Positive Predictive Value of Myelin Oligodendrocyte Glycoprotein Autoantibody Testing

Sechi, Elia; Buciuc, Marina; Pittock, Sean J.; Chen, John J.; Fryer, James P.; Jenkins, Sarah M.; Budhram, Adrian; Weinshenker, Brian G.; López-Chiriboga, A. Sebastian; Tillema, Jan Mendelt; McKeon, Andrew; Mills, John R.; Tobin, W. Oliver; Flanagan, Eoin P.

doi:10.1001/jamaneurol.2021.0912

Cited by 154 publications

(165 citation statements)

References 17 publications

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“…Similarly, complete or near complete T2 lesion resolution can be used, in addition to other measures, when a positive MOG-IgG test is encountered to help distinguish true vs false-positive results, particularly when antibody titer is low and the risk of false positivity is higher (up to a quarter of positive results may be false-positives when the test is performed indiscriminately in a real-life clinical setting). 32 …”

Section: Discussionmentioning

confidence: 99%

Comparison of MRI Lesion Evolution in Different Central Nervous System Demyelinating Disorders

et al. 2021

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Background and Objective:There are few studies that compare lesion evolution across different CNS demyelinating diseases, yet knowledge of this may be important for diagnosis and understanding differences in disease pathogenesis. We sought to compare MRI T2-lesion evolution in myelin-oligodendrocyte-glycoprotein-IgG-associated disorder (MOGAD), aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder (AQP4-IgG-NMOSD), and multiple sclerosis (MS).Methods:In this descriptive study, we retrospectively identified Mayo Clinic patients with MOGAD, AQP4-IgG-NMOSD, or MS and: 1) brain or myelitis attack; 2) available attack MRI within 6 weeks; and 3) follow-up MRI beyond 6 months without interval relapses in that region. Two neurologists identified the symptomatic or largest T2-lesion for each patient (index lesion). MRIs were then independently reviewed by two neuroradiologists blinded to diagnosis to determine resolution of T2-lesions by consensus. The index T2-lesion area was manually outlined acutely and at follow-up to assess variation in size.Results:We included 156 patients (MOGAD, 38; AQP4-IgG-NMOSD, 51; MS, 67) with 172 attacks (brain, 81; myelitis, 91). The age (median [range]) differed between MOGAD (25 [2-74]), AQP4-IgG-NMOSD (53 [10-78]) and MS (37 [16-61]) (p<0.01) and female sex predominated in the AQP4-IgG-NMOSD (41/51 [80%]) and MS (51/67 [76%]) groups but not among those with MOGAD (17/38 [45%]). Complete resolution of the index T2-lesion was more frequent in MOGAD (brain, 13/18[72%]; spine, 22/28[79%]) than AQP4-IgG-NMOSD (brain, 3/21[14%]; spine, 0/34[0%]) and MS (brain, 7/42[17%]; spine, 0/29[0%]), p<0.001. Resolution of all T2-Lesions occurred most often in MOGAD (brain, 7/18[39%]; spine, 22/28[79%]) than AQP4-IgG-NMOSD (brain, 2/21[10%]; spine, 0/34[0%]), and MS (brain, 2/42[5%]; spine, 0/29[0%]), p< 0.01. There was a larger median (range) reduction in T2-lesion area in mm2 on follow-up axial brain MRI with MOGAD (213[55-873]) than AQP4-IgG-NMOSD (104[0.7-597]) (p=0.02) and MS, 36[0-506]) (p< 0.001) and the reductions in size on sagittal spine MRI follow-up in MOGAD (262[0-888]) and AQP4-IgG-NMOSD (309[0-1885]) were similar (p=0.4) and greater than MS (23[0-152]) (p<0.001).Conclusions:The MRI T2-lesions in MOGAD resolve completely more often than AQP4-IgG-NMOSD and MS. This has implications for diagnosis, monitoring disease activity, and clinical trial design, while also providing insight into pathogenesis of central nervous system demyelinating diseases.

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Section: Discussionmentioning

confidence: 99%

Comparison of MRI Lesion Evolution in Different Central Nervous System Demyelinating Disorders

et al. 2021

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“…This is particularly relevant for rare disorders like autoimmune neurologic disorders, for which the reported overall incidence and prevalence range between 3.5 and 9/million person-years and 4-6.5/100.000 persons, respectively (107)(108)(109). When similar rare disorders are faced, caution is advised in clinical practice as the risk of false positive results is not negligible if the test is performed indiscriminately, despite very high specificity and sensitivity (110). The example in Figure 4 illustrates how the PPV can vary when a given autoantibody is tested in different populations.…”

Section: Positive Predictive Value False Positives and "Phenotype Creep"mentioning

confidence: 99%

“…The same concept is applicable in clinical practice where antibody-mediated CNS disorders are far less common than other immune-mediated and non-immune-mediated neurologic diseases (e.g., multiple sclerosis in the extremes of latitude, epilepsy, cancers). Thus, a thorough assessment of the clinical-MRI phenotypes is mandatory when autoantibody testing is performed, as “atypical” or “rare” manifestations for a given antibody-associated syndrome should prompt investigating alternative etiologies (which are simply more likely to occur than rare manifestations of a rare disorder) ( 110 ). The concept of “phenotype creep” has been coined to specifically describe the incorrect tendency in the scientific literature and clinical practice to accept poorly fitting manifestations as an uncommon part of the disease spectrum, just based on autoantibody positivity ( 111 ).…”

Section: Diagnosis Of Antibody-mediated Cns Disordersmentioning

confidence: 99%

“…Although preliminary diagnostic criteria and recommendations have been proposed for MOG antibody associated disorder ( 19 , 112 ), there are international efforts to produce more unified consensus diagnostic criteria. These criteria will be important, given there is a higher risk of false positives, particularly at low titer with MOG antibody associated disorder than with aquaporin-4 antibody positive NMOSD ( 110 ).…”

Section: Diagnosis Of Antibody-mediated Cns Disordersmentioning

confidence: 99%

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Antibody-Mediated Autoimmune Diseases of the CNS: Challenges and Approaches to Diagnosis and Management

Sechi

Flanagan

2021

Front. Neurol.

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Antibody-mediated disorders of the central nervous system (CNS) are increasingly recognized as neurologic disorders that can be severe and even life-threatening but with the potential for reversibility with appropriate treatment. The expanding spectrum of newly identified autoantibodies targeting glial or neuronal (neural) antigens and associated clinical syndromes (ranging from autoimmune encephalitis to CNS demyelination) has increased diagnostic precision, and allowed critical reinterpretation of non-specific neurological syndromes historically associated with systemic disorders (e.g., Hashimoto encephalopathy). The intracellular vs. cell-surface or synaptic location of the different neural autoantibody targets often helps to predict the clinical characteristics, potential cancer association, and treatment response of the associated syndromes. In particular, autoantibodies targeting intracellular antigens (traditionally termed onconeural autoantibodies) are often associated with cancers, rarely respond well to immunosuppression and have a poor outcome, although exceptions exist. Detection of neural autoantibodies with accurate laboratory assays in patients with compatible clinical-MRI phenotypes allows a definite diagnosis of antibody-mediated CNS disorders, with important therapeutic and prognostic implications. Antibody-mediated CNS disorders are rare, and reliable autoantibody identification is highly dependent on the technique used for detection and pre-test probability. As a consequence, indiscriminate neural autoantibody testing among patients with more common neurologic disorders (e.g., epilepsy, dementia) will necessarily increase the risk of false positivity, so that recognition of high-risk clinical-MRI phenotypes is crucial. A number of emerging clinical settings have recently been recognized to favor development of CNS autoimmunity. These include antibody-mediated CNS disorders following herpes simplex virus encephalitis or occurring in a post-transplant setting, and neurological autoimmunity triggered by TNFα inhibitors or immune checkpoint inhibitors for cancer treatment. Awareness of the range of clinical and radiological manifestations associated with different neural autoantibodies, and the specific settings where autoimmune CNS disorders may occur is crucial to allow rapid diagnosis and early initiation of treatment.

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“… 2 However, MOG-IgG positivity may occasionally occur in patients with typical MS lesions on MRI. 4 Although MOG-IgG is assumed to be a false positive result in such patients, some have suggested they might represent atypical manifestations of MOGAD. In this systematic review, we studied the clinical characteristics, treatment response, and outcomes in patients with typical MS lesions on MRI and MOG-IgG positivity.…”

Section: Introductionmentioning

confidence: 99%

Clinical Significance of Myelin Oligodendrocyte Glycoprotein Autoantibodies in Patients with Typical MS Lesions on MRI

Zara

Floris

Flanagan

et al. 2021

Multiple Sclerosis Journal - Experimental, Translational and Cl

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Background Myelin-oligodendrocyte-glycoprotein (MOG)-IgG-positivity in patients with typical MS lesions on MRI may lead to diagnostic/therapeutic uncertainty. Objective and Methods We reviewed reports of cases with MS phenotype on MRI and MOG-IgG-positivity published in Pubmed between 01/2012–06/2021. Results Sixteen patients were included (median age [range], 37,5 [25–66] years; 60% female). Three patients initially tested negative for MOG-IgG. Disease course was: relapsing-remitting, 10; or progressive, 6. Intrathecal IgG-synthesis was common (79%). Low and high-efficacy MS-targeted agents prevented relapses in 30% and 100%, respectively. None of the patients showed resolution of MRI T2-lesions over time. Conclusions MOG-IgG-positivity is unlikely to alter the expected treatment response and outcomes in patients with otherwise typical MS phenotype on MRI.

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Positive Predictive Value of Myelin Oligodendrocyte Glycoprotein Autoantibody Testing

Cited by 154 publications

References 17 publications

Comparison of MRI Lesion Evolution in Different Central Nervous System Demyelinating Disorders

Comparison of MRI Lesion Evolution in Different Central Nervous System Demyelinating Disorders

Antibody-Mediated Autoimmune Diseases of the CNS: Challenges and Approaches to Diagnosis and Management

Clinical Significance of Myelin Oligodendrocyte Glycoprotein Autoantibodies in Patients with Typical MS Lesions on MRI

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