What is radiologically isolated syndrome (RIS)?

RIS is diagnosed when central nervous system (CNS) white matter anomalies characteristic of multiple sclerosis (MS) are incidentally found on MRI of the brain and spinal cord without relapsing or progressive symptoms typical of inflammatory demyelination. RIS is often identified when imaging studies are performed for nonspecific symptoms (i.e., headache) or in specific clinical scenarios (i.e., head trauma or research studies in healthy controls).1 A subset of patients with RIS will develop clinical manifestations of MS over time. As a result, detection of RIS is a notable opportunity for early monitoring and possibly treatment before clinical manifestations of MS occur. Future iterations of the McDonald criteria for MS likely will allow patients with RIS who also have certain clinical, imaging, and laboratory features to be diagnosed with MS prior to the onset of symptoms.

Initial studies of RIS required the diagnosis to be made when MRI studies were obtained in a true “incidental” fashion. However, more recently, the umbrella of RIS has widened to also include individuals presenting with symptoms in absence of a typical clinical event or true neurological progression. These symptoms can include heat intolerance, mood disorders, cognitive dysfunction, and paroxysmal symptoms. These symptoms partially overlap with those in the so-called “MS prodrome” and may simply reflect an early form of the disease. In addition, many of these symptoms are relatively non-specific so the relationship with RIS is not always clear.

How is RIS diagnosed?

Stringent criteria must be met to diagnose RIS.1–3 Proposed criteria have evolved over time as more data have accumulated. Current diagnostic criteria for RIS were published in 2023 and contain similarities with the McDonald criteria for MS. They are as follows3:

I Inclusion Criteria

A. MRI with incidental CNS white matter anomalies demonstrating radiological characteristics highly suggestive of demyelinating disease and meeting the following criteria:

    1. Ovoid, well-circumscribed, and homogeneous foci > 3 mm2 with or without the involvement of the corpus callosum
    2. Involvement of periventricular, juxtacortical, infratentorial, and spinal cord regions
    3. Anomalies inconsistent with microvascular or non-specific white matter disease pattern

With

B. Index MRI fulfilling 3 or 4 out of 4 dissemination in space criteria according to the 2005 multiple sclerosis diagnostic imaging criteria.

Or

C. Index MRI fulfilling at least one of 4 dissemination in space requirements, additionally fulfilling 2 of the following:

    1. Presence of abnormal cerebrospinal-fluid restricted oligoclonal bands
    2. Presence of at least one spinal cord lesion consistent with inflammatory demyelination
    3. 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 MS

II Additionally:

  1. No historical account of relapsing-remitting or progressive clinical symptoms consistent with neurological dysfunction
  2. MRI anomalies or neurological examination findings do not account for clinically apparent impairment(s) to the individual
  3. Another disease process has not been identified to better account for the CNS MRI anomalies.

Presence of a typical clinical event would support a diagnosis of clinically isolated syndrome or relapsing MS, and presence of clinical progression from onset may indicate a primary progressive MS disease course, rather than RIS, when other disease processes have been excluded.

Patients may only partially meet diagnostic criteria. These are individuals, despite not meeting the strict criteria for RIS, who have MRI anomalies suspicious for MS. These individuals may also be at-risk to develop clinical manifestations of MS and may be approached similarly to those meeting RIS criteria, although greater caution should be taken since their radiologic findings are less specific to RIS.

What is the epidemiology of RIS?

RIS patients are on average in their 30s to 40s and majority female, similar to the characteristics of patients with MS, though patients are seen across a broad range of ages, from pediatric to elderly.3–5 In Sweden, a population-based study of 1,907 individuals found a cumulative incidence rate of 0.1% per year, in a region with an incidence rate of MS of 10.2 cases per 100,000 person-years.6 While not found to be a statistically significant difference, the prevalence of RIS appears to be slightly higher in relatives of patients with MS compared with controls who did not have a family history (2.9% compared with 2.4%), with similar proportions of patients in each group affected by tobacco use, hypertension, and migraine.7 Family history has not been found to predict development of symptomatic MS among those with RIS.3,7

Individuals with RIS are commonly affected by comorbidities that would prompt an MRI. Common reasons for undergoing MRI include headache, occurring in about half of patients, though seizures, paroxysmal symptoms, and psychiatric symptoms are also common indications.1 These indications for MRI may impact the epidemiology of RIS.

What is the natural history of RIS?

A notable proportion of patients with RIS will go on to develop clinical symptoms of MS over time. In studies of individuals meeting 2009 RIS criteria, a clinical event was identified among 13.8% of patients within 2 years, 34% at 5 years, and 51% at 10 years.4,8 Approximately 10% of individuals who become symptomatic will meet criteria for primary progressive MS, highlighting a similar distribution to that seen in all MS cases.4,9

What features help determine which patients with RIS will go on to develop MS?

Several studies have identified factors that increase the risk of developing clinical symptoms of MS and these include: male sex, age younger than 37 years, the presence of ≥1 spinal cord lesion on MR imaging.10 In some studies, presence of gadolinium-enhancing lesions on index scan also increased the risk to develop clinical symptoms of MS. 4 When presence of multiple risk factors, namely age, spinal cord lesions, and gadolinium-enhancing lesions are considered, 27.9% of patients experience an event within two years when two factors are present at baseline, which increases to 90.9% within two years for individuals with all three factors present at baseline.4

Other factors that increase the likelihood of clinical manifestations of MS include high T2-lesion load on MRI and abnormal visual evoked potentials, which may be considered alongside the above factors.1 The presence of OCT abnormalities has also been associated with a 7.5-8 fold increased risk in the odds of developing clinical manifestations of MS.11

What is the recommended evaluation of the patient with RIS?

On identification of possible RIS, further evaluation is carried out to uncover additional sites of potential CNS demyelination and increase diagnostic certainty using tests which are relatively specific for MS. At the Mellen Center, there is some heterogeneity among clinicians with regard to specific tests ordered, though we include a list of suggested tests to perform (Table 1). Lesion location in topographies known to be specific for MS (periventricular, juxtacortical, infratentorial) with associated features (gadolinium enhancement, T1-weighted hypointensity) should be evaluated carefully. Additional MRI biomarkers with high specificity for MS include the central vein sign (CVS) and paramagnetic rim lesions (PRLs); when available, these should be performed (discussed further below). Imaging of the cervical and thoracic spine with and without gadolinium-based contrast should be conducted looking for intramedullary lesions typical of MS.

Lumbar puncture with cerebrospinal fluid analysis will permit detection of oligoclonal bands (OCBs) and can be used to inform risk of a clinical event, as well as rule-out other mimickers. At the Mellen Center, some clinicians perform lumbar puncture on all patients with RIS, while others perform lumbar puncture on patients with more subtle or ambiguous imaging findings. In particular, a lumbar puncture may be useful if presence or absence of certain features (i.e., OCBs) will impact the decision to start treatment (as discussed further in the section below). OCT and visual evoked potentials can also be used to further substantiate CNS involvement in locations typical of MS.

Finally, work-up should focus on exploring alternative causes of brain lesions. Determination of other causes of brain lesions should start with baseline assessment of comorbidities that portend increased risk of white matter changes, including hypertension, hyperlipidemia, tobacco use, and migraine headache. These alternate conditions may produce smaller (<5 mm), only rarely venocentric lesions with an anterior and subcortical predominance with infrequent infratentorial lesions. Lesions from these etiologies should not involve the spinal cord or produce gadolinium enhancement.1 Screening blood work for other conditions known to cause white matter changes including metabolic, infectious and autoimmune etiologies is advised.

What other tests can help in the evaluation of RIS?

Continued efforts to characterize additional radiographic features that provide diagnostic clarity to RIS are on-going. In addition to the listed diagnostic criteria above. The central vein sign (CVS) is a central linear hypointensity seen within MS lesions on T2*-weighted scans or susceptibility-weight scans, corresponding to perivenular demyelination characteristic of MS. Paramagnetic rim lesions (PRL), visible on similar scans, reflect iron-laden macrophages at the edge of chronic active lesions. The CVS and presence of PRLs reliably differentiate demyelinating lesions from other non-specific white matter changes that are caused by other disease processes and therefore may be useful in evaluating patients with RIS.12–15 Use of 3.0 Tesla MRI studies or 7.0 Tesla when available (instead of 1.5T) use of dedicated T2*-weighted imaging can increase sensitivity of detecting CVS and PRLs.1

Most cases of RIS have a high proportion of lesions with CVS.16 CVS performs similarly when differentiating either RIS from non-MS or MS from non-MS.17 In 180 participants with RIS, 66.4% of lesions were found to contain CVS, compared with 70.4% in MS and 12.9% in non-MS. When 6 or more CVS-containing lesions were detected on a scan, sensitivity of correct diagnosis was found to be 95% and specificity 83% in RIS patients. Specificity rose to 100% when fluid biomarkers (OCBs, kappa free light chain index) were added, though sensitivity was diminished.17

PRLs have been found in a proportion of patients, ranging from 27% to 63% of RIS patients.18–21 Presence of one or more PRLs demonstrated high specificity (99.7%) in differentiating demyelinating processes from healthy controls. Specificity rose to 100% when CVS was present in a PRL.13

Future iterations of the McDonald criteria may incorporate these biomarkers to aid in making a diagnosis of MS, with studies investigating their use are on-going.22

What is the management of the patient with RIS?

In patients with RIS, a major therapeutic question is whether to initiate MS disease modifying treatments (DMT) or monitor off DMT. The decision of treatment with DMT or monitoring is nuanced, requiring a balance of individualized risks and benefits based on the patient’s likelihood of going on to develop clinical symptoms of MS. Side effects, psychological burden, and increased out-of-pocket costs associated with DMTs may outweigh treatment benefit when risk for development of symptomatic MS is low or when risk of misdiagnosis is high.23 Additionally, the incremental long-term benefit of starting treatment during RIS instead of waiting until clinical manifestations of MS develop has not been shown. Conversely, initiation of DMT in patients with high risk of developing clinical manifestations of MS may be associated with improved long-term outcomes. In high-risk patients, RIS may be the ideal opportunity for early treatment initiation. Additional factors to consider include psychological burden of an anticipated clinical episode as well as the potential for accrual of lesion burden and the potential long-term impact of untreated early disease activity.

Regardless of whether DMT is started or not, periodic MRI studies of the brain (every 6 to 12 months) are indicated to assess increase in number of T2 lesions with characteristics of demyelination, along with continued assessment for clinical events.

Treatment with DMT is usually reserved for patients with a combination of risk factors including presence of gadolinium enhancing lesions, spinal cord lesions, presence of OCBs, or increasing burden of T2 lesions/gadolinium-enhancing lesions . Lesion burden needs to considered, as does likelihood of clinical disease and patient age, as risk/benefit ratio of DMT in patients with late-onset MS often differs from patients in their 20s and 30s.

The goal of starting DMT in people with RIS is to prevent clinical manifestations, and therefore there may be patients who, while treated, never develop symptoms; it is important to convey this to patients and emphasize the benefit of DMT will be prevention of relapses and new lesions on MRI, and effective treatment may obscure whether they were destined to develop MS. While only a few DMTs have been studied in clinical trials (see section below), once a decision to treat RIS is made, this should be approached as one would in any patient with MS (see Mellen Center Approaches on individual DMTs).

What data support the use of DMTs in patients with RIS?

Two randomized clinical trials have been conducted in RIS. The TERIS study was a multicenter, double-blinded, phase 3, randomized clinical trial which investigated the efficacy of teriflunomide in delaying diagnosis of MS in individuals with RIS, with a 3-year follow-up. Treatment with teriflunomide resulted in an adjusted risk reduction of 72%, relative to placebo, in preventing a first demyelinating event (defined by a clinical symptom localized to the optic nerve, brain stem, cerebellum, spinal cord, or long sensory or motor tracts, lasting more than 24 hours and followed by symptom improvement or a progressive event was defined by the onset of a clinical symptom with the temporal profile revealing at least a 12-month progression), suggesting a benefit to early treatment in the MS disease spectrum.24 However, secondary imaging end point outcomes including presence of new or enlarging T2 lesions and new gadolinium-enhancing lesions were not found to differ between the two groups. A multi-center, randomized, double-blinded, placebo-controlled study of dimethyl fumarate (ARISE) demonstrated reduced hazard ratio of a first clinical demyelinating event (defined by the same criteria as the TERIS trial) when followed for 96 weeks (1.84 years).25 Similar results have been noted in real-world data, supporting treatment for RIS.19 Neither of these trials demonstrated a reduced disability long-term with DMT, although they were not powered to identify this, either.

How long should DMT treatment be continued in RIS?

There are no published studies examining discontinuation of DMT in RIS patients. One study examining 3 initial doses of ocrelizumab to prevent development of MS was halted due to slow recruitment.26 However, the general approach used in relapsing forms of MS should be followed, as ongoing inflammation would be expected to return upon DMT discontinuation in younger individuals.

Citations

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