Defining Relapse and Disease Activity in Neurosarcoidosis: A Systematic Review and Proposed Framework

There is no consensus or standardized framework to characterize disease activity in CNS neurosarcoidosis, and the existing literature is highly heterogeneous. Here, we aimed to aggregate all longitudinal monitoring metrics in neurosarcoidosis through a systematic review. The review protocol is registered in PROSPERO (ID:533857). Articles were included if they incorporated at least 1 longitudinal monitoring or outcome metric relevant to neurosarcoidosis disease activity. In addition, we aimed to establish an evidence-based clinical framework for characterizing, monitoring, and communicating neurosarcoidosis disease activity, applicable to both clinical care and research.

Of 387 articles initially identified, 67 met the inclusion criteria. Most studies focused on metrics within a single domain (clinical, imaging, or laboratory) or analyzed multiple domains independently. Often, the definitions were not formally outlined. Only 11 studies included a multidomain monitoring metric. Our proposed framework integrates 3 critical domains for assessing the neurosarcoidosis disease activity: (1) clinical, (2) imaging, and (3) laboratory and supports a standardized characterization of the disease, especially when domain results are discordant. The overarching goal in defining the elements of each domain was to prioritize specificity in attributing activity to neurosarcoidosis while minimizing the risk of misattribution. Each domain includes criteria for 4 categories of disease status: "improved," "stable," "worsened," or "resolved." The overall disease status of activity or inactivity is then determined by reconciling the independent domains into a summary disease activity assessment, communicated with additional clinical context, including immune treatment status and neuroanatomic localization. Sustained clinical stability of persistent neurologic symptoms or signs in the absence of MRI or CSF activity is considered in the summary assessment to reflect inactive disease with sustained neurologic deficits.

A systematic review highlighted substantial heterogeneity in how CNS neurosarcoidosis disease activity is measured, with many studies lacking formal definitions and often reporting activity only within isolated domains. This proposed framework integrates multiple domains to comprehensively characterize CNS neurosarcoidosis disease activity. With further validation, this approach has the potential to standardize research practices and improve clinical reasoning and communication.