Cross-sectional examination of the brain MRI scans from the cohort of 41 UK seropositive NMOSD patients (excluding those with lesions consistent with cerebrovascular disease) demonstrated T2 hyperintense lesions in 26 of 41 (63.4%). The lesion probability distributions for the RRMS and NMOSD patient groups are shown in . The majority of lesions in the patients with NMOSD were smaller in size and fewer in number compared with patients with MS. The distribution throughout the brain tissue was also widely variable: this is reflected in the low probability of lesions occurring in the same spatial location in more than 2 patients. The area of highest probability of a lesion occurring in the NMOSD group was within the frontal deep white matter (MNI coordinate −24 mm, 8 mm, 20 mm at a probability of 20%). Conversely, the most likely place for an RRMS lesion to occur was adjacent to the posterior of the body of the lateral ventricle in the parietal white matter (MNI coordinate 30 mm, −50 mm, 14 mm), at a high probability of 54% indicating greater lesion load and coherence of lesion location among patients in the RRMS group. shows a subtraction map in which the average NMOSD lesion map has been subtracted from the average RRMS lesion map to allow direct comparison of the distributions. Lesions in NMOSD and RRMS are found throughout the supra- and infratentorial white and gray matter. However, distinguishing features of note were more NMOSD lesions in the medulla oblongata, whereas in the RRMS group, more lesions were noted within the cerebellum, bordering the lateral aspect of the body of the lateral ventricles (including within the periventricular gray matter) and in the temporal lobes. Both conditions were associated with lesions in the corpus callosum. shows the voxel-wise permutation-testing comparison of the lesion distributions in each group. RRMS lesions are significantly more likely than NMOSD lesions to be adjacent to the body of the lateral ventricle (corrected p < 0.05). The lesional region with the greatest likelihood to be within the NMOSD and not the RRMS group was adjacent to the fourth ventricle within the pons. This did not reach statistical significance (corrected p = 0.35) because of the lower lesion load in NMOSD.
Visual comparison of lesion probability distributions in neuromyelitis optica spectrum disorder (NMOSD) and relapsing-remitting multiple sclerosis (RRMS)
The proportion of NMOSD T2 lesions occurring in specific spatial locations within the brain is shown in . Examples of these patterns are shown in . Of note, the most common distribution for patients with NMOSD is supratentorial deep white matter lesions.
Lesion location for 26 patients with NMOSD who tested positive for aquaporin-4 antibodies
Neuromyelitis optica spectrum disorder (NMOSD) lesions
Seven of 26 patients with NMOSD who had brain lesions, or 15.9% of all patients with NMOSD, fulfilled Barkhof criteria for the dissemination of RRMS lesions in space,17
based on unenhanced brain MRI alone. There are important differences, however, in the morphology of the lesions. None of the patients with NMOSD had juxtacortical T2 hyperintensities with morphology suggestive of location in the U-fiber, unlike the RRMS cohort. It is also of note that lesions adjacent to the lateral ventricles in NMOSD tend to be located at the anterior and posterior horns (), and that no patients had ovoid lesions in a perpendicular alignment (Dawson's fingers).
CSF examination had been performed in 34 of the patients with NMOSD. Of those, 9 tested positive for oligoclonal bands. Of the 7 patients who fulfilled Barkhof criteria, 1 tested positive for oligoclonal bands; therefore, there is no increased likelihood within this subgroup. The clinical phenotypes of this group of patients were 5 with NMO as described by the 2006 Wingerchuk criteria,1
and 2 with relapsing LETM.
Within the NMOSD cohort, colocalized T1 hypointensity was found in 0% to 83.3% of T2 lesions (38% of all T2 lesions). This compares with 25% to 95% of MS lesions (53.4% of all T2 lesions).
Formulation of criteria for the separation of RRMS and NMOSD.
Using the findings summarized above, we were able to hypothesize that RRMS could be distinguished from NMOSD on the basis of T2 brain lesion distribution. We tested criteria of having at least 1 lesion adjacent to the body of the lateral ventricle and at least 1 lesion in the inferior temporal lobe for the identification of RRMS. This was able to identify RRMS with 78% sensitivity, 96.2% specificity, 97.5% positive predicative value, and 69.4% negative predictive value (). Of the patients with RRMS who did not fulfill both criteria, 7 of 11 had either an ovoid lesion perpendicular to a lateral ventricle or a subcortical lesion with morphology suggestive of location in the U-fiber (examples of these lesions are shown in figure e-2). Adding this as a further criterion resulted in a 92% sensitivity, 96.2% specificity, 97.9% positive predictive value, and 86.2% negative predictive value. A flow diagram summarizing the way in which these criteria should be applied is given in .
Numbers of subjects fulfilling and the sensitivity and specificity of each criterion/combination of criteria for the separation of RRMS from NMOSD
Flow diagram summarizing application of criteria for the separation of relapsing-remitting multiple sclerosis (RRMS) and neuromyelitis optica spectrum disorder (NMOSD)
The definition of an NMO typical brain lesion (e.g., a lesion that occurs in the periependymal brain tissue or hypothalamus)18
is relatively subjective and RRMS lesions can also occur in these locations. The criteria are designed to be used objectively by nonexperts and therefore the term “NMO typical” has been avoided in this study. However, we investigated whether a lesion adjacent to the fourth ventricle could help to correctly identify NMOSD. This did not improve the accuracy of the criteria—in fact, only 9% of patients with NMOSD who were AQP4-ab positive in this study had lesions that may be considered NMO typical, consistent with previous literature.19