Dia­gnostics and management of patients with radiologically isolated syndrome

Overview

Radiologically isolated syndrome (RIS) represents one of the earliest identifiable stages of MS, characterized by the presence of asymptotic demyelinating lesions on MRI corresponding to MS. With the increasing availability of MRI, these incidental findings are being detected more frequently and their prognostic significance and therapeutic implications are becoming the subject of intensive research. In this review article, we summarize the development of RIS diagnostic criteria –⁠ from their initial formulation in 2009 to the recent 2023 revision. We focus on risk factors for conversion of RIS to clinical MS, on differential diagnosis, useful biomarkers (including the central vein sign, oligoclonal bands, kappa index, and neurofilament light chain levels) and the early interventional trials evaluating the effectiveness of disease-modifying drugs in patients with RIS –⁠ teriflunomide and dimethyl fumarate were among the first to demonstrate the ability to delay the first clinical attack. Previous studies underline the importance of accurately stratifying patients based on a combination of radiological, laboratory, and demographic data, which can help identify individuals at the highest risk of early conversion. This review aims to promote a clinical understanding of RIS and highlight its growing importance, particularly in relation to its position within the newly prepared diagnostic criteria for MS from 2024.

Keywords:

prognostic factors – Multiple sclerosis – magnetic resonance imaging – risk stratification – oligoclonal bands – radiologically isolated syndrome – neurofilament – teriflunomide – dimethyl fumarate

This is an unauthorised machine translation into English made using the DeepL Translate Pro translator. The editors do not guarantee that the content of the article corresponds fully to the original language version.

 

Introduction

Multiple sclerosis is a chronic inflammatory demyelinating disease of the CNS, the diagnosis of which, due to the continued absence of a key diagnostic biomarker, requires typical findings on MRI [1,2]. The traditional classification into clinical forms such as clinically isolated syndrome (CIS), relapsing-remitting (RRMS), secondary progressive (SPMS), or primary progressive (PPMS) phases now appears arbitrary. The disease is now perceived more as a "broader continuum of multiple sclerosis," as the development and availability of MRI has made it possible to detect the earliest, still asymptomatic phase of MS, known as radiologically isolated syndrome (RIS), and, more recently, the even earlier biological phase [3–6]. For example, elevated serum neurofilament levels have been found not only in patients during their first clinical episode of MS, but also 6 years earlier [7]. The concept thus emphasizes the need for early detection of the disease in the preclinical phase and consideration of initiating treatment even before irreversible damage to the CNS occurs [8–10].

The increasing availability and use of MRI has significantly increased the detection of unexpected asymptomatic abnormalities of the brain and spinal cord, whose clinical significance remains uncertain [11,12]. Individuals usually do not show typical neurological symptoms of MS, but their MR reveals findings of T2-hyperintense white matter lesions, which, by their number, morphology, size, and location, strongly suggest a demyelinating disease of the CNS and thus meet the radiological, but not the clinical, criteria for MS [1,6,13].

Current findings from prospective studies show that some individuals with RIS (especially in the presence of certain risk factors) are significantly more likely to progress to clinically manifest MS [9,14–16]. The prevalence of RIS is not yet precisely known, but in some pathological-anatomical studies, clinically silent demyelinating lesions of the brain were found in 0.1–0.3% of autopsies [17,18]. Similarly, 0.1–0.7% of the general population shows incidentally detected lesions similar to demyelination [6,19]. In a Swedish cohort, the estimated incidence of RIS was 0.8 per 100,000 persons/year [20].

Given the growing interest in studying this group of patients, this review aims to provide a critical summary of the latest findings regarding diagnostic criteria, prognostic factors, and emerging evidence regarding the treatment of individuals with RIS.

 

RIS diagnostic criteria and their development

Just as the diagnostic criteria for MS have undergone and continue to undergo gradual development, from Poser's [21] to the currently valid McDonald criteria, revised in 2017 [22], to the most recently proposed criteria from 2024 [23], the diagnostic criteria for RIS have also undergone some development. However, their history does not go back very far, as RIS was first defined in 2009 by Professor Okuda's team [13].

The emphasis here is not only on localization but also on the nature of the lesions. A large part is also devoted to exclusion criteria, which aim not only to distinguish clinically symptomatic individuals but, above all, to prevent misdiagnosis due to insufficient differential diagnosis.

According to Okuda [13], radiologically isolated syndrome was defined as the presence of clinically asymptomatic lesions of the white matter of the CNS on MRI, which are ovoid in shape, well-defined, homogeneous, longer than 3 mm in any dimension, and hyperintense on T2-weighted images, with or without involvement of the corpus callosum, and not corresponding to vascular changes. At the same time, these lesions must meet Barkhof's criteria for dissemination in space (DIS) from 2005 [13]. This means fulfilling three of the four criteria, which are the presence of:

at least one Gd-enhancing lesion or nine or more T2-hyperintense (characteristic) lesions;

at least one infratentorial lesion;

at least one juxtacortical lesion;

at least three periventricular lesions [24].

 

The exclusion criteria included a history of relapsing symptoms correlating with MS, MR findings suggestive of leukoaraiosis or extensive white matter involvement without involvement of the corpus callosum, and conditions where MR abnormalities or pathological findings on neurological examination are conditioned by clinically apparent impairment of the individual. The diagnosis of RIS can therefore only be made if there is no other, better explanation for the lesions on MRI.

Although McDonald's criteria for MS were revised in 2010, redefining both dissemination in time (DIT) and, above all, DIS, for which the presence of one or more hyperintense lesions in two of four locations (periventricular, juxtacortical, infratentorial, or spinal) is now sufficient [25], the criteria for RIS remained the same.

Another new version of the McDonald criteria for MS from 2017 [22] has already sparked debate about their revision. This was followed by extensive longitudinal studies evaluating and refining the risk factors for conversion of RIS to CIS or MS, on the basis of which the revised criteria were published in March 2023. The aim of this update was to enable the diagnosis of RIS even in individuals who do not meet the 2009 RIS criteria but meet the new 2017 DIS criteria and two of the three selected conditions, see below [6].

These revised RIS criteria are now clearly divided into two parts: radiological criteria and exclusion criteria. The exclusion criteria more or less correspond to those from 2009. In order to meet the radiological criteria, the condition regarding the location and characteristics of lesions that do not correspond to microvascular or nonspecific changes in white matter and at the same time meet Barkhof's criteria for DIS from 2005 has been retained. For individuals who do not meet the 2005 DIS criteria, the diagnosis of RIS can be made based on the presence of at least one lesion in one of four typical locations (periventricular, juxtacortical, infratentorial, or spinal) and the simultaneous fulfillment of at least two of the following three conditions:

presence of a spinal lesion;

    presence of oligoclonal bands (OB) in cerebrospinal fluid not corresponding to serum;

    dissemination over time on any of the following MRIs defined as one or more new T2-weighted or Gd-enhancing lesions typical of MS [6].

 

A clear comparison of the diagnostic criteria for RIS from 2009 and 2023 is shown in Table 1.

The revised criteria for RIS were subsequently validated in two MS centers in Germany on a cohort of 115 patients, and the findings were evaluated blindly by two neuroradiologists. The results confirmed their high sensitivity and low specificity [26]. The inclusion of additional, non-radiological parameters better reflects the individual risk of progression to CIS/MS, thus enabling earlier intervention or monitoring of these individuals.

 

Prognostic factors for the conversion of RIS to clinically definite MS

A retrospective multicenter study of a large patient cohort in 2014 showed that the 5-year risk of RIS conversion to the first clinical symptoms consistent with MS is 34%. Of this group, 10% were PPRS [14]. Another study mentions up to 12% [27]. The same cohort of patients was subsequently analyzed after 10 years in a study by Lebrun-Frenay et al. [28], with up to 51% of patients developing clinical symptoms. Preliminary, as yet unpublished data predict a risk of developing the first clinical attack within 15 years for individuals meeting the RIS criteria of up to 72% [6]. In children, the development of clinical symptoms appears to be even earlier, with up to 42% of them progressing to the symptomatic phase within 2 years of the initial MRI examination [29].

Studies have also described several risk prognostic factors. These include:

younger age (< 37 years) [6,14,16,28];

spinal cord lesions (in the cervical or thoracic spinal cord) [6,14,15,27];

    infratentorial lesions on initial MRI [6,14,28,30];

    contrast-enhancing lesions on follow-up MRI [6,28];

    OP positivity in cerebrospinal fluid [6,16,31].

 

Male gender was a risk factor only within a 5-year horizon; after 10 years, it was no longer associated with an increased risk [14,28]. However, together with older age and the presence of spinal lesions, it appears to be a predictor of the transition from RIS to PPRS [32]. If we stratify patients according to these risk factors, the probability of clinical manifestations increases with the number of factors. Within 10 years, the risk in a patient with RIS is 29% with one factor present, but up to 87% with all four factors present [28].

This was followed by a large study involving 747 patients, which became the basis for the new revised criteria for RIS from 2023. Spinal lesions, OP positivity in cerebrospinal fluid, and evidence of a new T2-hyperintense lesion or post-contrast enhancing lesion were ultimately identified as risk factors. If a patient with at least one lesion in a typical MS area (periventricular, juxtacortical, infratentorial, or spinal) —⁠ i.e., not meeting the 2009 RIS criteria —⁠ had at least two of the above risk factors, the probability of RIS conversion to clinically symptomatic disease within 5 years was close to that of patients with a number of lesions meeting the 2009 RIS criteria (38% vs. 38.7%) [6].

 

Differential diagnosis of RIS

The differential diagnosis of RIS largely overlaps with the differential diagnosis of MS. Many systemic and neurological diseases can manifest as white matter lesions in the brain and spinal cord on MRI. Here we select the most important ones. However, it remains to be discussed whether these diseases primarily contribute to the radiographic findings or whether they are comorbidities.

 

Migraine

Migraine is one of the most common neurological diseases, and an MRI scan is usually indicated at the initial diagnosis to rule out secondary causes of headaches. The literature reports that migraine sufferers are 3.9 times more likely to have white matter lesions (WML) on brain MRIs than healthy individuals [33]. According to some authors, lesions are more common in patients suffering from migraine with aura [34], while other authors have not observed this difference between migraine subtypes [35]. It appears that the frequency of headache attacks correlates positively with the risk of WML [34,35]. Lesions are mostly located in the deep white matter of the hemispheres, not periventricularly [35,36].

 

Neuromyelitis optica and its broader spectrum

A classic, albeit rare, diagnosis within the spectrum of demyelinating diseases that must be differentiated is neuromyelitis optica spectrum disorder (NMOSD). Radiologically isolated findings have also been described in NMOSD, but these were reported in case studies [37]. Asymptomatic lesions in the corpus callosum or internal capsule are sometimes described together with symptomatic lesions during relapse, but the characteristics of lesions in NMOSD are often pathognomonic and different from those typical of MS (lesions of the brainstem in the area postrema, longitudinally extensive transverse myelitis, bilateral optic neuritis, and others) [38,39].

Other diseases

It is also necessary to rule out rheumatic diseases such as systemic lupus erythematosus, primary or secondary antiphospholipid syndrome, Behçet's syndrome, or Sjögren's syndrome [40], as well as extrapulmonary manifestations of sarcoidosis [32,40]. In older people, ischemic etiology must be considered first and foremost [32,40]. Cerebral vessels may also be affected in the rarer Fabry disease, which is also manifested by WML on MRI [40]. Among infectious diseases, we exclude Lyme disease in particular. Contrast-enhancing lesions that show growth during follow-up examinations may be of neoplastic origin (lymphoma or glioma) [40].

 

Usable biomarkers

In magnetic resonance imaging

The central vein sign (CVS) on MR is a supratentorial lesion larger than 3 mm in at least one dimension with a vein running through the center, which can be detected on T2* sequences or susceptibility weighted imaging (SWI) MR sequences. CVS appears to be a very useful biomarker for MS, with sensitivity ranging from 95% to 98% and specificity from 83% to 92% according to various studies [41,42]. 3T and 7T devices are more sensitive to this symptom than 1.5T devices [43]. A threshold value of at least six CVS on MR distinguishes RIS from non-demyelinating lesions with a sensitivity of 95% [23,32].

Cortical lesions (CL) are a manifestation of gray matter demyelination. They are visible on special MR sequences, such as double inversion recovery (DIR), and in some cases may even precede WML [44]. The prevalence of cortical lesions in RIS is reported to be in the range of 20–40% [10]. In a study by Cagola et al. , at least one CL was detected in almost 60% of patients with RRMS ( ), whereas in other diagnoses (NMOSD, diseases with positive antibodies against myelin oligodendrocyte glycoprotein, migraine, inflammatory vasculopathies, or cerebrovascular disease), the proportion of patients with CL was lower. The study also showed that CLs have high specificity (93.6%) and that combining them with CVS significantly increases diagnostic accuracy (area under the curve [AUC] = 0.92) for distinguishing MS from other diagnoses [45].

Lesions with a hyposignal ring on SWI sequences –⁠ known as paramagnetic rim lesions (PRL) –⁠ contain accumulated iron at their edges and are considered a sign of chronic inflammation, but they are also present in the early stages of MS [41,46]. According to a recent meta-analysis, they have a prevalence of about 41% in patients with MS [47]. Another study followed patients with CIS and MS and compared them with a group of patients with diseases mimicking MS, finding PRL in 56% of patients with CIS or MS, but no such lesions were detected in patients in the group with other diseases [48].

 

In laboratory findings

OPs in cerebrospinal fluid are a generally recognized biomarker for MS. They are also significant in RIS and are reflected in the risk factors mentioned above. The finding of at least two OP in cerebrospinal fluid without correlation in serum (in the IgG spectrum) increases the risk of progression to clinical disease in children with RIS by almost 11 times [3], and slightly less in adults (10.3 times) [31]. Positive OP is found in up to 90% of patients with MS, 70% of patients with CIS, and 65% of patients with RIS [49].

Another established marker of demyelination is the kappa light chain index, which reflects the synthesis of free light chains (FLC) limited to the intrathecal space. Unlike OP, the determination of FLC is not dependent on the evaluator, as it is assessed immunochemically. A positive index has been shown to predict the development of new T2-hyperintense lesions in both RIS and CIS [49]. In addition, the kappa index has been shown to have better sensitivity than OP for the diagnosis of MS at a threshold value of 3.045, with slightly lower specificity [50]. A threshold value of 9.1 has better sensitivity and comparable specificity to OP [50]. The advantage is almost zero distortion in the event of blood contamination [51] or glomerular filtration disorder [52].

A recently studied biomarker is the light chain neurofilament (NfL) measured in both cerebrospinal fluid and blood, with the values correlating [53]. Elevated NfL levels in patients with RIS can predict disease activity and clinical conversion [54].

 

Other biomarkers

Optical coherence tomography (OCT) and the much newer optical coherence tomography angiography (OCT-A) image the optic nerve and its vascularization in the peripapillary area. In RS, both the nerve fiber layer according to OCT and the retinal vascular density on OCT-A are reduced compared to healthy individuals [55]. According to a study by Aly et al., the reduction in nerve fibers on OCT in patients with RIS also independently predicted clinical conversion [56].

 

Treatment of patients with radiologically isolated syndrome

The approach to RIS treatment is complex and the individual characteristics of the patient must always be considered. Two recent studies using disease-modifying drugs (DMDs) in patients with RIS have shown promising results in 2023. It is important to note that all published studies to date have used the 2009 criteria for the diagnosis of RIS.

 

Teriflunomide

The efficacy of teriflunomide in patients with RIS was evaluated in a randomized, double-blind, placebo-controlled, multicenter phase III study (TERIS) [57]. The study enrolled 89 individuals who were randomly assigned in a 1 : 1 ratio to receive teriflunomide 14 mg daily (n = 44) or placebo (n = 45) and followed for 96 weeks. The primary endpoint was the time to the first clinical attack or progression of neurological symptoms due to demyelinating CNS disease. The results showed that teriflunomide led to a 63% reduction in the risk of the first clinical attack compared to placebo (18% vs. 44%), with an unadjusted hazard ratio (HR) of 0.37 (95% confidence interval [CI] = 0.16–0.84; p = 0.02). After adjusting for factors such as gender, age at diagnosis, family history of MS, Expanded Disability Status Scale (EDSS) score, volume of T2-hyperintense lesions, and presence of Gd-enhancing lesions at baseline, the HR was even more favorable: 0.28 (95% CI = 0.11–0.71; p = 0.007). Although the number of new or enlarging T2-hyperintense lesions and Gd-enhancing lesions was lower in the treated group, the differences were not statistically significant. The study also included assessments of fatigue, cognitive function, and quality of life, but no significant differences between the groups were observed in these measures either.

 

Dimethyl fumarate

Dimethyl fumarate (DMF) was evaluated in a randomized, double-blind, placebo-controlled, multicenter phase III study (ARISE) [58]. The study included 87 patients who were randomly assigned to receive DMF 240 mg twice daily (n = 44) or placebo (n = 43). The follow-up period was 96 weeks and, as with teriflunomide, the primary endpoint was the time to the first clinical attack related to a demyelinating disease of the CNS. DMF led to a significant reduction in the risk of the first clinical attack by 82% (7 vs. 33%), with an unadjusted HR of 0.18 (95% CI = 0.05–0.63; p = 0.007). After statistical adjustment for demographic, clinical, and radiological factors, the HR was even lower at 0.07 (95% CI = 0.01–0.45; p = 0.005). In addition to a reduction in the risk of clinical attack, a lower number of new or enlarging T2-hyperintense lesions was also observed in patients treated with DMF (0.12 vs. 0.62; rate ratio = 0.20; 95% CI = 0.04–0.94; p = 0.042). In contrast, the change in the volume of T2-hyperintense lesions between the groups was not significant. In the following year, 2024, Professor Okuda's team added volumetric data (including total brain volume, thalamus volume, subcortical gray matter volume, three-dimensional volume of the brainstem and upper cervical spinal cord), with standardized MR examinations performed at the beginning and end of the ARISE study. In the DMF-treated group, a significant difference in brainstem atrophy (or curvature of the dorsal part of the pons) was observed in patients with RIS. The benefit of DMD in RIS can thus also be related to CNS structures that are affected by neurodegeneration, which is below the resolution of conventional volume measurements [59].

 

Ocrelizumab

The CELLO study was a multicenter, randomized, double-blind, placebo-controlled phase IV clinical trial that evaluated the efficacy of short-term treatment with ocrelizumab in patients with RIS. The study was designed to enroll 100 patients who would receive three doses of ocrelizumab or placebo and be followed for at least 3 years. The primary endpoint was similar to that of the TERIS and ARISE studies [60]. Unfortunately, according to the authors of this article, the CELLO study was terminated prematurely due to insufficient patient recruitment, and according to current information, there are no plans to resume it at this time.

 

Discussion

Controversy –⁠ who to treat and who to simply monitor?

One of the main questions in the context of RIS remains the decision on the timing and indication of treatment. While some of the studies mentioned show that early initiation of treatment can delay the onset of clinical symptoms in patients at high risk of conversion to clinical MS [6,58], others also point to the risk of overtreatment in patients with a benign course [20,32]. If the 15-year conversion prediction in patients with RIS (72%) is correct [61], hypothetically 28% of patients will not develop any symptoms within 15 years, and the quality of life associated with the use of the aforementioned DMDs must also be considered. In this case, a strategy of long-term monitoring without DMDs, both clinical and radiological, can be considered. Patients must also be well informed about the need to monitor for any signs of a clinical MS attack and to report these changes to their treating physician.

Risk stratification can thus be an essential tool for further decision-making. A study by Professor Lebrun-Frenay et al. [28] mentions that the 10-year risk of clinical conversion increases from 29% in the presence of one risk factor to 87% in the presence of four risk factors. The question remains whether RIS treatment should be recommended in the future based on this stratification rather than purely on the fulfillment of rigid diagnostic criteria. At present, it is therefore essential to have a detailed discussion with even asymptomatic patients and to take into account their age, attitude to treatment, plans for parenthood, and other individual factors when deciding on the next steps.

 

New McDonald criteria 2024 and redefinition of RIS: Is RIS the same as "preclinical" MS?

The proposed revision of the 2024 McDonald criteria, presented at ECTRIMS 2024 [23], pushes the boundaries of MS diagnosis even closer to the preclinical stages. The optic nerve area is now included as a possible fifth typical MS topography, as is the possibility of replacing evidence of dissemination over time with the presence of six or more CVS. If the proposal is accepted, it is assumed that most patients who would previously have fallen into the RIS category will now meet the criteria for an MS diagnosis. The question arises as to whether RIS will remain a separate nosological entity or rather become part of the broader diagnostic spectrum of MS. This development may have implications for both research (e.g., reinterpretation of previous RIS studies) and clinical practice, including reimbursement policies (e.g., allowing the use of highly effective treatments beyond the scope of the previously published ARISE and TERIS drug studies) and informed consent when initiating therapy in asymptomatic patients. At the same time, this weakens the argument for waiting for the first clinical attack, as even asymptomatic patients would now meet the criteria for MS. In this context, the treatment of "preclinical" MS is more a question of the risks versus benefits of DMD than clear diagnostic boundaries.

 

Lumbar puncture: is it losing its significance, or is it still crucial?

The current diagnostic strategy still recommends performing a lumbar puncture (LP) when RIS is suspected [6]. Findings in cerebrospinal fluid still have important prognostic value. The presence of OP in CSF not only increases the specificity of MR findings [31], but is also one of the strongest predictors of conversion to clinical MS (up to 11 times higher risk in children, 10 times higher in adults) [3,31]. In addition to OP, the FLC kappa index is also increasingly used, which has comparable sensitivity and is less subjective in evaluation [49]. Despite this, LP is perceived in some workplaces as an overly invasive and potentially unnecessary examination, especially in cases where the MR findings are completely typical. However, this is likely to change in view of the new diagnostic criteria for RIS and RS.

 

Are patients with RIS really without clinical manifestations, or are they just "poorly examined"?

Although the definition of RIS is based on the absence of clinical symptoms of demyelinating disease, there is growing evidence that some patients with this diagnosis show discrete neurological abnormalities that are not detected in routine clinical examinations. Studies have shown, for example, bimanual coordination disorders [62] or measurable cognitive deficits [41]. These symptoms may be overlooked unless a systematic and targeted examination of cognitive and fine motor functions is performed. In clinical practice, this means that a patient should not be categorized as asymptomatic without a thorough multidisciplinary examination. Furthermore, the mere presence of PRL on MRI in patients with RIS may indicate that neurodegeneration linked to progression independent of relapse activity (PIRA) is also observable in these seemingly asymptomatic patients.

 

Conclusion

This article summarises the current information and knowledge regarding the relatively new diagnostic entity of RIS, which, according to current knowledge, often precedes the development of the first clinical symptoms of MS and thus represents an early asymptomatic phase of this disease.

Changes in the understanding of MS as more than just a clinical diagnosis were clearly reflected in the latest proposed revision of the McDonald criteria from 2024. Given the blurring differences between the current diagnostic criteria for CIS and the newly prepared criteria for MS, and especially given their complexity, the question arises of a further future revision of the criteria, which would lead to the unification of both into a single concept of a kind of MS continuum, with the possible inclusion of other latest biomarkers. However, the gradual adaptation of new diagnostic methods in an effort to ensure the highest possible sensitivity and specificity carries with it the risk of increasing complexity, confusion, and time and financial demands. The challenge therefore remains to create a clear and transparent concept that takes into account the latest findings and is at the same time easily applicable in routine neurological practice. In addition, it will be necessary to resolve the very complex issue of the timing and initiation of specific treatment, which must be based on data from large-scale clinical studies, which are not yet available for this spectrum of patients.

 

Conflict of interest

The authors declare that they have no potential conflicts of interest regarding the drugs, products, or services used in this review.

 

Table 1. Comparison of criteria for radiologically isolated syndrome.

Criteria	2009 (according to Okuda et al. [13])	2023 (according to Lebrun-Frenay et al. [61])
Nature of lesions	Ovoid, well-defined, homogeneous, more than 3 mm long, not corresponding to vascular changes	Ovoid, well-defined, homogeneous, larger than 3 mm2  (with or without corpus callosum involvement), not corresponding to microvascular or nonspecific white matter changes
Possible locations of lesions	periventricular, juxtacortical, infratentorial	periventricular, juxtacortical (and cortical), infratentorial, spinal
Proof of DIS	Meeting at least 3 of the 4 Barkhof criteria [63]: ≥ 9 T2-hyperintense lesions or ≥ 1 Gd-enhancing lesion ≥ 1 juxtacortical lesion ≥ 1 infratentorial lesion ≥ 3 periventricular lesions	Fulfilling at least 3 of the 4 Barkhof criteria [63]: ≥ 9 T2-hyperintense lesions or ≥ 1 Gd-enhancing lesion ≥ 1 juxtacortical lesion ≥ 1 infratentorial lesion ≥ 3 periventricular lesions	OR	Fulfilling at least 1 of the 4 DIS criteria applicable to the 2017 McDonald criteria [22]: ≥ 1 periventricular lesion ≥ 1 juxtacortical/cortical lesion ≥ 1 infratentorial lesion ≥ 1 spinal lesion
				+
				Simultaneous fulfillment of 2 out of 3 conditions: OP positivity ≥ 1 spinal lesion evidence of DIT
Clinical findings	exclusion of history of relapsing symptoms correlating with the diagnosis of MS	Exclusion of relapsing or progressive symptoms correlating with the diagnosis of MS
Exclusion of other possible diagnoses	based on medical history or documentation	active exclusion of other diagnoses with a recommendation for further clarifying examinations –⁠ i.e. no other disease was identified that would better explain the findings on CNS MRI

DIS –⁠ dissemination in space; DIT –⁠ dissemination in time; Gd –⁠ gadolinium; OP –⁠ oligoclonal bands