides insight into its pathogenesis.

No abstract

Background and Objectives:Although the diagnosis of myelin oligodendrocyte glycoprotein antibody associated disease (MOGAD) is based on serum MOG antibodies (MOG-Abs) positivity, patients with coexisting or restricted MOG-Abs in the CSF have been reported. The aim of this study is to characterize the relevance of CSF MOG-Abs positivity in clinical practice.Methods:Eleven medical centres retrospectively collected clinical and laboratory data of adult and pediatric patients with suspected inflammatory CNS disease and MOG-Abs positivity in serum and/or CSF, using live cell-based assays. Comparisons were performed using parametric or non-parametric tests, as appropriate. Potential factors of unfavourable outcomes were explored by Cox proportional hazard models and logistic regression.Results:The cohort included 255 patients: 139 (55%) females and 132 (52%) children (i.e. <18 year-old). Among them, 145 patients (56.8%) had MOG-Abs in both serum and CSF (MOG-Abs seropositive and CSF positive), 79 (31%) only in serum (MOG-Abs seropositive and CSF negative), and 31 (12%) only in CSF(MOG-Abs seronegative and CSF positive).MOG-Abs seronegative and CSF positivepredominated in adults (22% vs 3% of children), presented more commonly with motor (n=14, 45%) and sensory symptoms (n=13, 42%), and all but 4 (2 MS, 1 polyradiculoneuritis, 1 Susac syndrome) had a final diagnosis compatible with MOGAD. When comparing seropositive patients according to MOG-Abs CSF status,MOG-Abs seropositive and CSF positivepatients had a higher EDSS at nadir during the index event (median 4.5, IQR 3.0-7.5 vs. 3.0, IQR 2.0-6.8,p=0.007) and presented more commonly with sensory (45.5% vs. 24%,p=0.002), motor (33.6% vs 19%,p=0.021), and sphincter symptoms (26.9% vs 7.8%,p=0.001) thanMOG-Abs seropositive and CSF negative. At last follow-up,MOG-Abs seropositive and CSF positivecases had more often persistent sphincter dysfunction (17.3% vs 4.3%,p=0.008).Compared with seropositive patients, thoseMOG-Abs seronegative and CSF positivehad higher disability at last follow-up (p≤0.001) andMOG-Abs seronegative and CSF positivestatus was independently associated with an EDSS ≥3.0.Conclusion:Paired serum and CSF MOG-Abs positivity is common in MOGAD and is associated with a more severe clinical presentation. CSF only MOG-Abs positivity can occur in patients with a phenotype suggestive of MOGAD and is associated with a worse outcome. Taken together, these data suggest a clinical interest in assessing CSF MOG-Abs in patients with a phenotype suggestive of MOGAD, regardless of the MOG-Abs serostatus.

Phosphoinositide-3-kinase δ (PI3Kδ) is found in immune cells and is part of the PI3K/AKT/mTOR/S6K signalling pathway essential to cell survival, growth and differentiation. Hyperactivation of PI3Kδ enzyme results in Activated PI3-kinase delta syndrome (APDS). This childhood onset, autosomal dominant, combined immunodeficiency, is caused by heterozygous gain of function (GOF) mutations in PIK3CD (encodes PI3Kδ catalytic subunit p110δ), mutations in PIK3R1 (encodes PI3Kδ regulatory subunit p85α) or LOF mutations in PTEN (terminates PI3Kδ signalling) leading to APDS1, APDS2 and APDS-Like (APDS-L), respectively. APDS was initially described in 2013 and over 285 cases have now been reported. Prompt diagnosis of APDS is beneficial as targeted pharmacological therapies such as sirolimus and potentially PI3Kδ inhibitors can be administered. In this review, we provide an update on the clinical and laboratory features of this primary immunodeficiency. We discuss the common manifestations such as sinopulmonary infections, bronchiectasis, lymphoproliferation, susceptibility to herpesvirus, malignancy, as well as more rare non-immune features such as short stature and neurodevelopmental abnormalities. Laboratory characteristics, such as antibody deficiency and B cell and T cell, phenotypes are also summarised.

Objective: To report the clinical presentations and outcomes of patients with seizure and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Methods:We retrospectively reviewed the electronic medical records for clinical and paraclinical features among patients with seizures and MOG-IgG (immunoglobulin G) seropositivity. Results:We identified 213 patients with MOG-IgG seropositivity who fulfilled criteria for MOGAD. Seizures attributed to central nervous system (CNS) autoimmunity were observed in 10% of patients (n = 23: 19 children, 4 adults). The majority (n = 19, 83%) had pediatric disease onset. Focal motor seizures were the most common seizure semiology (16/23; 70%). Focal to bilateral tonic-clonic seizures were present in 12 patients (53%), and 3 patients (13%) developed status epilepticus. All patients had features of encephalitis at onset of seizures. Cerebral cortical encephalitis (CCE) was the most common radiological finding (10 unilateral and 5 bilateral cases). Eight of 23 patients (35%) had only CCE, six of 23 patients (26%) had only acute disseminated encephalomyelitis (ADEM), and seven of 23 patients (30%) had features of both. Fifteen patients (65%) had leptomeningeal enhancement. Three patients (13%) had coexistence of N-methyl-d-aspartate receptor (NMDAR) IgG. Only 3 of 23 patients (13%) developed drug-resistant epilepsy. Although the majority had MOGAD relapses (14/23, 60%) had only 5 of 23 patients had recurrence of episodes of encephalitis with associated seizures.Twenty-one of 23 patients (91%) had seizure freedom at last follow-up.Significance: MOG-IgG evaluation should be considered in patients who present with encephalitis and focal motor and/or focal to bilateral tonic-clonic seizures, especially pediatric patients with magnetic resonance imaging (MRI) brain findings consistent with CCE, ADEM, or other MOGAD presentations. The majority of these seizures are self-limited and do not require maintenance/chronic

No abstract