Factors associated with earlier clinical symptom onset in radiologically isolated multiple sclerosis

1. This cohort study found that younger age, spinal cord involvement, and gadolinium-enhancing lesions on magnetic resonance imaging were associated with earlier onset of multiple sclerosis clinical disease in patients with radiologically isolated syndrome.

2. With the widespread use of magnetic resonance imaging technology, early recognition and stratification of associated risk factors of preclinical multiple sclerosis will aid in the prevention of clinical manifestations with subsequent freedom from risk of neurological disability.

Evidence Rating Level: 2 (Good)

Study Rundown: For several decades, preclinical multiple sclerosis (MS) in asymptomatic patients was identified on magnetic resonance imaging (MRI) with findings consistent with central nervous system (CNS) demyelination. This led to the establishment of criteria for radiologically isolated syndrome (RIS) in 2009 to enhance risk stratification in this patient population. However, the clinical and demographic factors associated with time to clinical symptoms of MS among patients with RIS is unclear. This cohort study evaluated the 2-year risk of initial onset of clinical events suggestive of MS and estimated sample sizes needed for 24-month prospective clinical trials based on the primary outcome of a first clinical event. The main endpoint was risk of clinical event, where time to the first clinical event was compared by covariates and sample size estimates were modeled based on identified risk factors. Among 372 patients with RIS, young age, the presence of spinal cord lesions, and gadolinium enhancing lesions on the index MRI scan were associated with increased risk of onset of clinical symptoms of MS. These results identified 3 key preclinical risk factors associated with earlier clinical disease, where MS developed in more than 90% of individuals with 1 or more of these factors. With the widespread use of MRI technology and expansion of access throughout the world, early recognition, and stratification of associated risk factors of preclinical MS will aid in the prevention of clinical manifestations with subsequent freedom from risk of neurological disability. A limitation of this study was that not all patients included in the analysis underwent baseline spinal cord MRI scans and CSF analyses due to differences in regional practice patterns. This could have introduced biases in the analysis and explain why positive CSF findings were not associated with early occurrence of MS.

Click to read the study in JAMA Network Open

Relevant Reading: Radiologically isolated syndrome— incidental magnetic resonance imaging findings suggestive of multiple sclerosis, a systematic review

In-Depth [prospective cohort]: This cohort study included 372 individuals with RIS (mean [SD] age, 38.6 [12.1] years; 354 patients included in analysis [74.6% women]) from a tertiary center for MS care in France that collected data for the Observatoire Français de la Sclérose en Plaques database. Eligible patients were aged 10 to 80 years with 2 or more MRI scans after study entry and an index scan after 2000, with data analysis completed between July 2020 and January 2021. In total, a clinical event occurred in 49 patients (13.8%) within 2 years, equating to an estimated risk of conversion of 19.2% (95%CI, 14.1%-24.0%), where it was determined a total of 160 patients with RIS were needed for 24-month prospective clinical trials. In multivariate analysis, the following factors were independently associated with an increased risk of conversion to MS: age younger than 37 years (HR, 4.04 [95%CI, 2.00-8.15]; P < .001), spinal cord lesions (HR, 5.11 [95%CI, 1.99-13.13]; P = .001), and gadolinium-enhancing lesions on index MRI scan (HR, 2.09 [95%CI, 1.13-3.87]; P = .02). Furthermore, the presence of 2 factors at the time of the index scan was associated with a 27.9% risk (95%CI, 13.5%-39.9%) of a seminal event within 2 years, increasing to 90.9% (95%CI, 41.1%-98.6%) for individuals with all 3 factors (3 risk factors vs none: HR, 23.34 [95%CI, 9.08-59.96]; P < .001), both statistically significant associations.

Image: PD

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