Nonlesional diffusely abnormal appearing white matter in clinically isolated syndrome: Prevalence, association with clinical and MRI features, and risk for conversion to multiple sclerosis

Abstract

Background and Purpose While diffusely abnormal white matter (DAWM) is a nonlesional MRI abnormality identified in ∼25% of patients with multiple sclerosis (MS), it has yet to be investigated in patients at an earlier disease stage, namely clinically isolated syndrome (CIS). The goals of this study were to (1) determine the prevalence of DAWM in patients with a CIS suggestive of MS, (2) evaluate the association between DAWM and demographic, clinical, and MRI features, and (3) evaluate the prognostic significance of DAWM on conversion from CIS to MS. Methods One hundred and forty‐two CIS participants were categorized into DAWM and non‐DAWM groups at baseline and followed for up to 24 months or until MS diagnosis. The primary outcome was conversion to MS (2005 McDonald criteria) within 6 months. Results DAWM was present in 27.5% of participants, and was positively associated with brainstem symptom onset, receiving corticosteroids, dissemination in space, and T2 lesion volume. DAWM was associated with an increased risk of conversion to MS over 6 months after adjustment for age and disability (hazard ratio [HR] = 2.24, p = 0.004). This association remained at a trend‐level after adjustment for high‐risk imaging features (HR = 1.68, p = 0.10). Conclusions DAWM is present in a similar proportion of patients with CIS and clinically definite MS, and it is associated with increased risk of conversion to MS over 6 months.

Diffusely abnormal white matter in multiple sclerosis

“…22 Several large studies have examined the association between DAWM and the conventional MRI metrics of lesion and brain volume. In a study of 142 CIS patients, Holmes et al found the prevalence of DAWM in CIS to be 27.5%, 34 which is similar to most RRMS reports. CIS participants with DAWM were more likely to have brainstem symptoms at onset, receive glucocorticoid treatment for their CIS event, meet criteria for high risk of conversion to MS, have higher T 2 lesion volume, and have a lower brain parenchymal fraction.…”

“…For now, the use of at least two experienced MRI radiologists or individuals with similar expertise, working independently to reach a consensus, is recommended. 22,[32][33][34] For cases without consensus, an additional expert to arbitrate can be brought in. A similar multi-rater approach can be used for manual region of interest deliniation, 26,32 which is also subjective given that, unlike focal lesions, the boundaries of DAWM are not clearly defined.…”

“…Although the cause of DAWM is unclear at this time, it is by no means a rare phenomenon with recent studies describing DAWM in at least one quarter to more than one half of patients with CIS and RRMS 22,23,34 . Those individuals with DAWM appear to convert to definite MS sooner, and have more rapid progression on disability measures, such as EDSS 27,49,66 .…”

“…To determine the presence or absence of DAWM, the majority of the literature has used manual classification, which is time‐consuming, subjective, and may be impacted by intra and inter‐rater variability. For now, the use of at least two experienced MRI radiologists or individuals with similar expertise, working independently to reach a consensus, is recommended 22,32–34 . For cases without consensus, an additional expert to arbitrate can be brought in.…”

“…However, there are conflicting views on the interpretation of DAWM being a chronic pathological process. There is evidence that DAWM is present very early in the pathogenesis of MS: it is observed in CIS, 23,34,37 clinically definite MS subjects with DAWM have shorter disease duration and progress faster than subjects without DAWM with similar EDSS, 27,49 and there is emerging evidence that DAWM volume may be reduced as it becomes replaced by increases and expansion of MS lesional volume over time 31 . Second, there are conflicting reports on the nature and characteristics of DAWM in some cases of MS. Lycklama‐a‐Nijeholt et al.…”