The occurrence of incidental brain white matter lesions suggestive of multiple sclerosis (MS) in subjects who did not have symptoms or signs of MS during their lifetime is well-documented, as it was described several decades ago in several postmortem studies. The widespread use of MRI, as the standard in vivo study of central nervous system (CNS) demyelination, has greatly increased the detection of the asymptomatic brain and spinal cord abnormalities of uncertain clinical significance. In 2009, Okuda et al. neologized formally this entity, using the term radiologically isolated syndrome (RIS) (1). More recently, the concept of prodrome (an early set of signs, symptoms, or other findings that occur before the onset of the typical disease features) has begun to be considered in MS (2), thanks to several investigations based on population-based studies and biomarkers of early CNS damage (refer below).

The present review will focus on these conditions potentially leading to overt MS, to consider current attempts of secondary prevention, in the absence of an etiologic therapy. The possible integration of genetic data with endophenotypes, MRI data, and other biomarkers seems to promise fruitful approaches to the aim of counteracting the development of the overt disease. To provide a survey on these topics, we searched PubMed for all articles published from database inception to September 1, 2021, with no language limitations. Keywords included clinically silent demyelination, prodromal MS, RIS, subclinical MS, endophenotype of MS, MS prevention.

Neuropathological studies demonstrated that brain demyelination might remain clinically silent for the whole lifetime in a significant proportion of people (about 0.1–0.3% of the autopsies in those studies) (1). The location of lesions in clinically silent areas, the low degree of inflammation, or even a particularly effective individual response to injury (e.g., functional compensatory adaptation, neuronal plasticity, and repair) might explain the absence of clinically relevant signs of MS in those subjects. However, caution is needed when interpreting these data, as it is difficult to ascertain whether these subjects were truly asymptomatic with normal neurological examination during their life (3). A recent study demonstrated, for example, that 33% of patients consulting for a first demyelinating event had prior symptoms suggestive of central nervous system (CNS) demyelination that had gone unnoticed (4). Moreover, the samples included in the studies were not representative of the general population due to selection bias toward those who were subjected to autopsy. Finally, such figures are probably underestimated nowadays, in view of an increasing prevalence and incidence of MS.

The advent of MRI and its development as the most sensitive and prominent paraclinical tool for the evaluation of morphologic brain abnormalities has modified our perspective on the occurrence of incidental brain findings. In a large meta-analysis (more than 15,000 subjects from 16 studies), the prevalence of neoplastic and non-neoplastic incidental findings on brain MRI was 2.7%, with the observed incidence increasing with age (5). Among those, only <0.1% could be interpreted as inflammatory–demyelinating lesions if white matter hyperintensities of suspected cerebrovascular origin were excluded. Similar prevalence for an MRI pattern suggestive of MS was found in a recent study that performs a systematic revision of the MRI scans and related clinical charts (1,907 individuals) in a high-incidence region for MS (6). These figures are higher, however, in asymptomatic first-degree relatives of both patients with sporadic MS (4%) and families with members affected by MS (10%) (7). In a recent prospective population-based study, incidental findings on brain MRI necessitating further diagnostic evaluation, but mostly without direct clinical consequences, were found in over 3% of the general middle-aged and elderly population, although no case with demyelinating lesions was reported (8).

According to ex vivo and in vivo data, the occurrence of silent demyelination should be, therefore, considered uncommon in clinical practice, with a higher occurrence in specific conditions such as family members of patients with MS. However, it must be stressed that the growing use of MRI has significantly increased the probability to find asymptomatic intracranial abnormalities of potential clinical significance, which includes silent demyelination, in current prospective studies in comparison with previous retrospective or neuropathological studies.

The precise etiology of MS is not yet known, although the evidence pertaining to different research fields indicates that genetic and environmental factors interact with each other in a complex manner, which eventually determines an abnormal autoimmune response (9). In particular, the evidence that environmental factors can play a role long before the clinical onset of MS is well-established and suggests the existence of a prodromal phase for the disease. The possibility of a prodrome indicates a window of opportunity to potentially act on early disease processes before the clinical disease becomes evident.

The concept of a prodrome is defined as the time period between the onset of a decline in a baseline level of functioning until criteria for disease diagnosis are met (10). The question of whether there is a prodrome in MS has not been extensively studied so far. Other neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease, and other inflammatory autoimmune diseases, such as rheumatoid arthritis and inflammatory bowel disease, in which several biomarkers are better established, have a more advanced understanding of their prodromal phase than we currently have in MS (11). However, the last 10 years have provided increasing evidence that also MS may have a prodromal phase. Recently, population-based studies have demonstrated that it is possible to objectively measure a symptomatic prodromal period in MS, which may last 5–10 years or perhaps long before the occurrence of classical “MS symptom onset.” In one case-control study conducted in Canada (12), the analysis of health administrative data linked with MS revealed that the use of healthcare services by patients was higher in the 5 years preceding their first clinical demyelinating event than that of controls. In the year before the first clinical demyelinating event, hospitalizations and physician visits were 78 and 88% higher, respectively, for people with MS than for matched controls. Similarly, dispensed prescription medications were 49% higher among patients who went on to develop MS. A subsequent case-control study conducted in the UK revealed a significantly higher number of visits to general practitioners among patients with MS, considering a time window up to 10 years before the first MS record (13).

Regarding the clinical profile of the prodromes, an elevated mental health burden is evident, with more visits to psychiatrists and diagnoses of depression and anxiety. Other issues include pain and headache, gastrointestinal complaints, bladder issues, sleep disturbances, and cognitive problems (11). Low cognitive performance before the onset of typical MS symptoms has been reported in a nested case-control study in Norway in men who entered the mandatory national military service at the age of 18–19 years (2). Moreover, fewer pregnancies and greater use of hormonal contraceptives have also been observed in the 5-year prodromal period, particularly in the year before MS onset, relative to a matched population without MS (12).

However, the possibility of identifying a prodromal syndrome exclusively on a clinical base has to be interpreted critically, as the above observations rely mostly on symptoms that are non-specific and common in the general population as well. To reliably identify a prodromal phase of MS, further research is needed that focuses on the identification of biomarkers. Indeed, biological markers of inflammation or neurodegeneration that indicate preexisting disease provide support to a pathogenic process underlying the prodromal period in MS: serum levels of neurofilament light chain (NfL) were increased up to 6 years before MS onset in 30 MS cases relative to 30 healthy controls (14). Such biomarkers are likely to be critical to distinguish whether or not non-specific symptoms such as fatigue represent the prodromal phase of neurodegenerative disease.

Since its first description, RIS has been widely debated and the risk of RIS evolving into MS has been investigated. According to existing data (20, 22), several RIS subjects evolve to MS over time, which demonstrates that RIS, at least in some cases, represents a preclinical stage of MS (refer to the paragraph “predictors of evolution in RIS”). The first issue related to this lies in what still needs to be done to provide a more specific characterization of these asymptomatic subjects and accurately discriminate subjects who can have a subclinical form of MS. In this context, assuming a carefully collected clinical history and a meticulous clinical examination, the first step of the management of these asymptomatic subjects is to consider an appropriate differential diagnosis and assess the extent to which MRI lesions fulfilling the RIS criteria in asymptomatic subjects may be related to disorders other than MS. Moreover, the reason for the initial brain MRI should always be carefully considered. Whereas, there are subjects whose brain MRI is performed for reasons which have no relation with CNS or MS, on many occasions, MRI is performed due to symptoms that might be somehow related to MS. Headache is by far the most common reason for performing an MRI (about 50% of cases with RIS; 20), but other relatively less frequent indications for an MRI are also seizures, paroxysmal symptoms, anxiety, depression, and other psychiatric disorders. Whereas, it is not possible to establish whether these conditions are related to the MRI findings, it is also true that they might represent unusual clinical symptoms associated with MS (refer above: prodromal MS).

Another important contribution may come from laboratory studies, which start to delineate biological signatures capable of integrating MRI data to refine the condition of subclinical neuroinflammation. The potential utility of the NfL levels was already reported in the context of the prodromal MS and RIS (refer above). However, this biomarker, though sensitive and able to peripherally mirror CNS tissue damage, is not specific, as demonstrated by studies in other CNS diseases, especially of primary neurodegenerative nature (44).

As anticipated according to MRI data, studies in relatives of MS patients are especially informative to identify MS endophenotypes. A recent system biology approach on peripheral immune signatures in identical twin pairs discordant for MS showed remarkably similar patterns; however, distinct traits in effector CD4+ T-cells in clinically healthy twins, with signs of prodromal MS, were comparable with those of the overtly affected co-twins, suggesting the importance of these immune traits in subclinical neuroinflammation (45). On the same line, increased CSF sulfatide levels and serum autoantibody against glycosphingolipids were reported in healthy siblings of patients MS compared to unrelated healthy donors (46).

Concerning the identification of endophenotypes due to genetic risk, glutamate biology seems to contain relevant biomarkers that pose a risk for disease development. Associations of at-risk single nucleotide polymorphisms (SNPs) with high glutamate concentration in CNS (47) or with brain volume changes in MS (48) were described, and they may contribute to clarifying the MS genetic risk in the “target” organ. Recent development in multiomics approaches have demonstrated alterations in easily accessible fluids: correlating scores of genetic risk and blood analytes, Wainberg et al. showed changes in clinically healthy individuals that mirrored those seen in people with complex diseases, including MS, and that represented early signs of dysfunctions preceding the clinically overt disease (49). Considering the infectious mononucleosis (IM) as a non-genetic risk factor for MS, Jons et al. assayed MS-relevant CSF cyto- or chemokines from non-MS individuals with or without previous IM and MS people as a reference group. They found a stepwise inflammation from IM sequelae to an MS endophenotype in a subgroup of IM patients, which shows CSF changes comparable to those of the MS reference group (50).

Extreme caution is needed in classifying RIS subjects. Indeed, it should be stressed that only when these subjects are expertly diagnosed, the stratification of risk can be accurate, and we can thus have sufficient information to be able to differentiate subjects with a form of subclinical MS at low or high risk of developing the disease (22, 23, 29).

Even more, caution is needed to identify a prodromal MS syndrome, which is largely based on symptoms that are non-specific and common in the general population, and that currently lacks objective supports to disentangle a “real” condition preluding to MS. Future advances in MRI techniques, biological studies, and especially integrated approaches to identify and follow individuals at high disease risk are a concrete hope for the identification of the initial phases of the demyelinating process and better MS management. This kind of investigation may provide a powerful opportunity to understand the MS early causal cascade, and, more importantly, may help to identify a “therapeutic window” to potentially reverse early disease processes.

MPA has focused on prodromes, predictors of evolution, and silent demyelination. NDS contributed describing prodromal phase of MS and silent demyelination. MI reported the role of predictors of evolution in RIS. EM, GR, and MS contributed in treatment and biological endophenotypes description. MT has focused on Study Groups and Disease Registry information. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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