Brain MRI Findings in Pediatric-Onset Neuromyelitis Optica Spectrum Disorder: Challenges in Differentiation from Acute Disseminated Encephalomyelitis

Discussion

The most recent consensus criteria for the diagnosis of NMOSD make special mention of the difficulty in distinguishing pediatric-onset NMOSD from ADEM.⁴ Pediatric ADEM may also present with longitudinally extensive transverse myelitis similar to NMOSD; therefore, myelitis is not a reliable predictor of NMOSD in children.^4,20 Further complicating the issue, brain lesions are more frequent in children compared with adult-onset NMOSD.^{12⇓–14,21,22} Imaging findings that can help distinguish these rare neuroimmunologic diseases may help to confirm a diagnosis in children. Accordingly, in this study, we aimed to find differences in brain MR imaging features that could distinguish pediatric-onset NMOSD from its primary mimicker, ADEM.

Pediatric-onset NMOSD–related brain involvement, similar to adult-onset disease, has been characterized by large (>2 cm) subcortical white matter lesions and lesions within the areas of high AQP4 expression such as periependymal areas of the fourth and third ventricles.^12,14 Our results were similar to those of previous studies in regard to the high frequency of confluent lesions in the cerebral subcortical white matter and brain stem, though periventricular involvement was not distinctive. The periventricular areas of the fourth ventricle rather seemed to be secondarily involved by extension of confluent brain stem lesions. The bandlike circumventricular lesions with or without pencil-thin ependymal enhancement, which are highly suggestive of an immune-mediated reaction against ependymal linings, were not detected. Therefore, periventricular involvement around the fourth ventricle was not specific enough to be distinguished from periventricular extension of large, confluent brain stem lesions frequently observed in the ADEM cohort. This finding along with the lack of previously described periependymal diencephalic lesions could be partially explained by a low anti-AQP4 seropositivity ratio in the NMOSD cohort. Also, this pattern of diencephalic involvement was not a common MR imaging finding, even in the largest study conducted on children with anti-AQP4 antibodies,¹² and its absence may be due to the small number of cases in our study.

We have found that thalamic and internal capsule involvement could differentiate pediatric-onset NMOSD from ADEM. Thalamic involvement was infrequent and limited to a nonspecific lesion in 1 patient with NMOSD. This result was similar to those in the previous cohorts of pediatric-onset NMOSD, which noted frequencies of thalamic lesions ranging from none to 13%.^12,13,18,20 On the other hand, thalamic involvement in the ADEM cohort was frequent and characteristic, with mostly asymmetric, large, and poorly marginated lesions as previously reported.²³ The consistency of our findings with previous reports allowed us to postulate that thalamic lesion location could favor a diagnosis of ADEM over pediatric-onset NMOSD.

Another lesion location that resulted in a significant difference between these disease entities was the posterior limb of the internal capsule. We did not detect any posterior limb of the internal capsule lesion in the NMOSD cohort, contrary to ADEM. Prior pediatric-onset NMOSD cohorts did not specify involvement of the internal capsule; therefore, a correlation with the current study is not possible. However, previous reports of adult-onset NMOSD showed varying frequencies of corticospinal tract involvement from 3% to 44%.^5,7,10 The inconsistency of our findings with adult-onset NMOSD cohorts may reflect differences in disease mechanisms between children and adults. The statistical effects of small cohort size may also be responsible for this result. Re-evaluation with larger comparative cohorts is needed for validation.

Remarkably, no other MR imaging findings including lesion expansion, T1 hypointensity, contrast enhancement/pattern, and diffusion characteristics could be identified to differentiate pediatric-onset NMOSD from ADEM. Expansion and T1 hypointensity are common features in the acute attack of demyelinating/inflammatory entities as contrast enhancement.^23,24 Different patterns of contrast enhancement have been identified in NMOSD, such as cloudlike parenchymal, pencil-thin ependymal, leptomeningeal, or perivascular enhancement.^{24⇓⇓⇓–28} Among these, ependymal and leptomeningeal enhancement was found significantly more frequently in patients with NMOSD than in those with MS and was suggested as a characteristic feature in NMOSD.²⁷ In our study, we found similar results regarding leptomeningeal enhancement; it was seen in 3 patients (37.5%) with NMOSD and was not detected in patients with ADEM (P = .23). Although differences between the 2 entities were not statistically significant, considering the previous remarks on leptomeningeal enhancement in NMOSD and the possible statistical effects of our small-sized cohorts together, we hypothesized that this enhancement pattern could favor the diagnosis of NMOSD over ADEM. Future investigations with larger comparative cohorts are required to confirm this hypothesis.

Two patients with leptomeningeal enhancement tested negative for anti-AQP4 antibodies. This finding is difficult to explain by the anti-AQP4 antibody–mediated immune response alone, which was the previously proposed mechanism for leptomeningeal enhancement. Fluctuating anti-AQ4 antibody titers, relatively lower antibody titers that are undetectable by serum assays, or varied AQP4 expression could be responsible for leptomeningeal enhancement in these seronegative patients, or perhaps some other underlying pathophysiologic mechanisms could exist. Although the patchy or so-called cloudlike enhancement was frequent in the NMOSD group, it was not discriminative and was also seen in patients with ADEM.

There are only a few case series in the literature defining diffusion characteristics of brain lesions in NMOSD.^16,19,29 Brain lesions in those series were characterized by facilitated diffusion, which was attributed to vasogenic edema associated with acute inflammation. We present 2 NMOSD cases having brain lesions with patchy areas of restricted diffusion, different from previous data. Restricted diffusion in the affected regions may be due to swelling of myelin sheaths, reversible vascular compromise, or intense cell infiltration due to acute inflammatory reaction. Similar to findings in a previous report,³⁰ restricted diffusion in the brain lesions was not frequent in our ADEM cohort, either. All these findings suggest that restricted diffusion could infrequently associate brain lesions in both pediatric-onset NMOSD and patients with ADEM and could not help in differentiating these 2 entities.

As the main limitation, our comparative cohort comprised a relatively small number of patients in each group. Therefore, future studies with larger sizes are needed to test the validity of the identified MR imaging discriminators and to further investigate the role of leptomeningeal enhancement in the differentiation of pediatric-onset NMOSD from ADEM.

Another limitation is that not all patients were tested for the anti-myelin oligodendrocyte glycoprotein antibody because testing for this antibody was not widely available at the time of the study design. Anti-myelin oligodendrocyte glycoprotein antibody has been found in a subgroup of anti AQP4 antibody negative NMOSD patients including children. Although anti-myelin oligodendrocyte glycoprotein antibody disease emerged as a distinct entity with more favorable clinical outcomes recently,³¹ it is not specified in the NMOSD diagnostic criteria yet. Larger cohorts with anti-myelin oligodendrocyte glycoprotein antibody testing are needed to characterize brain MR imaging findings distinctive of this group of patients in future studies.

Other limitations were due to retrospective design of the study. MR images were obtained from scanners with different magnet strengths, there were differences in imaging parameters including slice thickness, and DWI was not performed in 2 children with NMOSD. All of these could affect the sensitivity of image evaluation and comparisons.