In the five years before symptoms of multiple sclerosis (MS) appear, adults start visiting hospitals more often, see their doctors more frequently, and use more prescription medications [1]. These shifts in healthcare usage suggest the existence of a prodromal stage – an early set of signs, symptoms and other features that may precede the onset of MS [2]. Detecting the prodromal stage of MS could be crucial for early disease management [2].
“Historically, opinion leaders in the field have dismissed the idea of an MS prodrome. However, we now understand that MS may start some years before the clinical onset”, Professor Helen Tremlett, from the University of British Columbia, in Vancouver, Canada points out, “I was fortunate enough to participate in several MS Society meetings, where I wanted to ensure that our discussion about the prodromal phase resonated with people living with MS. During these meetings, I described what we believe an MS prodrome is. Then I asked: «Thinking back at the years before your MS symptoms began, can you in hindsight tell me anything that might have predated them? ». It was fascinating to see the room pause, followed by a flood of responses. While I cannot use this anecdote as evidence, it was empowering to realise that the MS community could relate to this concept”.
Several lines of scientific evidence corroborate the existence of a MS prodrome. When individuals present for the first time with a clinically isolated syndrome (CIS), they often have both gadolinium-enhancing lesions and non-enhancing lesions [3]. The presence of lesions at different stages of evolution suggests that demyelinating events have occurred in the past that evaded clinical detection [3]. The prodromal phase of MS may last several years and is associated with neurodegeneration. Levels of serum neurofilament light chain (sNfL), a specific marker of neuroaxonal damage, are elevated, on average, 6 years before the clinical onset of MS and continue to increase as clinical onset approaches [4].
Possible symptoms of the MS prodromal stage
Individuals seek health care more frequently during the five years before an MS diagnosis. This is evident when looking at the digital records of healthcare service. Researchers examined health administrative data and clinical data of a large cohort, including 14,428 people with MS, from four Canadian provinces [1]. Annual healthcare use steadily increased in the five years leading up to the first demyelinating event compared to the general population. In the year before the first demyelinating event, individuals with MS had a 78% higher rate of hospitalisations, 88% higher rate of physician visits and a 49% increase in the number of prescribed drug classes compared to the general population [1]. Objective records of healthcare use provide key evidence suggesting the existence of an MS prodrome. However, the data of this study do not reveal the reasons why individuals sought medical attention. It is important to determine whether they consulted healthcare professionals for non-specific symptoms related to the prodromal phase of MS or for classical MS symptoms that were not identified [2].
Another study investigated various symptoms that may occur up to 10 years before an MS diagnosis [5]. Researchers used the Clinical Practice Research Datalink in the UK to explore the medical records of 10,204 individuals who were later diagnosed with MS. A wide range of disturbances were observed before an MS diagnosis, including gastric, intestinal, urinary, and anorectal problems, different types of pain, and psychiatric conditions up to 10 years before diagnosis, and fatigue up to 5 years before. The authors further validated these results by excluding from the analyses individuals who may have experienced a first demyelinating event before their clinical diagnosis [5].
Gut-related issues represent an early feature of MS and may be considered a feature of the prodromal phase [6]. Research shows that during the years before the clinical onset of MS, individuals undergo more frequent doctor visits for gastritis and duodenitis, and diseases of the esophagus [6]. These findings are particularly relevant, as it has been suggested that alterations in the gut microbiota may play a role in the development of MS [7].
During the period before MS symptom onset, visits to psychiatrists, particularly for anxiety and depression, exceed those of the general population [8]. Moreover, pain, sleep disorders, anaemia, and fatigue are suggested to be part of the MS prodrome [9]. Notably, MS has a stronger association with anaemia among men and with pain among older people [9]. Skin-related issues have also been reported, potentially indicating early inflammatory manifestation of MS [10]. Additionally, changes in behavior can occur. During the 5 years leading up to MS symptom onset, women are less likely to become pregnant and more likely to use oral contraceptives [11].
Revising the stages of MS?
Considering the current evidence, an international group of researchers has discussed the possibility of revising the stages of MS [2]. During the initial susceptibility stage, exposure to environmental factors can interact with genetics. In this period, smoking, obesity, Epstein-Barr virus (EBV) infection, and lack of vitamin D may significantly increase the risk of developing MS [2].
Recently, researchers showed that increased EBV antibody levels can appear 15-20 years before the clinical onset of MS. And almost a decade after, the levels of sNfL start to gradually increase – from 5 to 10 years before onset and only in individuals who are EBV seropositive [12]. Professor Tremlett tells us, “If you want to know what causes MS, you should not look just at the few years before the MS onset, as individuals may already be in the prodromal phase of MS. They may already have MS. And you may be confusing risk factors of MS for something that is already MS and a feature of the MS prodrome. You must look back further in time”.
If a pathological response is triggered during the susceptibility stage, it leads to the second phase, the subclinical stage. The subclinical stage is currently considered asymptomatic and is followed by the prodromal stage. It is during the prodromal stage that the first non-specific symptoms appear [2].
What is the relation between the prodromal stage and the radiologically isolated syndrome (RIS)? We ask Professor Giancarlo Comi, from the Vita-Salute San Raffaele University, Milan in Italy: “MS prodrome represents a subtle way in which the disease emerges, often with non-specific symptoms that go unrecognised. In contrast, RIS is diagnosed when a magnetic resonance imaging (MRI) scan of the brain, or less commonly the spinal cord, performed for unrelated reasons, reveals unexpected anomalies suggestive of MS. Approximately 33-34% of individuals with RIS may develop MS within the first 5 years following RIS diagnosis, and this percentage increases to about 50% after 10 years of follow-up. Therefore, RIS, at least in some cases, represents a subclinical stage of MS. In this case, when the non-specific symptoms of the MS prodrome appear, they may be more readily recognised as MS symptoms. Some individuals with RIS may already be in the prodromal stage, but further research is required to determine the proportion and better characterise this relationship. The new diagnostic criteria – that will soon be presented to the MS community – consider the possibility of diagnosing MS when an individual has RIS, provided specific supporting factors are present. Why is early recognition of MS so crucial? Early treatment is crucial for achieving optimal outcomes. Research has shown that starting treatment early, for instance with dimethyl fumarate [13] or teriflunomide [14], in people with RIS may significantly reduce the risk of developing clinical MS. Therefore, it is reasonable to hypothesise that treating MS before classical onset may limit disability accumulation, and potentially even stop the disease”.
Recognising MS earlier
Professor Tremlett explains, “The prodromal phase can represent an opportunity for early identification of people who may develop the disease. Currently, our ability to identify MS during this phase is limited due to the nonspecific nature of the signs and symptoms we are picking up. However, we hypothesise that by combining signs and symptoms with a biomarker, such as sNfL, and with known risks factors for MS, we might be able to detect individuals in the prodromal phase with sufficient confidence. This could allow us to offer them the opportunity to enroll into ethically appropriate clinical trials testing novel neuroprotective drugs, that may prevent classical onset of MS or stop disability progression. That remains, of course, a long-term goal, requiring more work to become reality”.
A better characterisation of the MS prodrome may be crucial for understanding the etiology of MS and initiate early treatment to reduce relapse rates and disability accrual [12]. Conversely, misdiagnosis and over diagnoses must be avoided. Given the nonspecific nature of the symptoms occurring during the prodromal phase, imaging and non-imaging biomarkers should be integrated in a reliable definition of the MS prodrome [15].
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Written by Stefania de Vito
Special thanks to Professor Helen Tremlett (University of British Columbia, Vancouver) and to Professor Giancarlo Comi (Vita-Salute San Raffaele University, Milan) for their insights.
References
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