In this issue of JAMA Neurology, Xia and coworkers1 report clinical and paraclinical findings in a cohort of first-degree relatives of patients with multiple sclerosis (MS) who subsequently were stratified based on a combination of genetic and environmental information. The past decade has generated more detailed information about genetic and environmental factors influencing the risk of MS. However, efforts directed at unraveling the molecular chain of events elicited by disease-associated genetic variants and environmental factors are hampered by the fact that we rarely know exact disease onset, which makes it difficult to tease out upstream events from those occurring later. While an individual’s genetic makeup for obvious reasons is stable over time, there is evidence that the effect of certain environmental factors is greatest years before the actual onset of clinical symptoms of MS.2 In typical cases, relapsing-remitting MS is diagnosed in the fourth decade of life.3 Even if patient or physician delay sometimes can amount to several years, the fact that most newly diagnosed patients already initially display significant signs of injury as shown by volumetric brain imaging or optical coherence tomography supports the notion of a subclinical disease phase perhaps lasting years or even decades.4,5 This occurrence can be exemplified also by the radiologically isolated syndrome, a condition in which an individual who underwent magnetic resonance imaging (MRI) for another indication than a suspected MS symptom, or even as a healthy control participant in a research study, is found to have MS-like pathological imaging findings.6 Radiologically isolated syndrome as a proof of principle for a presymptomatic MS disease stage is strengthened by the fact that a significant proportion of these individuals later convert to clinical MS during follow-up.7 However, the term presymptomatic can be deceiving. One study8 demonstrated that almost half of the patients with a clinically isolated syndrome or newly diagnosed as having MS displayed signs of cognitive impairment.
Piehl F. Multiple Sclerosis—A Tuning Fork Still Required. JAMA Neurol. 2017;74(3):264–265. doi:10.1001/jamaneurol.2016.5126
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