Radiologically isolated syndrome

Neuroimmunology

Updated 08.15.2024
Released 07.02.2020
Expires For CME 08.15.2027

Radiologically isolated syndrome

Authors: Aksel Siva MD, Ugur Uygunoglu MD, Melih Tutuncu MD

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Editor: Anthony T Reder MD

Radiologically isolated syndrome

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Introduction

Overview

“Asymptomatic multiple sclerosis” or “subclinical multiple sclerosis” describes a clinically silent disease state of multiple sclerosis discovered by chance, either by imaging or at autopsy, or with incidental findings shown by other diagnostic tools, that is consistent or highly suggestive of multiple sclerosis and that cannot be explained by any other disease or condition.

The increasing use of MRI in various neurologic or other problems in individuals without any clinical symptoms and signs of multiple sclerosis infrequently reveals unsuspected brain lesions compatible with multiple sclerosis. This condition corresponds to a subclinical state of multiple sclerosis and is termed “radiologically isolated syndrome” and, therefore, by definition, is a form of "asymptomatic multiple sclerosis.”

It has become clear that radiologically isolated syndrome is the earliest presymptomatic stage of multiple sclerosis, and detecting individuals during this time offers many opportunities to further understand the disease behavior and how to manage these individuals (66). Because at least half of the individuals with radiologically isolated syndrome will convert to clinical multiple sclerosis within 10 years of their imaging diagnosis, it is important to determine the high-risk people with radiologically isolated syndrome who are more likely to convert and start early treatment in this selected population. Currently updated diagnostic criteria for radiologically isolated syndrome allow the clinician to make an earlier diagnosis, even at a time that may be termed “pre-radiologically isolated syndrome” (64; 88).

Multiple sclerosis is an immune-mediated, neuroinflammatory, and neurodegenerative disease of the central nervous system with a highly heterogeneous clinical presentation and unpredictable course (91; 08; 81). Most commonly, its first clinical manifestations appear in young adults between the ages of 20 to 40, although the disease onset can occur at any age. It then remains as a lifetime disease with different clinical expressions and progression, mostly in an age-dependent manner (114). The disease is diagnosed in individuals who present with central nervous system symptoms and signs and with MRI findings consistent with multiple sclerosis according to a set of criteria. In the final revision of this set of criteria, the McDonald 2017 Criteria, the MRI findings should fulfill the concept of dissemination in space and dissemination in time, with cerebrospinal fluid studies replacing the MRI dissemination in time criteria when absent (107). The dissemination in space criteria require at least one or more lesions in two of the four sites -- periventricular, cortical/juxta-cortical, posterior fossa, and spinal cord. It is well known that at the time of diagnosis, regardless of whether the clinical presentation is monosymptomatic or polysymptomatic, the MRI will show a number of silent lesions independent of the clinical symptomatology in most of these individuals. This observation makes it clear that most multiple sclerosis patients already have preclinical disease, indicating that pathological disease changes develop over time in the central nervous system without corresponding clinical expression of neurologic symptoms and signs.

With the increased availability and widespread use of MRI globally and excess evaluation of people for primary headache disorders and other conditions unrelated to multiple sclerosis symptoms, the incidence of people with incidental MRI findings suggestive of multiple sclerosis, defined as radiologically isolated syndrome, is increasing. There is not a clear-cut consensus on whether these people should be diagnosed as having multiple sclerosis or not, whether they should be treated or not, and how they should be evaluated.

Key points

	• The incidental findings on brain or spinal cord magnetic resonance imaging suggestive of multiple sclerosis in individuals without any history and clinical symptoms or signs of the disease are named “radiologically isolated syndrome”.
	• With the widespread use of MRI, the incidence radiologically isolated syndrome is increasing.
	• Studies confirm that radiologically isolated syndrome is an early/preclinical stage of multiple sclerosis, with about half of these people converting to clinical disease within 10 years of their MRI diagnosis.
	• The presence of spinal cord and posterior fossa lesions on the MRI, enhancing MRI lesions, the oligoclonal bands in the CSF, and younger age are predictive factors for clinical conversion to clinical multiple sclerosis.
	• Two treatment trials in individuals with radiologically isolated syndrome showed a significant reduction in conversion to clinical disease in the active treatment groups. It is important to consider early intervention with disease-modifying drugs for high-risk individuals.
	• Radiologically isolated syndrome provides a unique opportunity to understand further the pathogenesis of the disease and to discover factors related to clinical expression of multiple sclerosis.

Historical note and terminology

Historical note and the evolution of the radiologically isolated syndrome concept and its terminology.

Postmortem studies: the emerging concept of asymptomatic multiple sclerosis. Pathology typical of multiple sclerosis has been documented on autopsies in people who were asymptomatic during life. Sixty-six cases of pathologically demonstrated multiple sclerosis were detected in a cohort of 15,644 autopsies studied in 1961 at the Basel Institute of Pathological Anatomy, giving a postmortem multiple sclerosis prevalence rate of 0.4% or 400/100,000 (36). Fifty-four of these cases had a confirmed clinical diagnosis of multiple sclerosis or other neurologic diseases. However, it was noteworthy that in the other 12 cases, the autopsy findings were “incidental,” as these cases were not known to have any neurologic disease in their lifetime. This corresponds to an 18% rate (72/100,000) of “clinically silent” disease of a postmortem multiple sclerosis cohort. These unsuspected cases are probably among the first “asymptomatic multiple sclerosis cases” to be reported. This report was soon followed by other postmortem studies reporting asymptomatic multiple sclerosis cases in autopsy series and that a subclinical form of multiple sclerosis is real and probably not infrequent! Following this initial report, Mackay and Hirano reported two more cases of pathologically proven multiple sclerosis without preceding clinical evidence of the disease (70). Three such cases were reported from France (16). In their report of unsuspected multiple sclerosis in another large autopsy series of 2540 routine autopsies from Canada, Gilbert and Sadler found lesions consistent with multiple sclerosis in five cases (37). A similar work from Scotland was also in line with these observations (92). In a study of all autopsied cases of multiple sclerosis from 1965 to 1986 recorded in the Danish MS Register it was calculated that each year about 40 persons would die with clinically silent multiple sclerosis, which corresponded roughly to 25% of deceased persons with a clinical diagnosis of multiple sclerosis (29). All of these neuropathological (autopsy) studies indicate that multiple sclerosis may remain clinically silent for an entire lifetime in a significant number of individuals. This suggests that for every three to four patients clinically diagnosed with multiple sclerosis, there is probably one additional asymptomatic individual with the disease.

The suggested explanations of the pathological changes consistent with multiple sclerosis in individuals who never had clinical signs and symptoms of the disease in their lifetime were either that the periventricular location of these lesions was in “silent” areas or low severity of inflammation (16; 37; 29). These leave us with the questions of whether number, size, severity, and location matter on the clinical expression of the disease and whether asymptomatic/subclinical multiple sclerosis is a very mild form of the disease or is a self-limited process. It is well known that symptomatic lesions in people with multiple sclerosis detected on MRI at onset and in the initial years of the disease are only a minority of the total lesions present in their central nervous system. Currently, it is known that clinical symptoms and signs of the disease are either due to the inflammatory lesions affecting anatomically critical sites, causing significant damage to the axons and myelin, or to accumulating damage reaching a certain threshold of axonal and myelin damage. The symptomatic lesions are likely to represent the prominence of the neuroinflammatory component of the disease. On the other hand, the clinical expression of ongoing neurodegeneration seen in multiple sclerosis is more closely correlated with disability progression, secondary to damage caused by an accumulation of lesions, ongoing subclinical neuroinflammation, and probably a primary neurodegeneration. These asymptomatic individuals with multiple sclerosis-like pathology on imaging (MRI and more recently PET) provide a unique opportunity to understand the pathogenesis underlying the clinical expression in multiple sclerosis.

Incidental findings suggestive of multiple sclerosis on MRI and epidemiology of the lesions. The use of MRI in various neurologic or other problems unrelated to multiple sclerosis reveals unsuspected brain lesions compatible with multiple sclerosis. The rate of detection of silent MRI lesions suggestive of inflammatory/demyelinating disease in people without any clinical evidence of multiple sclerosis was between in 0.06% and 0.15% in systematic reviews and meta-analyses of observational studies (22; 80) and in a hospital-based study in 15- to 40-year-old subjects from Sweden (32). Interestingly, in an earlier hospital-based study from Pakistan, where multiple sclerosis prevalence is known to be low, this rate was at an unexpectedly high rate of 0.7%, but the study population was limited to the younger age group, less than 40 years (117).

Asymptomatic family members of multiple sclerosis patients also have both MRI and CSF changes suggestive of multiple sclerosis (69; 110; 95). In another field study, up to 4% of asymptomatic relatives of sporadic multiple sclerosis patients have lesions consistent with multiple sclerosis on their MRI; this rate increases to 10% in families with multiple affected members (24) and the rate of detection of silent MRI lesions in the non-multiple sclerosis discordant monozygotic twins further increases up to 20% (115; 95; 108). There were also two earlier case reports in which two individuals who had an MRI study for reasons unrelated to multiple sclerosis were found to have incidental lesions consistent with multiple sclerosis. In the first a 39-year-old man had an MRI study as a normal control in a Parkinson disease study and remained free of any clinical symptoms or signs of multiple sclerosis despite continuing MRI activity for the next 9 years and then developed primary progressive disease (77). In the other case a French woman who had an MRI study because of headaches was found to have lesions suggestive of multiple sclerosis and then 3 years later developed relapsing-remitting disease (23). These two cases were among the first case reports suggesting that multiple sclerosis could be detected by MRI at a subclinical stage.

The emergence of the radiologically isolated syndrome concept. Although the aforementioned studies described incidental brain lesions, primarily in family members of people with multiple sclerosis, they were limited in scope to these findings. Around the same time three independent study groups found that such incidental lesions may mark the early phase of multiple sclerosis (58; 84; 103). Inclusion criteria were having an MRI for multiple sclerosis-unrelated reasons, such as migraine, other primary headaches, head trauma, or other conditions, and finding incidental brain MRI lesions fulfilling Barkhof-Tintore criteria.

Diagnostic criteria for radiologically isolated syndrome. The initial diagnostic criteria for radiologically isolated syndrome were first published in 2009 and were defined by the presence of asymptomatic CNS white matter lesions on MRI. These should be ovoid in shape, well circumscribed, 3 mm² in length or more, and hyperintense on T2-weighted images with or without the involvement of the corpus callosum. These should fulfil the 2005 multiple sclerosis criteria for dissemination in space (ie, three of the four following features: one gadolinium-enhancing lesion or nine T2-hyperintense lesions; one or more infratentorial lesion; one or more juxtacortical lesion; and three or more periventricular lesions), and these findings should not be explained by any other medical condition (84) (Table 1).

Table 1. Radiologically Isolated Syndrome Diagnostic “Okuda” Criteria

	(1) Initial MRI demonstrating anomalies suggestive of demyelinating disease
	(2) Incidental anomalies identified on MRI of the brain or spinal cord with the primary reason for the acquired MRI being evaluation of a process not suggesting a first clinical event of multiple sclerosis
	(3) Central nervous system white matter anomalies meeting MRI criteria:
		(a) Ovoid, well-circumscribed, and homogeneous foci with or without involvement of the corpus callosum
		(b) T2-hyperintensities measuring > 3 mm² and fulfilling three of four Barkhof criteria for dissemination in space
		(c) Central nervous system anomalies not consistent with a vascular pattern
		(d) Qualitative determination that central nervous system anomalies have a characteristic appearance of demyelinating lesions
	(4) MRI anomalies do not account for clinically apparent impairments
	Adapted from (84)

Another study group suggested that the updated criteria for dissemination in space and dissemination in time in multiple sclerosis could be adapted for radiologically isolated syndrome as well (25), but this recommendation was not supported by scientific evidence and was not validated. Some asymptomatic individuals may present with only one or two lesions, less than the original four dissemination in space criteria that were highly suggestive of multiple sclerosis, inspiring a new validation study by the RISC-study group. This study of a cohort of individuals who may be termed “people with pre-radiologically isolated syndrome,” led to an updated version of the diagnostic criteria for radiologically isolated syndrome, which was validated (64). According to this update, when the 2009 radiologically isolated syndrome criteria are not fulfilled, patients could be classified as having radiologically isolated syndrome if they have one or two “dissemination in space” locations associated with two of the three following features: spinal cord lesions, oligoclonal bands in the cerebrospinal fluid, or fulfillment of “dissemination in time” on a follow-up MRI (Table 2).

Table 2. The Revised Radiologically Isolated Syndrome Diagnostic Criteria, 2023

A. Diagnostic-inclusion criteria
	I. The individual fulfills the 2009 Radiologically Isolated Syndrome Criteria (84); or
	II. The individual doesn’t fulfill the 2009 Radiologically Isolated Syndrome (84) imaging criteria, but the Index MRI fulfills at least one of the four dissemination in space criteria and additionally fulfills at least two of the following:
		a. Presence of CSF-restricted oligoclonal bands
		b. Presence of at least one spinal cord lesion consistent with inflammatory demyelination
		c. Evidence of dissemination in time on any follow-up MRI defined by the presence of one or more new T2-weighted hyperintensities or gadolinium enhancement typical for multiple sclerosis
B. Exclusion criteria
	I. No history of clinical symptoms indicating relapsing-remitting or progressive neurologic dysfunction
	II. MRI anomalies or neurologic examination findings do not account for clinically apparent impairment(s) to the individual
C. No other disease identified that better accounts for the CNS MRI anomalies
Adapted from (64)

Clinical manifestations

Presentation and course

By definition, people with radiologically isolated syndrome have no clinical manifestations. However, they are likely to have some subclinical predictors and biomarkers that may predict whether they are likely to convert to clinical disease.

Prognosis and complications

The leading authors of the initial three studies (84; 103) joined their efforts and founded the “Radiologically Isolated Syndrome Consortium” (RISC) in 2009 to study this state of subclinical disease, understand its evolution in time, and clarify treatment strategies. The RISC has started many research projects and continues to conduct multicenter multinational studies related to radiologically isolated syndrome (61). The initial studies on radiologically isolated syndrome focused on individual factors predicting conversion to clinical disease such as spinal cord lesions, pregnancy, and MRI and CSF findings (59; 85; 60). In a major multinational study lead by the consortium, a cohort of 451 individuals with radiologically isolated syndrome were evaluated for demographic features and risk factors for conversion to clinical disease at 5 years and then in 277 of the initial 451 at 10 years (86; 62). The mean age at diagnosis of radiologically isolated syndrome was 37.2 (range:11-74) years with a mean clinical follow-up time of 4.4 (range: 0.01–21.1) years and 6.7 (range:1-26.6) years in the two studies, respectively.

The cumulative probability of a first clinical event was 34.7% at 5 years, and 51.2% at 10 years. In the multivariate model (younger) age of less than 37, positive CSF for oligoclonal bands, and the spinal cord and posterior fossa lesions on MRI were identified as baseline factors associated with a subsequent first clinical event by 10 years. The probability of a first clinical event at 10 years follow-up was 29% for individuals with at least one risk factor, 54% for two risk factors, 68% with three risk factors, and 87% for all four risk factors. Although the presence of contrast enhancement at baseline was not associated with an increased risk for a clinical conversion, there was the observation of continuing radiological activity during follow-up. A positive family history for multiple sclerosis, observed in 10.0% of the study group, was not predictive for a clinical event (62). These findings may assist the physician in treatment decisions with radiologically isolated syndrome.

In the first prospective study of individuals with radiologically isolated syndrome, multiple sclerosis occurred in more than 90% of individuals within 2 years of the index scan among young patients with spinal cord and gadolinium-enhancing lesions (63). When considering the three independent risk factors of young age, and spinal cord and gadolinium-enhancing lesions at baseline, a multivariable analysis revealed that the probability of an early conversion was 11.3% (95% CI: 3.5%–18.5%) when no risk factor was present, 14.5% (95% CI: 8.0%–20.5%) with one risk factor, 27.9% (95% CI: 13.5%–39.9%) with two risk factors, and 90.9% (95% CI: 41.1%–98.6%) with three risk factors for a clinical event at 2 years.

In a study conducted during the COVID-19 pandemic, 1) COVID-19 infection or immunization in individuals with radiologically isolated syndrome didn’t increase the risk of disease activity and 2) COVID-19 vaccination could be safely administered to this population (19).

Some individuals with radiologically isolated syndrome later present with progressive disease suggestive of primary progressive onset rather than a relapse; 11.7% of these patients fulfilled criteria for primary progressive multiple sclerosis (48). This rate of primary progressive multiple sclerosis at onset within the radiologically isolated syndrome population is similar to that seen in the general multiple sclerosis populations in an age-dependent manner, further suggesting that radiologically isolated syndrome is biologically part of the multiple sclerosis spectrum. This finding necessitates redefining primary progressive disease and a review of the concept of progression! Because primary progressive multiple sclerosis may develop from radiologically isolated syndrome, it suggests that these individuals could go through the relapsing form of the disease subclinically. Then, once they enter in the so-called secondary progressive stage, they start showing the first clinical signs of the disease, hence, diagnosed as primary progressive multiple sclerosis. It may be hypothesized that they accumulate central nervous system damage and have asymptomatic radiological relapses that remain clinically silent possibly due to efficient repair plasticity. Once a certain threshold is reached, the disease manifests itself clinically and appears to be primary progressive (112; 47). This pattern is consistent with a number of studies showing that all progressive forms of multiple sclerosis whether primary, secondary, or single-attack progressive are similar in terms of the age at onset of progression (20; 51; 114; 47). It may be hypothesized that the progressive forms of multiple sclerosis have similar biology, differentiated by the plasticity of the central nervous system and severity of inflammatory degeneration. This view has considerable treatment implications.

Radiologically isolated syndrome in the pediatric population. In a multinational/multicenter study, 38 children (£ 18 years) fulfilling the radiologically isolated syndrome criteria were followed for a mean of 4.8±5.3 years. A first clinical event consistent with central nervous system demyelination occurred in 42% of the study population at a median of 2.0 years, a higher rate in a shorter time compared with the adult population, whereas radiologic evolution developed in 61% (74).

Oligoclonal bands in the CSF and spinal cord lesions on MRI were associated with an increased risk of a first clinical event. In an expanded cohort of 61 children with radiologically isolated syndrome, the same group confirmed their earlier results and showed that oligoclonal bands increased the specificity of magnetic resonance imaging criteria for predicting clinical conversion (73). Incidental lesions suggestive of multiple sclerosis found on MRI in the absence of clinical symptoms have a significant impact in children regarding counselling and management issues.

In a multinational study investigating whether age and sex affected the type and timing of diagnostic tests in children with radiologically isolated syndrome, younger children with radiologically isolated syndrome (those under 12 years of age) and boys, in general, were less likely to have a CSF study as part of their diagnostic workup, delaying their diagnosis (75). Spinal MRIs were obtained sooner in children aged 12 and older. However, these age- and sex-dependent differences in the investigations of children with radiologically isolated syndrome decreased after 2017, most likely due to increased awareness of radiologically isolated syndrome among healthcare practitioners.

Biological basis

Etiology and pathogenesis

Pathology of radiologically isolated syndrome and what we have learned from the imaging studies. There is only a single report based on the biopsies of three patients with radiologically isolated syndrome who had MRI for non-multiple sclerosis causes. Brain MRI showed a tumefactive enhancing lesion with additional nonenhancing white matter lesion/s in each. Pathology confirmed inflammatory demyelinating disease compatible with multiple sclerosis pathology in all (49). Access to central nervous system tissue in individuals diagnosed with radiologically isolated syndrome is not expected. However, it is still possible to obtain some information through more advanced MRI technology and software programs.

To assess brain damage in asymptomatic first-degree relatives of patients with sporadic and familial multiple sclerosis, De Stefano and colleagues studied subjects and healthy volunteers who underwent brain MRI and magnetization transfer imaging on a mobile MR scan (24). In asymptomatic first-degree relatives of patients with established multiple sclerosis, magnetization transfer ratios of focal brain lesions were lower than in control white matter whereas magnetization transfer ratios values from the normal-appearing white matter and brain volumes from asymptomatic individuals were similar to healthy controls. Thus, despite morphological (imaging) evidence of subclinical disease, the central nervous system damage remained very limited and is likely under the influence of yet unknown protective mechanisms that remain subclinical.

In subjects with radiologically isolated syndrome who were studied with magnetic transfer imaging and volumetric measurements, there were some lesions with similarities to lesions in relapsing-remitting multiple sclerosis (26). However, these were much milder than the ones seen in relapsing-remitting multiple sclerosis patients. This suggests that the lack of clinical manifestations in radiologically isolated syndrome subjects may be due to more limited and less-severe tissue involvement. In another imaging study of 15 individuals with radiologically isolated syndrome, the same group found cortical lesions in 40% of the subjects, another finding commonly seen in patients with clinical multiple sclerosis (38). These subjects had higher white matter lesion volumes than those without cortical lesions but no more cortical atrophy or cognitive decline. These subjects also had oligoclonal bands in their CSF and most had cervical lesions on spinal MRI, suggesting that they are more likely to convert to clinical multiple sclerosis than individuals with radiologically isolated syndrome who are free from such affection. In another study from Spain, regional cortical thinning was primarily distributed in frontal and temporal lobes (55).

Decreased brain NAA/Cr levels in subjects with radiologically isolated syndrome suggest that axonal damage can be significant even at this early stage (106). However, not all individuals with radiologically isolated syndrome show these abnormalities.

Thalamic atrophy, a metric associated with neurodegeneration in early stages of multiple sclerosis, was also shown in radiologically isolated syndrome (07). The normalized cerebellar white matter volume and the anterior cerebellar gray matter volume were significantly decreased in individuals with radiologically isolated syndrome compared to healthy controls, suggesting that regional brain atrophy develops prior to an initial clinical episode in these people (35).

In radiologically isolated syndrome with visible spinal lesions, there was no evidence of spinal cord atrophy but the magnetization transfer ratio was lower. This suggests that inflammation and demyelination may reflect microstructural changes detectable in the very earliest stage of multiple sclerosis, a finding consistent with the known pathologic mechanisms of multiple sclerosis (02).

The central vein sign in the diagnosis and differential diagnosis of multiple sclerosis has become a reliable marker in the differential diagnosis between multiple sclerosis and multiple sclerosis-like lesions (96; 79; 71). Most individuals with radiologically isolated syndrome have a central vein sign in their lesions (98). In this study, the proportion of central vein sign lesions correlated with the presence of spinal cord lesions. Spinal cord lesions are a major risk factor for clinical conversion in individuals with radiologically isolated syndrome, so the central vein sign in this population is also likely to have prognostic value.

The central vein sign in radiologically isolated syndrome is an effective imaging biomarker (56). The central vein sign improves the diagnostic accuracy of brain lesions associated with radiologically isolated syndrome in comparison to non-multiple sclerosis subjects when a 40% central vein sign threshold or a 6-lesion central vein sign threshold is applied. Interestingly, when the CSF biomarkers of oligoclonal bands or Kappa index are included with the imaging biomarker of central vein sign, the diagnostic specificity of radiologically isolated syndrome increased to 100% from 87%.

It is expected that radiologically isolated syndrome will be included in the upcoming 2024 revision of the McDonald diagnostic criteria. Specific findings, such as central vein sign (and polymyalgia rheumatica sign) that are detected by advanced imaging techniques will be of particular interest in confirming a diagnosis of radiologically isolated syndrome and will increase confidence in whether white matter hyperintensities seen on MRI are likely to be demyelinating.

Susceptibility-based imaging in multiple sclerosis demonstrates a paramagnetic rim sign indicative of chronic active demyelination and associated with the presence of iron inside phagocytes (01). This sign was also detected in individuals with radiologically isolated syndrome. The lesions with paramagnetic rims correlated with white matter lesions showing the central vein sign (97). These findings collectively suggest that many of the lesions observed in radiologically isolated syndrome develop from perivenous inflammation and demyelination and that most lead to chronic, active inflammation.

The above-mentioned MRI studies in radiologically isolated syndrome have a number of major implications. The central vein sign and the paramagnetic rim sign are additional findings to consider in the differential diagnosis of this syndrome, especially when the diagnostic criteria of radiologically isolated syndrome are not fulfilled. Many of these imaging studies reveal that central nervous system changes already exist in this preclinical stage. Microstructural and metabolic changes in the central nervous system tissue, years before the onset of the clinical disease, as well as the demonstration that cortical, thalamic, and cerebellar atrophy is similar to that of clinically isolated syndrome and relapsing-remitting multiple sclerosis shows that radiologically isolated syndrome is the earliest stage of clinical multiple sclerosis. However, changes are not uniform in all these individuals and not all of them convert to clinical disease. Some protective mechanisms may be effective in some of these individuals with radiologically isolated syndrome but not in others!

Optical coherence tomography in radiologically isolated syndrome. Optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA) studies in people with radiologically isolated syndrome have led to reports of reduction in macular retinal nerve fiber layer (RNFL), macular ganglion cell inner plexiform layer (GCIP), temporal peripapillary RNFL thickness, and decreased vessel density in the superficial parafoveal region in people with radiologically isolated syndrome compared with people who have no evidence of neurologic disease on brain MRI (50; 31; 04; 116; 120). Although these findings were not uniform, most showed correlation of radiologically isolated syndrome spinal cord or infratentorial lesions (50), or reduced brain and thalamic volumes (116) and, in one, even in the absence of spinal cord lesions (31), with lower GCIP thickness or thinner peripapillary RNFL. Findings also predicted conversion to multiple sclerosis, as did decreased vessel density in the superficial parafoveal region (120). These OCT/OCTA findings were also useful in differentiating people with radiologically isolated syndrome from healthy controls.

Nonimaging/fluid biomarkers in radiologically isolated syndrome.

Cerebrospinal fluid studies. Asymptomatic twins or first-degree relatives of multiple sclerosis patients can have oligoclonal bands and other CSF findings supportive of multiple sclerosis (Xu and McFarlin 1984; 28). In a Swedish study, 19% of the healthy siblings of multiple sclerosis patients had oligoclonal bands, in contrast to 4% in unrelated healthy controls, as well as increased antiviral reactivity, named as a multiple sclerosis immunopathic trait (41). In the same population asymptomatic siblings had CSF neurofilament light chain protein and glial fibrillary acidic protein levels similar to controls (42). However, their siblings with clinical multiple sclerosis had higher levels of these proteins, which are sensitive markers of axonal damage and astrogliosis. The lack of an increase in neurofilaments, despite the presence of oligoclonal bands and increased antivirus immune reactivity suggests that despite biological (immunopathic) evidence of subclinical disease, these individuals are free from central nervous system damage and remain asymptomatic. Because there were no MRI data in this study, we can’t argue whether these asymptomatic siblings also had asymptomatic brain and spinal lesions.

The presence of CSF oligoclonal bands is a predictive factor for clinical conversion both in adult and pediatric subjects with radiologically isolated syndrome (73; 62). Oligoclonal bands and CSF neurofilament light chain protein levels are also independent predictors for clinical conversion in patients with radiologically isolated syndrome and are associated with a shorter time to onset of clinical multiple sclerosis (76; 93; 94). On the other hand, chitinase-3-like protein, a biomarker that predicts conversion from clinically isolated syndrome to relapsing-remitting multiple sclerosis, did not independently influence conversion to clinical disease in radiologically isolated syndrome (76; 109; 94).

Progranulin is a fundamental neurotrophic factor involved in inflammatory wound repair. It is elevated in the CSF of individuals with radiologically isolated syndrome and is suggested to be an early marker of inflammatory repair before axonal disintegration occurs (90).

Multiple sclerosis cases were identified among active-duty military personnel with at least one presymptomatic serum sample stored in the US Department of Defense Serum Repository. Serum neurofilament light protein levels were higher in these presymptomatic people compared to matched controls, both at a median of 6 years and at 1 year before the clinical onset of multiple sclerosis (10). This study confirms a biological prodromal phase for multiple sclerosis lasting several years and that neuroaxonal damage may already occur during this phase. This study was not conducted in a cohort of people with radiologically isolated syndrome, but this asymptomatic period is comparable to the study above in which neurofilament light protein levels in the CSF predicted clinical conversion in patients with radiologically isolated syndrome (76). In a study, elevated concentrations of both serum and CSF neurofilament light chain were confirmed to be evidence of disease activity, defined as clinical conversion or new MRI activity, in individuals with radiologically isolated syndrome (94).

CSF kappa free light chain (KFLC) is an emerging multiple sclerosis biomarker that reflects intrathecal B-cell activity. It is an alternative to the detection of oligoclonal bands in the CSF and is likely to find its way into the upcoming revision of the McDonald criteria for multiple sclerosis (45). In a French study, detection of kappa free light chains and KFLC index in the CSF of people with radiologically isolated syndrome may predict new imaging activity in people with radiologically isolated syndrome (67).

Preclinical phase – is there a multiple sclerosis prodrome? The radiologically isolated syndrome is imaging evidence that there is an asymptomatic period of multiple sclerosis. Some work done in this preclinical phase raises concerns whether this prodromal phase is truly asymptomatic.

Cognitive function was investigated in individuals with radiologically isolated syndrome in two separate studies. Depending on the type of the neuropsychological testing and the number of tests failed, about one fourth or more of the radiologically isolated syndrome cohort showed mild cognitive impairment (59; 06). When quantitative MRI metrics were included, comparable levels of lesion load and brain atrophy were detected in patients with well-established relapsing-remitting multiple sclerosis (06). Based on these studies, mild cognitive impairment is present in some individuals with radiologically isolated syndrome, and they have a similar profile to the cognitive impairment seen in clinically isolated syndrome and relapsing-remitting multiple sclerosis (59; 06; 54). It is noteworthy that neither the individuals with radiologically isolated syndrome who failed on tests, nor their family members, noticed any cognitive deficits or changes, suggesting that these changes were mild and did not correlate with significant clinical expression (06). In an earlier study, four individuals with (at that time defined as) “subclinical multiple sclerosis” had mild cognitive impairment on neurocognitive testing done at different times after the initial imaging study (43). This finding was independent of clinical conversion to multiple sclerosis and didn’t progress over the years!

Because at least some individuals with radiologically isolated syndrome have a similar cognitive profile to multiple sclerosis patients, this raises the question of whether these individuals are likely to be multiple sclerosis patients with an undiagnosed “clinically isolated syndrome” who present with cognitive dysfunction (59). However, neither these individuals with radiologically isolated syndrome nor their family members were aware of any sign of cognitive deficits or functional deficits. There may be some signs that remain subclinical unless explored with special techniques and tools, similar to the demonstration of subclinical disease by imaging. Such “sophisticated findings” may not predict conversion to clinical disease and may correlate with a “subclinical disease state” that may persist for long periods or even a lifetime. In an Israeli cohort of radiologically isolated syndrome in which cognitive performance was below average for age- and education-matched norms, cognitive performance did not differ between individuals with radiologically isolated syndrome who converted to multiple sclerosis and those who remained asymptomatic (78). These findings suggest that cognitive deficits may develop independently of focal and inflammatory disease activity (54).

When finger motor performance was quantitated with engineered gloves, worse finger motor performance was found in individuals with radiologically isolated syndrome compared to healthy controls (11). Subclinical motor impairment was related to diffuse microstructural white matter damage on diffuse tensor imaging. The impaired hand motor performance could be detected only by sophisticated technology in these individuals with radiologically isolated syndrome who didn’t have any functional/clinical impairment in their daily life, suggesting that some motor signs may remain subclinical. In the new era of digital biomarkers, a smartphone application called MS Screen Test (MSST) was developed by a French group to explore several dimensions of the neurologic exam, such as finger tapping speed, agility, hand synchronization, low contrast vision, and cognition (18). This application was tested on a cohort of subjects with radiologically isolated syndrome compared with age- and sex-matched healthy controls. Subjects with radiologically isolated syndrome had a lower finger tapping speed on the dominant hand, a longer inter hand interval during the hand synchronization task, and poorer scores on the low contrast vision and cognition tests. However, these people had a normal neurologic exam, and their daily living activities weren’t affected.

Therefore, such “sophisticated findings” may not always predict conversion to clinical disease and may correlate with a “subclinical disease state” that may remain as such for long periods or even for a lifetime (101).

Is preclinical cognitive performance affected long before the clinical onset of multiple sclerosis? This question was addressed in a number of studies. In the Norwegian multiple sclerosis registry, men born between 1950 and 1995 and who underwent the conscription examination when they were 18 to 19 years of age, some later developed multiple sclerosis. Their cognitive performance was correlated with a cohort of randomly selected controls from the Norwegian Conscript Service database (21). Men developing their first clinical multiple sclerosis symptoms up to 2 years after the examination scored significantly lower than controls, corresponding to a 6-intelligence quotient point difference, and those who developed primary progressive multiple sclerosis scored 4.6 to 6.9 points lower than controls up to 20 years prior to first progressive symptoms. These findings suggest that relapsing/remitting multiple sclerosis may start years prior to the clinical presentation and that primary progressive multiple sclerosis could begin even decades prior to the first apparent clinically detectable progressive symptoms (21). An Argentinean study looking at school performance as a marker of cognitive decline prior to diagnosis of multiple sclerosis showed similar results (100). On the other hand, in a Swedish study in which the time of multiple sclerosis was not considered, a significant difference wasn’t observed (40). From these studies it may be said that cognitive problems may be present in all multiple sclerosis phenotypes before apparent clinical symptoms develop.

Patients with multiple sclerosis reported higher rates of fatigue or psychiatric morbidity in the years prior to the initial neurologic episode of their diagnosis compared with non-multiple sclerosis controls (14; 09; 17). More frequent use of health care such as more hospital admissions, physician claims, and prescriptions in patients with multiple sclerosis than in controls in the 5 years before a first demyelinating event, according to health administrative data, suggested the existence of a measurable multiple sclerosis prodrome (118; 17). The same Canadian group then studied the major causes for more physician and hospital encounters and found that these were related to nervous, sensory, musculoskeletal, and genito-urinary systems, and in another study reported that fatigue, sleep disorders, anemia, and pain were more common within this period (119; 121). Consistent with these symptoms, cases had more psychiatrist and urologist encounters and higher proportions of musculoskeletal, genito-urinary, or hormonal prescriptions. In a separate study, they also observed higher rates of gastrointestinal-related physician visits and drug dispensations for gastritis and duodenitis and diseases of the esophagus in the 5 years prior to the onset of their multiple sclerosis (123). In a similar study conducted in the UK, multiple sclerosis patients had a higher risk of presenting up to 10 years prior to index date with gastric, intestinal, urinary, and anorectal disturbances, anxiety, depression, insomnia, fatigue, headache, and various types of pain (27). A systematic review assessing studies of morbidities before or at disease onset confirmed that anxiety, depression, migraine, and lower cognitive performance are more common in multiple sclerosis patients than in control populations and appear during a multiple sclerosis prodrome (122).

In another study from Germany with a systematic assessment of medical diagnoses preceding the first diagnosis of multiple sclerosis, it was emphasized that patients with multiple sclerosis are frequently not diagnosed at their first demyelinating event but often years later (34). It was highly likely that symptoms and physician encounters before multiple sclerosis diagnosis were related to already ongoing disease rather than a prodrome.

Although most studies suggest that a multiple sclerosis prodrome exists for some individuals with multiple sclerosis, more research and advanced methodologies, including multi-country prognostic cohort studies, are needed (89; 44).

These observations indicate that some people with multiple sclerosis have mild cognitive changes and non-multiple sclerosis–specific health-related problems in the years before they develop clinical multiple sclerosis. What we may term “radiologically isolated syndrome” may not always be isolated! However, the concept of “multiple sclerosis prodrome” (113) doesn’t seem to have practical consequences unless combined with further and more solid evidence. Before the clinical application of the multiple sclerosis prodrome concept can be justified, it will be essential to demonstrate the cost-effectiveness of any prodromal detection and treatment program before any policy changes are recommended (44).

Differential diagnosis

The diagnosis of radiologically isolated syndrome depends on what we may name “1 positive criterion,” which is a pattern consistent with multiple sclerosis on an MRI study that was performed for non-multiple sclerosis causes, and “1 negative criterion,” which is the absence of any clinical symptom or sign suggestive of multiple sclerosis, ever.

Neurologically normal patients with small vessel disease or migraine, and many healthy people with so-called “nonspecific white matter abnormalities” can have white matter abnormalities that are easily confused with multiple sclerosis lesions (52; 105; 102). The practicing neurologist should be extremely careful before making a diagnosis of radiologically isolated syndrome (as well as multiple sclerosis!), which also has important psychological consequences on the individual. When in doubt, the lack of the central vein within these lesions may add in differentiating these ischemic or nonspecific lesions from multiple sclerosis–related white matter lesions (105; 96; 79; 102; 56).

The MRI criteria for a diagnosis of radiologically isolated syndrome are outlined in Tables 1 and 2. Some physicians, rather than considering these detailed criteria, would prefer McDonald’s dissemination in space MRI criteria (107). However, it’s clear that the current McDonald’s 2017 criteria don’t include radiologically isolated syndrome and, therefore, can’t be used to make a “radiologically isolated syndrome” diagnosis. The upcoming McDonald’s 2024 criteria will include radiologically isolated syndrome and its specific diagnostic criteria.

It should be kept in mind that periventricular and juxtacortical regions of the “dissemination in space” sites, when demyelinating in nature, should touch the ventricles or the cortex, respectively. Subcortical lesions should not be mistaken for either of them. In many non-multiple sclerosis cases, and mainly in people with migraine, periventricular and juxtacortical “non-specific white matter lesions” may coexist and could be confused with demyelinating lesions. Juxtacortical lesions in people who do not have multiple sclerosis lack the “S” or “U” shape that usually suggests multiple sclerosis-related demyelination (102; 66). In people with radiologically isolated syndrome or clinical multiple sclerosis, demyelinating periventricular lesions are expected to be ovoid and perpendicular to the ventricles, and they should touch the ventricles. The presence of temporal periventricular lesions is also highly suggestive for multiple sclerosis. Bilateral and mostly subcortical lesions, not in the juxtacortical white matter, with a semi-symmetrical and umbrella-like distribution and which are very small and punctate or nodular in shape, should not be mistaken for multiple sclerosis lesions (102; 66). Total absence of posterior fossa, corpus callosum, and spinal cord lesions also suggest non-multiple sclerosis pathologies.

Enhancement may serve as a clue to confirm the demyelinating-inflammatory nature of the lesions. A total lack of enhancement in any MRIs raises suspicion against demyelination. However, small vascular malformations or granulomatous lesions that continue to enhance over many months should not be confused with demyelinating lesions of radiologically isolated syndrome or multiple sclerosis.

The differential diagnosis of people suspected of having radiologically isolated syndrome should also consider the age of the individual. In children and adolescents, some genetic or metabolic diseases (eg, leukodystrophies and mitochondrial disease) and infections may mimic the imaging findings of radiologically isolated syndrome or multiple sclerosis. Other differential diagnoses, such as vascular disease, nutritional deficiencies, other inflammatory diseases (eg, sarcoidosis), and rheumatological diseases (eg, lupus and antiphospholipid syndrome), can occur, mostly in adults and sometimes in children (66). In adults older than 50 years, the high prevalence of non-specific white matter hyperintensities most likely related to noninflammatory vasculopathies adds to the diagnostic confusion.

Once the MRI is deemed to be consistent with “radiologically isolated syndrome,” the other major diagnostic criterion is to be sure that the individual has had no symptom related to multiple sclerosis, ever. The task of the neurologist should be to define that he or she is truly asymptomatic for multiple sclerosis and is indeed “a definite case” of radiologically isolated syndrome. There are a number of non-multiple sclerosis and nonspecific neuropsychiatric symptoms that may mimic a demyelinating event (102). Somatoform symptoms, dizziness, visual blurring related to the eye itself, and numbness due to nerve entrapments are some of these symptoms and require clinical expertise in the differential diagnosis of people who may coincidentally turn out to have either demyelinating or demyelinating-like nonspecific white matter lesions.

Management

Prior to treatment trials in radiologically isolated syndrome, there was no consensus on whether to start treatment in people with radiologically isolated syndrome or not. There were suggested treatment algorithms (99; 03; 25), debates, controversies regarding treatment policies in people with radiologically isolated syndrome (12; 13; 53; 82), reviews, and cautionary editorials (101; 39; 72; 05). However, in common practice at that time, mainly in the U.S. and partly in Europe, a significant number of physicians would start off-label treatment for these individuals (111; 30). The pro-treatment decisions were mostly influenced by observing one or more spinal cord lesions on MRI, gadolinium-enhancing lesions, and more than one new or enlarging T2 brain lesion at a follow-up scan. In Argentina, neurologists were more conservative and less likely to start treatment in radiologically isolated syndrome (15). However, there was a general consensus in all surveys to perform a lumbar puncture to determine the presence of oligoclonal bands and to perform a spinal cord MRI.

Two multicenter, randomized, double-blind clinical trials have been completed in people with radiologically isolated syndrome. The ARISE study in the United States randomly assigned people with radiologically isolated syndrome to dimethyl fumarate or placebo in a 1:1 ratio (87), and the TERIS study in Europe randomly assigned people with radiologically isolated syndrome to teriflunomide or placebo in a 1:1 ratio (66). The methodology was identical in both studies, and the primary endpoint for both was the time to the first demyelinating clinical event related to CNS demyelination. Secondary endpoints included the number of gadolinium-enhancing lesions, the number of new or enlarging T2 lesions, T2 lesion volume, and whole-brain volume. The ARISE study showed that treatment with dimethyl fumarate reduced the risk of a first clinical demyelinating event by 80% in individuals with radiologically isolated syndrome compared to placebo (hazard ratio [HR] 0.2; 95% CI: 0.11–0.35; p=0.006) over 2 years, providing the first scientific evidence of the prevention or delay of a first clinical event in people with radiologically isolated syndrome. Compared with placebo, the number of new or newly enlarging T2-weighted hyperintense lesions in the dimethyl fumarate group was significantly reduced compared to placebo (HR: 0.20; 95% CI: 0.04–0.94; p=0.042). Primary outcome results from the TERIS study supported the efficacy of teriflunomide, with a 62% reduction in the number of clinical events in the teriflunomide group compared to placebo (HR: 0.38; 95% CI: 0.17–0.88; p=0.025) over 2 years. These two studies clearly showed that initiating a disease-modifying therapy at the presymptomatic stage of multiple sclerosis is highly effective in the earliest stage of the disease. However, we have yet to determine which people with radiologically isolated syndrome are more likely to benefit from disease-modifying therapies because subgroup analyses regarding these issues weren’t studied in the above-mentioned trials (64). There is no information on whether the benefits persist beyond 2 years.

In a detailed substudy to explore the effect of dimethyl fumarate on volumetric measures, including whole brain, thalamic, and subcortical gray matter volumes; brainstem and upper cervical spine 3-dimensional volumes; and brainstem and upper cervical spine surface characteristics, Okuda and colleagues studied the 64 subjects with radiologically isolated syndrome (dimethyl fumarate treated: 30, placebo: 34) from the ARISE study population (87). A significant difference was observed in dorsal pons curvature; the treated group had a lower least squares mean change when compared to placebo. In individuals who experienced a first clinical event, there was a greater reduction in medulla-upper cervical spinal cord volume (p = 0.044) and a decrease in surface curvature in the dorsal medulla (p = 0.009) but not in the dorsal pons (p = 0.443). These results clearly show that the benefit of disease-modifying therapy in radiologically isolated syndrome extended to CNS structures impacted by neurodegeneration, a benefit that is below the resolution of conventional volumetric measures.

The “CELLO” study, a phase 4, multicenter placebo-controlled study, assessed the effectiveness of three courses of the anti-CD20 drug ocrelizumab in people with radiologically isolated syndrome defined according to the 2017 MAGNIMS recommendations but was stopped early due to the slow pace of recruitment (25; 68). Keeping in mind that many individuals with radiologically isolated syndrome will develop active or even aggressive multiple sclerosis, it is logical to consider highly effective disease-modifying therapies in a highly selected radiologically isolated syndrome population. However, since there are no strong predictors to determine in whom progressive or aggressive disease may develop, evidence for such a treatment policy remains hypothetical until another similar study is conducted.

When making treatment decisions in people with radiologically isolated syndrome, caution is needed as up to 50% of people with radiologically isolated syndrome may not convert to clinical disease within 10 years after their initial MRI (62), and most of this remaining population may not ever experience any clinical episode during their lifetime. Therefore, it is important to identify individuals with radiologically isolated syndrome who have a high-risk profile for clinical conversion. These people are young individuals with high-risk MRI factors, such as spinal cord and posterior fossa lesions on their initial imaging studies; enhancing lesions initially or at any follow-up MRI and new T2 lesions; and CSF oligoclonal bands and elevated neurofilament light chains in their CSF or serum. Each of these risk factors increases the probability of converting to clinical disease. Individuals with three or more risk factors should be considered high-risk and may be considered for early treatment or should be followed closely with imaging and, if possible, with serum neurofilament light chain levels.

Currently, neither of the two drugs used in the two radiologically isolated syndrome studies (dimethyl fumarate and teriflunomide), nor any other treatment, is approved for use in people with radiologically isolated syndrome. Nevertheless, these two drugs with different modes of action both represent a major step forward (66). If disease-modifying therapies are given off-label, it is crucial that these individuals have counselling regarding long-term therapy use and be followed closely.

One other important issue to consider before deciding to initiate treatment in people with a diagnosis of radiologically isolated syndrome is whether the diagnosis is correct. Unfortunately, the probability of misdiagnosing individuals with “radiologically isolated syndrome” in clinical practice is not low and may result in unnecessary treatment in people who are healthy and have only nonsignificant white matter abnormalities or who may have other nondemyelinating conditions (104; 102; 46). Finally, because some people with radiologically isolated syndrome may remain asymptomatic throughout their lifetime, whether it is appropriate to start long-term therapy with multiple sclerosis disease-modifying therapies in people with radiologically isolated syndrome continues to be a subject of active debate today (65).

Needless to say, because people with radiologically isolated syndrome don’t present with clinical symptoms and don’t have “an attack,” there is no evidence that treating them with steroids even if they do have gadolinium-enhancing lesions at their initial or at any other follow-up MRI offers any benefit.

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

Aksel Siva MD

Dr. Siva of the Istanbul University Cerrahpasa School of Medicine received honorariums or consulting fees from Alexion, Biogen/Gen Ilac of Turkey, Genzyme, Merck-Serono, Novartis, Roche, and Teva. He also received travel and registration reimbursements from Merck-Serono and Roche and fees for advisory board membership from Abdi Ibrahim Ilac.
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Ugur Uygunoglu MD

Dr. Uygunoglu of Istanbul University Cerrahpasa School of Medicine received advisory board honorariums and speaker fees from F Hoffmann La-Roche, Sanovel, Genveon, Merck-Serono, Novartis, and Biogen Idec/Gen Pharma of Turkey.
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Melih Tutuncu MD

Dr. Tutuncu of Istanbul University Cerrahpasa School of Medicine received advisory board honorariums and speaker fees from F Hoffmann La-Roche, Novartis, and Merck-Serono.
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Editor

Anthony T Reder MD

Dr. Reder of the University of Chicago received honorariums from Biogen Idec, Genentech, Genzyme, and TG Therapeutics for service on advisory boards and as a consultant as well as stock options from NKMax America for advisory work and an unrestricted lab research grant from BMS.
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Radiologically isolated syndrome

Differential Diagnosis

subcortical lesions
periventricular and juxtacortical lesions
white matter abnormalities
somatoform symptoms
dizziness
- visual blurring related to the eye
- numbness due to nerve entrapments

Radiologically isolated syndrome

Radiologically isolated syndrome

Introduction

Overview

Key points

Historical note and terminology

Table 1. Radiologically Isolated Syndrome Diagnostic “Okuda” Criteria

Table 2. The Revised Radiologically Isolated Syndrome Diagnostic Criteria, 2023

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Differential diagnosis

Diagnostic workup

Management

Special considerations

Pregnancy

Anesthesia

References

Contributors

Authors

Editor

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

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Progressive encephalomyelitis with rigidity and myoclonus and glycine receptor antibodies

Radiologically isolated syndrome

Introduction

Overview

Key points

Historical note and terminology

Table 1. Radiologically Isolated Syndrome Diagnostic “Okuda” Criteria

Table 2. The Revised Radiologically Isolated Syndrome Diagnostic Criteria, 2023

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Differential diagnosis

Diagnostic workup

Management

Special considerations

Pregnancy

Anesthesia

References

Contributors

Authors

Editor

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Autoantibodies: mechanism and testing

Multiple sclerosis: treatment of its symptoms

Anti-GQ1b antibody syndrome

Paraneoplastic syndromes

Anti-IgLON5 disease

Balo concentric sclerosis

Anti-LGI1 encephalitis

Progressive encephalomyelitis with rigidity and myoclonus and glycine receptor antibodies

This is an article preview.
Start a Free Account
to access the full version.