Radiologically Isolated Syndrome & Clinically Isolated Syndrome

Radiologically isolated syndrome (RIS) and clinically isolated syndrome (CIS) represent the earliest recognized stages of the multiple sclerosis (MS) disease spectrum. Understanding these entities is crucial for risk stratification, early treatment decisions, and preventing both overdiagnosis and undertreatment. The 2024 McDonald criteria now formally include RIS within the MS diagnostic framework, marking a paradigm shift toward recognizing MS as a biological continuum that begins before the first clinical attack.

Clinically Isolated Syndrome (CIS)

Definition and Clinical Features

CIS is defined as a first clinical episode with features suggestive of inflammatory CNS demyelination, lasting at least 24 hours, in the absence of a prior history of such events. Typical CIS presentations include:

• Optic neuritis — unilateral visual loss with eye pain; the most common CIS presentation (~25% of all MS initial presentations)
• Partial transverse myelitis — unilateral sensory or motor symptoms, often with a sensory level; bladder/bowel dysfunction may accompany
• Brainstem/cerebellar syndrome — diplopia (INO, sixth nerve palsy), vertigo, ataxia, nystagmus
• Hemispheric syndrome — sensory symptoms in a CNS pattern, hemiparesis (less common initial presentation)

Objective neurologic findings on examination corresponding to the reported symptoms are required. Symptoms such as fatigue, cognitive dysfunction, and mood changes in isolation do not qualify as CIS, though they may accompany a typical attack.

Diagnostic Workup for CIS

Conversion from CIS to MS

The likelihood of converting from CIS to clinically definite MS depends heavily on MRI findings at presentation:

Additional factors associated with higher conversion risk include younger age, gadolinium-enhancing lesions, infratentorial or spinal cord lesions, and higher lesion burden.

CIS Under the 2024 McDonald Criteria

With the 2024 revisions, many patients who would previously have been classified as CIS can now be diagnosed with MS at their initial presentation. The expanded criteria include:

• Optic nerve as a fifth DIS location (via OCT, VEP, or MRI)
• DIS plus positive CSF (OCBs or kFLC index) is sufficient — DIT no longer required
• Typical lesions in ≥4 of 5 anatomical locations is sufficient for diagnosis
• CVS (select 6) or PRLs can provide additional diagnostic confirmation

This means that the diagnostic category of CIS is shrinking, as many patients with a single attack will meet MS criteria earlier. However, patients who have a typical attack but do not fully meet the expanded criteria should still be classified as CIS, monitored closely, and have diagnostic criteria revisited over time.

Treatment Considerations in CIS

Multiple randomized controlled trials (CHAMPS, ETOMS, BENEFIT, PreCISe, REFLEX) have demonstrated that early DMT initiation in CIS delays the time to a second attack and reduces the risk of conversion to clinically definite MS. Benefits include:

• Reduced relapse rate and new MRI lesion formation
• Delayed disability accumulation in some studies
• The greatest benefit is seen in patients with higher baseline lesion burden and positive CSF

Treatment decisions should be individualized based on prognostic features, patient preferences, family planning considerations, and risk-benefit assessment of available DMTs.

Radiologically Isolated Syndrome (RIS)

Definition

RIS refers to the incidental discovery of CNS white matter anomalies on MRI that are morphologically and topographically suggestive of MS, in the absence of current or historical clinical symptoms of inflammatory demyelination. RIS typically comes to attention when brain MRI is performed for an unrelated indication (e.g., headache, trauma, psychiatric symptoms).

Diagnostic Criteria for RIS

• Ovoid, well-circumscribed, and homogeneous foci, with or without corpus callosum involvement
• T2 hyperintensities measuring >3 mm, fulfilling DIS criteria
• No historical symptoms consistent with neurologic dysfunction due to demyelination
• MRI anomalies do not account for clinically apparent functional impairment
• Findings not attributable to substances, medical conditions, or leukoaraiosis
• No better explanation by another disease process

Risk of Developing MS

Approximately 51% of individuals with RIS develop clinical symptoms within 10 years of follow-up. Risk factors for developing MS from RIS include:

The cumulative number of risk factors directly correlates with both the probability and timing of developing clinical MS.

RIS Under the 2024 McDonald Criteria

The 2024 McDonald criteria represent a landmark change by incorporating RIS into the MS diagnostic framework. Individuals with RIS can now be diagnosed with MS when DIS is demonstrated plus any of the following:

This framework also applies to patients with non-specific neurological presentations (e.g., paroxysmal symptoms, seizures, trigeminal neuralgia) who do not have a clear typical attack but whose imaging is highly suggestive of MS.

The MS Prodrome

Studies from multiple regions have demonstrated that 5–10 years before the clinical diagnosis of MS, patients exhibit:

• Higher utilization of healthcare services (more visits to GPs and specialists)
• Increased use of prescription medications
• A constellation of nonspecific symptoms: pain, headache, fatigue, mood symptoms
• Elevated serum neurofilament light chain levels up to 6 years before diagnosis

The MS prodrome suggests that pathophysiologic processes are active years before the first recognized typical clinical event. Whether the diagnostic framework should eventually include a "prodromal" stage of MS (analogous to prodromal Parkinson disease or preclinical Alzheimer disease) is an area of active investigation and may be revisited in future criteria revisions.

Solitary Sclerosis

Solitary sclerosis describes individuals with a single "critical" CNS demyelinating lesion causing progressive neurologic decline without meeting MS criteria due to the paucity of lesions. These patients often have a course suggestive of progressive MS but cannot be formally classified under current criteria. With the emergence of therapies targeting progressive MS, the question of whether solitary sclerosis should be included in the MS spectrum is clinically relevant and under ongoing study.

Disease Continuum Model

Increasing evidence supports a model of MS as a continuum rather than distinct stages:

References

1. Oh J. Diagnosis of multiple sclerosis. Continuum (Minneap Minn). 2022;28(4):1006-1024.
2. Montalban X, Lebrun-Frénay C, Oh J, et al. Diagnosis of multiple sclerosis: 2024 revisions of the McDonald criteria. Lancet Neurol. 2025;24:850-865.
3. Okuda DT, Mowry EM, Beheshtian A, et al. Incidental MRI anomalies suggestive of multiple sclerosis: the radiologically isolated syndrome. Neurology. 2009;72(9):800-805.
4. Lebrun-Frenay C, Kantarci O, Siva A, et al. Radiologically isolated syndrome: 10-year risk estimate of a clinical event. Ann Neurol. 2020;88(2):407-417.
5. Wijnands JMA, Zhu F, Kingwell E, et al. Prodrome in relapsing-remitting and primary progressive multiple sclerosis. Eur J Neurol. 2019;26(7):1032-1036.
6. Bjornevik K, Munger KL, Cortese M, et al. Serum neurofilament light chain levels in patients with presymptomatic multiple sclerosis. JAMA Neurol. 2020;77(1):58-64.