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.

MOG-IgG testing strategies in accordance with the 2023 MOGAD criteria: a clinical-laboratory assessment.

BACKGROUND: Live cell-based assay (LCBA) is the gold standard for MOG-IgG detection, and fixed CBA (FCBA) is a widely used commercial alternative. Recent criteria attributed a diagnostic value to MOG-IgG titration with both LCBA and FCBA, with low-titre samples requiring additional supporting features for MOGAD diagnosis. However, FCBA titration is not validated. We aimed to assess the impact of the criteria-based MOG-IgG testing in MOGAD diagnosis. METHODS: Thirty-eight serum samples of LCBA MOG-IgG1-positive MOGAD patients were titred on MOG-IgG LCBA and FCBA, and the presence of supporting features for MOGAD assessed. MOGAD criteria were evaluated in four testing scenarios: (a) FCBA without titration; (b) FCBA with titration; c) LCBA without titration; (d) LCBA with titration. RESULTS: FCBA without titration failed to reach MOGAD diagnosis in 11/38 patients (28.9%, negative results in 5, lack of supporting features in 6). Patients with unconfirmed diagnosis had optic neuritis (ON, n = 8), or transverse myelitis (TM, n = 3). FCBA with titration allowed MOGAD diagnosis in 4 additional patients. Correlation between LCBA and FCBA titres was moderate (Spearman's rho 0.6, p < 0.001). CONCLUSIONS: FCBA yields high rate of misdiagnosis mainly due a lower analytical sensitivity. FCBA titration provides a moderate diagnostic advantage in FCBA positive patients.

Marked central canal T2-hyperintensity in MOGAD myelitis and comparison to NMOSD and MS.

OBJECTIVE: To assess marked central canal T2-hyperintensity in patients with myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGAD) myelitis compared to myelitis patients with aquaporin-4-antibody-positive neuromyelitis optica spectrum disorder (AQP4 + NMOSD) and multiple sclerosis (MS). MATERIAL/METHODS: Two blinded raters evaluated spinal cord magnetic resonance imaging (MRIs) of myelitis patients with MOGAD (n = 63), AQP4 + NMOSD (n = 37), and MS (n = 26), assessing for marked central canal T2-hyperintensity and its evolution. If there were conflicting results, a third neurologist assessed the MRI. RESULTS: Marked central canal T2-hyperintensity was more frequent in patients with MOGAD (18/63[29%]) than MS (1/26[4%]; p = 0.01) myelitis but did not differ from AQP4 + NMOSD (13/37[35%]; p = 0.49). Marked central canal T2-hyperintensity had completely resolved on follow-up axial MRI for most MOGAD (12/14[86%]) and AQP4 + NMOSD (10/10[100%]; p = 0.49) patients. CONCLUSIONS: Marked central canal T2-hyperintensity is a common transient radiologic accompaniment of MOGAD and AQP4 + NMOSD myelitis, but not MS myelitis.

Serum Neurofilament to Magnetic Resonance Imaging Lesion Area Ratio Differentiates Spinal Cord Infarction From Acute Myelitis.

BACKGROUND AND PURPOSE: The diagnosis of spontaneous spinal cord infarction (SCI) is limited by the lack of diagnostic biomarkers and MRI features that often overlap with those of other myelopathies, especially acute myelitis. We investigated whether the ratio between serum neurofilament light chain levels and MRI T2-lesion area (neurofilament light chain/area ratio-NAR) differentiates SCI from acute myelitis of similar severity. METHODS: We retrospectively identified Mayo Clinic patients (January 1, 2000-December 31, 2019) with (1) SCI, (2) AQP4 (aquaporin 4)-IgG or MOG (myelin oligodendrocyte glycoprotein)-IgG-associated myelitis at disease clinical presentation, or (3) idiopathic transverse myelitis from a previously identified population-based cohort of patients seronegative for AQP4-IgG and MOG-IgG. Serum neurofilament light chain levels (pg/mL) were assessed at the Verona University (SIMOA, Quanterix) in a blinded fashion on available stored samples obtained ≤3 months from myelopathy presentation. For each patient, the largest spinal cord lesion area (mm2) was manually outlined by 2 independent raters on sagittal T2-weighted MRI images, and the mean value was used to determine NAR (pg/[mL·mm2]). RESULTS: Forty-eight patients were included SCI, 20 (definite, 11; probable, 6; possible, 3); acute myelitis, 28 (AQP4-IgG-associated, 17; MOG-IgG-associated, 5; idiopathic transverse myelitis, 6). The median expanded disability status scale score (range) at myelopathy nadir were 7.75 (2-8.5) and 5.5 (2-8), respectively. Serum neurofilament light chain levels (median [range] pg/mL) in patients with SCI (188 [14.3-2793.4]) were significantly higher compared with patients with AQP4-IgG-associated myelitis (37 [0.8-6942.9]), MOG-IgG-associated myelitis (45.8 [4-283.8]), and idiopathic transverse myelitis (15.6 [0.9-217.8]); P=0.01. NAR showed the highest accuracy for identification of SCI versus acute myelitis with values ≥0.35 pg/(mL·mm2) yielding 86% specificity and 95% sensitivity (area under the curve=0.93). The positive and negative likelihood ratios were 6.67 and 0.06, respectively. NAR remained independently associated with SCI after adjusting for age, gender, immunotherapy before sampling, and days from myelopathy symptoms onset to sampling (P=0.0007). CONCLUSIONS: NAR is a novel and promising clinical biomarker for differentiation of SCI from acute myelitis.

Spectrum of anti-myelin oligodendrocyte glycoprotein antibody (MOG-Ab)-associated diseases: an Indian perspective.

Myelin oligodendrocyte glycoprotein antibody (MOG-Ab) is involved in the pathogenesis of central nervous system (CNS) demyelination disorders. We aimed to explore the spectrum of MOG-Ab-associated diseases in eastern India. A single-center, prospective observational study was done over a period of 2 years in a tertiary care hospital of eastern India. Patients with CNS demyelination disorders who tested positive for MOG-Ab using live cell-based assay were included in the study; while, those with age less than 1 year, documented preexisting CNS structural lesions, developmental delays or diagnosed multiple sclerosis were excluded. Demographic profile, clinical spectrum, disease course, radiological features as well as response to treatment were analyzed among included patients. Twenty MOG-Ab-positive patients were included (M:F 1:1.85). The median age of symptom onset was 10.5 years. The median follow-up of patients was 13 months. Acute disseminated encephalomyelitis (ADEM) was the commonest presentation at first attack (55%), followed by optic neuritis (ON) (45%). Patients with ADEM had a significantly lower age at first attack (p = 0.025). Monophasic and relapsing disease courses were seen in 45% and 55% patients, respectively. While all patients with only ADEM had a monophasic course, 77.8% with ON had a relapsing course. Among patients who presented with isolated transverse myelitis, 75% had a monophasic course and all had disease confined to the spinal cord. Good response to corticosteroids was seen in majority of participants. Second-line drugs were needed in 55% patients, rituximab being the commonest second-line agent used. 35% patients had significant disability (EDSS > 4) at last follow-up. MOG-Ab-associated diseases have diverse clinical phenotypes characterized by age-dependent pattern-specific courses.

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.

Clinical features of transverse myelitis associated with systemic lupus erythematosus.

OBJECTIVE: This study aimed to identify the clinical characteristics and prognostic factors of systemic lupus erythematosus with transverse myelitis (SLE-TM) in a relatively large patient series. METHODS: This retrospective study considered 45 SLE-TM individuals treated as inpatients and outpatients at Peking Union Medical College Hospital between 1993 and 2018. SLE-TM patients were compared with 180 controls, and SLE-TM patients with neuromyelitis optica spectrum disorder (NMOSD) were compared to those without NMOSD. RESULTS: Compared to controls, the SLE-TM group frequently had a fever and had a significantly higher positive rate of anticardiolipin and lupus anticoagulant. Among the 45 patients, 22 met the NMOSD criteria. Compared to non-NMOSD patients, NMOSD patients had a lower incidence of rash (p = 0.023), serositis (p = 0.042) and renal disorder (p = 0.073); a lower prevalence of decreased complement (p = 0.083); and lower rates of positive anti-dsDNA (p = 0.074) and anti-Sm (p = 0.042). Among 22 SLE-TM patients with NMOSD, 18 underwent aquaporin 4 antibody testing, with 11 showing positive results. Out of the 45 patients, 39 were given methylprednisolone pulse treatment. After treatment, 32 patients had lower-limb muscle strength recovery (recovered group), whereas 13 had no change and persistent severe neurological deficits (non-recovered group). Compared to the recovered group, the non-recovered group were younger (p = 0.002), had a higher likelihood of having a fever (p = 0.020), initial severe myelitis (p < 0.001), long spinal segment involvement (p = 0.017) and higher C-reactive protein levels (p = 0.020). Methylprednisolone pulse given within two weeks of onset was more frequent in the recovered group than in the non-recovered group (p = 0.082). CONCLUSIONS: Disease characteristics differed between SLE-TM patients with and without NMOSD. SLE and NMOSD tended to be co-morbidities. Initial severe neurological impairment, extensive spinal cord lesions, hyper-inflammation and delayed steroid impulse treatment could be predictors of poor outcome for SLE-TM.

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.

Seropositive neuromyelitis optica spectrum disorder in Emirati patients: A case series.

OBJECTIVE: To describe clinical and radiological characteristics of seropositive neuromyelitis optica (NMO) in Emirati patients. While epidemiology of seropositive NMO in Abu Dhabi has been reported in a previous paper, its clinical and MRI profiles among Emirati patients have not been previously fully investigated. METHODS: In our case series, we describe clinical and MRI characteristics of 5 Emirati patients with NMO, consecutively admitted at Cleveland Clinic Abu Dhabi, a major tertiary hospital in Abu Dhabi, United Arab Emirates. RESULTS: Patients were all females, mean age of onset (SD) was 41 (11) years, and 67% had autoimmune comorbidities. Most patients initially presented with acute myelitis (80%) while 20% got optic neuritis. Mean (SD) number of further relapses after onset was 3 (1) and mean (SD) disease duration was 12 (11) years. At MRI, apparent longitudinal extensive transverse myelitis was present in all patients affecting mostly the central gray matter of the cervical cord but extending as well to the thoracic portion. Furthermore, seropositive NMO related brain lesions were also observed. CONCLUSIONS: Our work provides valuable information regarding seropositive NMO with the potential to increase recognition of this disorder in Abu Dhabi and confirms NMO findings described in the other populations with this disorder. Further research is needed to advance clinical and MRI characterization of seronegative NMO in the region.

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.

Myelin Oligodendrocyte Glycoprotein Antibody Associated Transverse Myelitis.

Antibodies against myelin oligodendrocyte glycoprotein cause inflammatory lesions of central myelin - in optic nerves, of the brainstem, and spinal cord. There are characteristic changes of CNS white matter, protein-cytological association in cerebrospinal fluid, MOG IgG antibodies, a very important differential diagnosis and a relatively mild course.

Different magnetic resonance imaging features between MOG antibody- and AQP4 antibody-mediated disease: A Chinese cohort study.

Few studies have compared radiological features obtained on magnetic resonance imaging (MRI) between myelin oligodendrocyte glycoprotein antibody (MOG-ab)- and aquaporin 4 antibody (AQP4-ab)-positive patients. In this study, 77 MOG-ab and 92 AQP4-ab patients were enrolled. The results demonstrated that the brain MRI-based incidence of subcortical white matter lesions was higher in MOG-ab patients (p < .000) than in AQP4-ab patients and that the former therefore had a higher incidence of periventricular lesions (p = .003). The posterior limb of the internal capsule was more prone to lesions in MOG-ab patients (p = .019). Large lesions and U- or S-shaped lesions were also more frequent in MOG-ab (p < .000 and p = .013, respectively). Half of the MOG-ab patients had spinal cord involvement, and 36.5% presented with longitudinally extensive transverse myelitis (LETM). However, among the MOG-ab and AQP4-ab patients with spinal attack, there was no significant difference in the proportion with LETM (p = .057). In conclusion, a higher proportion of MOG-ab patients than AQP4-ab patients had brain lesions in white matter. Among MOG-ab patients who had an attack in the spinal cord, 65.5% also had LETM during the disease course. Conus medullaris lesions were rare in Chinese MOG-ab patients.

Isolated recurrent myelitis in a persistent MOG positive patient.

MOG-Ab positive CNS demyelination typically involves the optic nerve and spinal cord. Recurrent episodes of myelitis without optic neuritis are very rare and according to current literature review represent about 3-5% of positive MOG-Ab cases. We report a 30-year-old woman with positive serum MOG-Ab suffering two discrete episodes of transverse myelitis without ophthalmic involvement. Repeated serum MOG-Ab test after the second relapse was positive, correlating with high likelihood of relapsing disease. Of note, our patient relapsed under Rituximab therapy, which does not seem to be uncommon for MOG-Ab patients. Patients with isolated or recurrent myelitis without optic involvement should be screened for anti MOG IgG as a part of their workup.

Aquaporin-4 antibody positive short transverse myelitis associated with breast cancer.

Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelinating disease of the central nervous system (CNS). A typical finding on spinal magnetic resonance imaging (MRI) of NMOSD is longitudinally extensive transverse myelitis (LETM). However, patients with NMOSD presenting with short-segment transverse myelitis (STM) during myelitis attacks associated with breast cancer are uncommon. We report a case of a 35-year-old woman with STM and left eye optic neuritis. The patient was positive for serum aquaporin-4 antibodies (AQP4-IgG), and a biopsy of the left breast showed invasive ductal carcinoma. The patient was diagnosed with NMOSD and breast malignancy. This is the first report of a patient with NMOSD whose spinal MRI showed STM and serum test showed that the patient's AQP4-IgG was positive and complicated by breast cancer. This case improves our understanding of the association between NMOSD and cancer and raises the question of whether it was a coincidental occurrence. It is important to search for extensive malignancies in patients presenting with atypical MRI or no reaction to traditional therapies.

Multiple sclerosis: Serum anti-CNS autoantibodies.

BACKGROUND: It is uncertain whether there are autoantibodies detectable by indirect immunofluorescence in the serum of patients with multiple sclerosis (MS). OBJECTIVE: To determine whether there are anti-central nervous system (CNS) autoantibodies detectable by indirect immunofluorescence in the serum of MS patients. METHODS: Sera and in some cases cerebrospinal fluid from 106 patients with multiple sclerosis, 156 patients with other neurological diseases, and 70 healthy control subjects were examined by indirect immunofluorescence using cryostat sections of rat cerebrum fixed by perfusion with paraformaldehyde. RESULTS: Autoantibodies were detected that recognized more than 30 neuronal, glial, and mesodermal structures in 28 of 106 MS cases. Most were also detected in patients with other related and unrelated neurological diseases and several were also found in healthy controls. Novel anti-CNS autoantibodies recognizing particular sets of interneurons were detected in both normal controls and in subjects with CNS diseases. INTERPRETATION: Serum anti-CNS autoantibodies of diverse specificities are common in MS patients. The same anti-CNS autoantibodies are not uncommon in patients with other neurological diseases. The findings provide no support for the proposition that myelin breakdown in MS is caused by exposure of intact myelin sheaths or oligodendrocytes to a pathogenic serum anti-myelin or anti-oligodendrocyte autoantibody.