The Multiple Sclerosis Prodrome: Past, Present, and Future

Multiple sclerosis (MS) is an immune-mediated demyelinating disease affecting the central nervous system. It is classically thought of as involving discrete relapses with neurologic symptoms in the case of relapsing forms of MS (RMS) or progressive decline in primary progressive MS (PPMS).¹ The 2017 McDonald diagnostic criteria for MS require the presence of reported symptoms and objective findings reflecting a focal or multifocal inflammatory demyelinating event in the central nervous system occurring at least once to fulfill the diagnosis of MS.² However, there is emerging evidence that MS may have a prodromal state prior to the onset of objective findings.³ A prodrome is defined as an early set of signs and symptoms that predates the onset of classical disease.⁴ Although there was previously evidence for an “incubation” period, it was not believed that MS had distinct prodromal signs.⁵ Prodromes have been identified in other immune-mediated diseases as well as other neurodegenerative diseases.^6,7 This article explores the current evidence for the different clinical features of the MS prodrome, individual characteristics that can affect the prodrome, possible biomarkers to detect the prodrome, and future implications in regard to MS diagnosis and management.

Clinical Features

Over the past decade, large population studies have found that people with MS use the health care system more often compared with the general public without MS, even prior to the first demyelinating event.⁸ A Canadian study comparing clinical data from 14,000 people with MS and 70,000 matched controls found that the number of hospitalizations and clinic visits was increased in people with MS in the year prior to MS diagnosis. People with MS also had 49% higher use of prescription medications when compared with controls in the year prior to diagnosis. A similar study in the United Kingdom looked at clinical data from more than 10,000 people with MS compared with 40,000 matched controls and found that people who went on to develop MS made more visits to general practitioners for up to 10 years prior to the first demyelinating event. The causes for the increased health care usage were varied and not limited to neurologic complaints, although the increased use in general possibly points to an underlying process.

Systemic symptoms associated with the MS prodrome include fatigue, depression, anemia, bowel and bladder disturbances, fibromyalgia, pain, insomnia, and migraines.¹² Multiple studies have also demonstrated increased mental health disturbances in the 5 years prior to an MS event, with mental health visits increased by 50% in people with MS compared with controls during that time period. In a Norwegian study of more than 20,000 men 18 to 19 years of age who underwent cognitive testing as part of their mandatory national military service, it was found that cognitive performance was lower for up to 2 years before MS onset in the nearly 1,000 men who went on to develop RMS. In those who went on to develop PPMS, cognitive performance was lower for up to 20 years before disease onset.

All these studies demonstrate some factor of symptomatology prior to the first classical demyelinating event, suggesting the disease process had already started years previously. However, the symptoms of the prodrome can be common and nonspecific and are often seen in other systemic and neurologic disorders, and thus do not always warrant screening for possible MS.⁶ In addition, the symptoms of the prodrome can be varied and could be affected by, or determined by, specific individual characteristics.

Individual Characteristics

Multiple studies have demonstrated that different characteristics affect the prodrome and the likelihood of progressing to clinical MS. This is best illustrated by studies on radiologically isolated syndrome (RIS). The presence of white matter lesions on MRI of the brain that are typical in appearance for MS but without a clear demyelinating event is currently diagnosed as RIS. In RIS, the people most likely to develop MS within 5 years were younger at RIS diagnosis, were male, had infratentorial or spinal cord lesions on MRI, or had elevated immunoglobulin G index or oligoclonal bands in the cerebrospinal fluid (CSF).^15,16 A Canadian study demonstrated higher odds for anemia in men with MS compared with male controls (odds ratio, 2.40), but those odds were more modest in women with MS.¹² In addition, pain was more likely to be present in older people with MS in the 5 years preceding the first demyelinating event.¹²

Subtypes of MS may also affect the prodromal features. In one study,¹⁷ people with RMS had more dermatologic visits during the prodrome as compared with those with PPMS, whereas people with PPMS were more likely to report neurologic complaints compared with those with RMS. The differences in subtypes were also demonstrated in a Norwegian cognitive study,¹⁴ in which people with PPMS had lower performance scores up to 20 years prior to a clinical event compared with 5 years for those with RMS.

Family history also appears relevant. Studies demonstrate that 3% to 10% of asymptomatic relatives of people with sporadic or familial MS have RIS.^18,19 A study specifically looking at first-degree relatives of people with MS, and stratifying their risk of developing MS based on weighted genetic and environmental factors, found that those with the highest risk had poorer performance in vibratory testing of the distal extremities.²⁰ This suggests that the MS prodrome may also demonstrate signs on physical examination, further supporting that the disease process starts sooner than the previously believed first demyelinating event.

Future studies looking at individual characteristics in regard to the MS prodrome may better help identify those at risk for development of MS based on demographic or prodromal features.

Biomarkers

Clinical features alone are not sufficient to identify MS prodrome, because symptoms can be common and nonspecific. However, by combining them with demographic characteristics and possibly also biomarkers, we may be able to identify people at greatest risk of developing a clinical event consistent with MS. It has long been known, through postmortem studies, that MS can present asymptomatically with clinically silent lesions.²¹ With the advent and increased use of MRI, there was recognition of MS-typical lesions prior to a clinically defined demyelinating event, which has led to the creation of RIS as a disparate diagnosis.¹⁵ RIS may be a prodromal neuroimaging correlate. Almost one-third of people with RIS will go on to develop a clinical event consistent with MS within 5 years, and approximately half will do so within 10 years.^15,16 Although the official diagnostic criteria of RIS exclude any neurologic symptoms, there are studies supporting that people with RIS may have subtle or nonspecific symptoms, such as headache.^16,22 A study in France demonstrated that people with RIS have measurable cognitive impairment as demonstrated by lower performance scores on a range of cognitive tests when compared with healthy controls; however, when comparing performance of people with RIS with those with MS, the scores were similar.²³ RIS is rarer in pediatric-onset MS, but when it is present, children and adolescents are more likely than adults to develop a demyelinating event and be diagnosed with MS; in one study, just under half of children and adolescents with RIS developed a demyelinating event within 5 years, as compared with only one-third of adults.^15,24 These studies seem to suggest that RIS is a prodromal neuroimaging correlate. This is consistent with the previously identified latent period or “incubation” period that has been known for some time.⁵

Quantitative neuroimaging, mainly used in the research setting and not commonly used in clinical practice, has also demonstrated differences in people with RIS compared with healthy controls. Whole brain volume, as well as regional brain volume (in the thalamus and cerebellum in particular), were found to be reduced in people with RIS compared with matched controls in several case–control studies.^25,26 The cortical atrophy in people with RIS was similar to that in those with MS, and both were significantly lower than in healthy controls.²⁷ The same study found that cognitive performance correlated with brain volume change in RIS.²⁷ Although not yet used in a clinical setting, quantitative analysis of brain volume could help identify prodromal MS.

The typical MS serum and CSF biomarkers have also been found at higher rates prior to the first demyelinating event. Neurofilament light chain (NfL), a marker of axonal injury, has already been proven to be a helpful biomarker in MS, although it is not yet used routinely in the clinical setting.²⁸ A small case–control study in 30 US military personnel demonstrated higher serum levels of NfL, indicating more evidence of axonal injury, 6 years prior to the development of a demyelinating event.²⁹ NfL can also be detected in the CSF, and a study looking at the CSF results of 75 people with RIS (23 of whom went on to develop a demyelinating event) found that high CSF levels of NfL, as well as unique oligoclonal bands in the CSF, were associated with earlier development of a clinical demyelinating event.³⁰ These findings demonstrate that inflammation and axonal injury occur prior to the development of a clinical event and may therefore help with prognostication. Further studies on larger populations are needed to identify immune activation and axonal injury before development of the first demyelinating event more definitively. These limited studies illuminate a picture of a disease process that starts much sooner than previously believed, and, although not amounting to a typical MS demyelinating event, could be contributing to symptoms manifesting as the MS prodrome.

Clinical Implications and Future Research

As more disease-modifying therapies became available for MS, studies have demonstrated that initiating early aggressive treatment improves overall outcomes. The Food and Drug Administration–approved treatments are available for clinically isolated syndrome, and there are trials currently underway for people with RIS in hopes of delaying or preventing the first demyelinating event and development of MS. When screening for possible RIS, screening for a prodromal MS state may help support the decision to treat (currently off-label). The decision to treat becomes even more important when considering the evidence that axonal injury and cognitive impairment start during the prodrome.

Further studies are needed to identify a true MS prodrome, as well as people who will go on to develop MS. Approximately 50% of RIS cases do not convert to MS within 10 years¹⁶; therefore, proper identification of people truly at risk for MS is paramount to avoiding unnecessary exposure to immunosuppressive drugs. The next steps would be to combine prodromal symptoms, individual characteristics, and biomarkers to develop diagnostic criteria for the MS prodrome, which would allow for early identification and appropriate treatment initiation.

Limitations

Based on existing studies, an MS prodrome likely exists; however, there are limitations to the data. Because of the nature of the prodrome, most studies are retrospective health care datasets. A truly prospective study with long-term follow-up is time-intensive and resource-extensive, but has been done in certain populations, including Norwegian and US military datasets. Furthermore, many of the signs and symptoms of the prodrome are nonspecific and are seen in other disease states, making it difficult to attribute the symptoms purely to a neuroinflammatory etiology. For example, anemia and fatigue have both been associated with the MS prodrome, and fatigue originating from the anemia or the MS prodrome is difficult to differentiate. A temporal association is also not yet well-established for the prodromal state, because the timing and duration vary among populations and between studies. Part of the variance may be attributed to different individual characteristics and the MS subtype that the person will develop.

Because causation cannot yet be established, the symptoms of the prodrome could be part of the disease process itself, or could be factors that increase the risk for developing MS. Better understanding of these interactions will help guide prognostication and possibly open up treatment options early, thus potentially preventing disability.

Conclusion

MS classically has been considered as beginning with a clear demyelinating event, but that concept is changing with the preponderance of evidence that there exists a phase of nonspecific symptoms: the MS prodrome. The presence of a prodrome is supported not only by the increased health care use and reported symptoms prior to disease onset in people who go on to develop MS, but also by biomarkers in imaging, serum, and CSF analysis that indicate an inflammatory and axonal degenerative process before confirmation of the diagnosis of MS. Further studies are needed to characterize this phase in regard to symptoms, duration, and biomarkers that can help identify people at risk of developing MS, with the goal of early treatment initiation and disability prevention.