Differentiating Multiple Sclerosis From AQP4-Neuromyelitis Optica Spectrum Disorder and MOG-Antibody Disease With Imaging

Abstract

Background and objectives: Relapsing-remitting multiple sclerosis (RRMS), aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) may have overlapping clinical features. There is an unmet need for imaging markers that differentiate between them when serologic testing is unavailable or ambiguous. We assessed whether imaging characteristics typical of MS discriminate RRMS from AQP4-NMOSD and MOGAD, alone and in combination.

Methods: Adult, nonacute patients with RRMS, APQ4-NMOSD, and MOGAD and healthy controls were prospectively recruited at the National Hospital for Neurology and Neurosurgery (London, United Kingdom) and the Walton Centre (Liverpool, United Kingdom) between 2014 and 2019. They underwent conventional and advanced brain, cord, and optic nerve MRI and optical coherence tomography (OCT).

Results: A total of 91 consecutive patients (31 RRMS, 30 APQ4-NMOSD, and 30 MOGAD) and 34 healthy controls were recruited. The most accurate measures differentiating RRMS from AQP4-NMOSD were the proportion of lesions with the central vein sign (CVS) (84% vs 33%, accuracy/specificity/sensitivity: 91/88/93%, p < 0.001), followed by cortical lesions (median: 2 [range: 1-14] vs 1 [0-1], accuracy/specificity/sensitivity: 84/90/77%, p = 0.002) and white matter lesions (mean: 39.07 [±25.8] vs 9.5 [±14], accuracy/specificity/sensitivity: 78/84/73%, p = 0.001). The combination of higher proportion of CVS, cortical lesions, and optic nerve magnetization transfer ratio reached the highest accuracy in distinguishing RRMS from AQP4-NMOSD (accuracy/specificity/sensitivity: 95/92/97%, p < 0.001). The most accurate measures favoring RRMS over MOGAD were white matter lesions (39.07 [±25.8] vs 1 [±2.3], accuracy/specificity/sensitivity: 94/94/93%, p = 0.006), followed by cortical lesions (2 [1-14] vs 1 [0-1], accuracy/specificity/sensitivity: 84/97/71%, p = 0.004), and retinal nerve fiber layer thickness (RNFL) (mean: 87.54 [±13.83] vs 75.54 [±20.33], accuracy/specificity/sensitivity: 80/79/81%, p = 0.009). Higher cortical lesion number combined with higher RNFL thickness best differentiated RRMS from MOGAD (accuracy/specificity/sensitivity: 84/92/77%, p < 0.001).

Discussion: Cortical lesions, CVS, and optic nerve markers achieve a high accuracy in distinguishing RRMS from APQ4-NMOSD and MOGAD. This information may be useful in clinical practice, especially outside the acute phase and when serologic testing is ambiguous or not promptly available.

Classification of evidence: This study provides Class II evidence that selected conventional and advanced brain, cord, and optic nerve MRI and OCT markers distinguish adult patients with RRMS from AQP4-NMOSD and MOGAD.

Figure 1. Differences in Brain and Cervical Cord Measures Between RRMS, AQP4-NMOSD, MOGAD, and Healthy Controls

The boxplots show a lower number and volume of lesions and a higher degree of atrophy in patients with RRMS than patients with AQP4-NMOSD and MOGAD and healthy controls. AQP4-NMOSD = aquaporin-4 antibody–positive neuromyelitis optica spectrum disorder; MOGAD = myelin oligodendrocyte glycoprotein antibody–associated disease; RRMS = relapsing-remitting multiple sclerosis.

Figure 2. Examples of Cortical Lesions Seen on Phase-Sensitive Inversion Recovery (PSIR) Images and Lesions With and Without the Central Vein Sign (CVS) on Susceptibility-Weighted Imaging (SWI) in RRMS, AQP4-NMOSD, and MOGAD

In the upper figures, PSIR imaging showing lesions located exclusively in the cortex (intracortical, red arrow) or within the cortex and adjacent juxtacortical white matter (leukocortical, blue arrow) in RRMS, AQP4-NMOSD, and MOGAD. Intracortical and leukocortical lesions were detected in patients with RRMS (A), whereas 1 leukocortical lesion in 1 patient with AQP4-NMOSD (B) and 1 intracortical lesion in 1 patient with MOGAD (C) were found. In the lower figures, T2 and corresponding SWI of deep white matter lesions with (red arrow) or without (blue arrow) CVS in RRMS and AQP4-NMOSD. The dark vein was located centrally in a lesion in an RRMS patient (D), while it was absent in three lesions in an AQP4-NMOSD patient (E). AQP4-NMOSD = aquaporin-4 antibody–positive neuromyelitis optica spectrum disorder; MOGAD = myelin oligodendrocyte glycoprotein antibody–associated disease; RRMS = relapsing-remitting multiple sclerosis.

Figure 3. Central Vein Sign (CVS) Detected on Susceptibility-Weighted Imaging (SWI) in the Patient Groups

The scatterplot shows the proportion of lesions with CVS (out of the total number of lesions) for each patient in the 3 diseases (orange = RRMS, green = AQP4-NMOSD, and blue = MOGAD). Patients without brain lesions are not displayed. Two of 8 patients with MOGAD were excluded from the rating (1 for poor SWI quality and 1 for extensive, confluent PD/T2 abnormalities). Note: 100% means that all lesions assessed showed the CVS. MOGAD = myelin oligodendrocyte glycoprotein antibody–associated disease; RRMS = relapsing-remitting multiple sclerosis.