By Jai S. Perumal, MD
Assistant Professor of Neurology, Weill Cornell Medical College
Patients with multiple sclerosis (MS) can have an acute clinical event suggestive of a relapse, but their magnetic resonance imaging (MRI) shows no corresponding changes (labeled by the authors as an acute clinical event with stable MRI [ACES]). These events have not been systematically analyzed. The authors reported that this number is significant, and a quarter of the relapses reported by patients fall under this category. Patients with ACES had higher relapse rates and a greater risk of transition to secondary progressive MS.
Gavoille A, Rollot F, Casey R, et al. Acute clinical events identified as relapses with stable magnetic resonance imaging in multiple sclerosis. JAMA Neurol 2024; Jul 1. doi:10.1001/jamaneurol.2024.1961. [Online ahead of print].
A relapse of multiple sclerosis (MS) is defined as new or worsening symptoms lasting longer than 24 hours, without fever or infection. It is important to distinguish a true relapse from pseudo-relapse. Hence, in theory, one would expect a new T2 lesion or contrast-enhancing lesion in the context of a true relapse. However, this is not the case every time a patient reports symptoms suggestive of a relapse. These events have not been analyzed adequately. In this study, the authors examined such events, which they labeled as ACES: acute clinical event with stable magnetic resonance imaging (MRI).
This was a multicenter observational cohort study. A total of 637 events in 608 patients met the criteria for inclusion in the study. Patients needed to have brain MRI 12 months before the event and spinal cord imaging 24 months before the event, respectively. They also needed to have a post-event MRI within 50 days, with contrast administration. Apart from examination of the clinical characteristics of these events, the authors also studied factors associated with ACES, including relapse rate, disability progression, and the effect of disease-modifying treatments.
A significant number of patients who reported symptoms suggestive of a relapse had ACES, which was seen in 166/637 events (26.1%). Patients who had ACES tended to a have a higher relapse rate preceding the event and were more at risk for transitioning to secondary progressive MS. Even though their baseline disability worsened after the event, the degree of change was less than that seen after a relapse associated with change on MRI. Instances of ACES were more likely in patients on higher-efficacy treatments, such as one of the anti-CD 20 therapies (natalizumab, fingolimod, or alemtuzumab). ACES also was associated with longer disease duration and fatigue.
The authors hypothesized that ACES still could be an inflammatory event, but the level of inflammation falls below the threshold of detection of MRI. In patients with extensive radiological lesion load, a new lesion might be harder to discern. ACES also could be a pseudo-relapse with subclinical undiagnosed infections, or symptom worsening due to excessive fatigue or psychological stresses, including anxiety or depression, which are known to cause clinical worsening. The authors pointed out that recognition of ACES is important for both clinical practice and for accurate evaluation in clinical trials.
COMMENTARY
Acute symptoms suggestive of a relapse without MRI changes are not uncommon in clinical practice. This study sheds light on the prevalence and characteristics of these events. Apart from providers becoming aware of this while taking care of patients, this knowledge also is relevant for researchers involved in clinical trials, since relapse rate often is the primary end point in most MS treatment trials.
The study has some limitations, since the data were extracted from a database where some of the events, classified as ACES, could have been pseudo-relapses caused by subclinical infections or the result of fatigue or stress, which are well known to cause exacerbation of MS symptoms. However, for those events that indeed was ACES, this study illustrates the limitation of MRIs in assessing all disease activity/progression in multiple sclerosis.
