Radiologically Isolated Syndrome

Radiologically Isolated Syndrome (RIS) occurs when brain or spinal cord scans reveal abnormalities characteristic of multiple sclerosis, yet the person experiences no neurological symptoms. This unexpected discovery creates both uncertainty and opportunity for early monitoring and possible intervention.

Table of contents

• What is Radiologically Isolated Syndrome?
• Symptoms and Clinical Presentation
• Causes and Risk Factors
• How is RIS Diagnosed?
• Relationship to Multiple Sclerosis
• Treatment and Management
• Outlook and Prognosis

What is Radiologically Isolated Syndrome?

Radiologically Isolated Syndrome (RIS) is diagnosed when central nervous system (brain and spinal cord) white matter abnormalities characteristic of multiple sclerosis are incidentally found on MRI (magnetic resonance imaging) scans without relapsing or progressive symptoms typical of inflammatory demyelination (damage to the protective coating around nerves).^[1]

The increased use of brain MRI in multiple settings has led to more frequent discovery of such unexpected findings. RIS is often identified when imaging studies are performed for unrelated reasons, such as headaches, head trauma, dizziness, or during research studies in healthy individuals.^[1][3] These white matter lesions appear similar to what is seen in patients with multiple sclerosis, but the person is not experiencing any typical physical or neurological symptoms associated with that condition.^[2]

While the exact prevalence of RIS remains unknown, incidentally found white matter lesions resembling demyelination occur in 0.1% to 0.7% of the general population.^[3] The incidence of RIS has been estimated at 0.8 per 100,000 person-years in a Swedish cohort, compared with the 10.2 per 100,000 person-year incidence of multiple sclerosis.^[3]

Symptoms and Clinical Presentation

Patients with RIS generally do not experience symptoms and are considered asymptomatic.^[2] This absence of symptoms is what distinguishes RIS from other conditions affecting the central nervous system.

Initial studies of RIS required the diagnosis to be made when MRI studies were obtained in a truly incidental fashion. However, more recently, the definition has widened to also include individuals presenting with symptoms in the absence of a typical clinical event or true neurological progression. These symptoms can include heat intolerance, mood disorders, cognitive dysfunction, and paroxysmal symptoms (sudden, short-lived episodes).^[1]

These symptoms partially overlap with those in the so-called “MS prodrome” and may simply reflect an early form of the disease. However, many of these symptoms are relatively nonspecific, so the relationship with RIS is not always clear.^[1]

Causes and Risk Factors

There is increasing evidence that the disease process of multiple sclerosis often begins in advance of clinical symptoms. There have been documented cases of lesions consistent with MS being discovered at autopsy in individuals who had no clinical symptoms during their lifetime.^[6] Emerging data have shown increased healthcare utilization and elevated serum neurofilament light chain levels (a biomarker of nerve damage) in people who go on to develop MS up to 5 to 6 years before the clinical onset of disease, suggesting that a prodromal state exists in some individuals.^[6]

Since the risk of multiple sclerosis is significantly higher when a parent has been diagnosed with the disease, genetic factors may play a role. The unusual relationship between a person’s geographic location during childhood and the risk of multiple sclerosis later in life suggests that there may be environmental factors at work in the disease.^[2]

How is RIS Diagnosed?

Diagnosis of RIS often occurs during diagnosis of another unrelated condition, such as migraine headaches or trauma to the area.^[2] After a brain abnormality is observed on an MRI, the physician will typically take a detailed medical history and perform a neurological examination.^[2]

Stringent criteria must be met to diagnose RIS. 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 multiple sclerosis.^[1]

The inclusion criteria require MRI with incidental central nervous system white matter abnormalities demonstrating radiological characteristics highly suggestive of demyelinating disease. These abnormalities must be ovoid, well-circumscribed, and homogeneous foci greater than 3 mm² with or without the involvement of the corpus callosum (the structure connecting the two brain hemispheres). They must involve periventricular (around the fluid-filled spaces in the brain), juxtacortical (near the outer layer of the brain), infratentorial (lower part of the brain), and spinal cord regions. The abnormalities must be inconsistent with microvascular or nonspecific white matter disease patterns.^[1]

The index MRI must fulfill three or four out of four dissemination in space criteria according to the 2005 multiple sclerosis diagnostic imaging criteria. Alternatively, if the index MRI fulfills at least one of four dissemination in space requirements, it must additionally fulfill two of the following: presence of abnormal cerebrospinal-fluid restricted oligoclonal bands (proteins indicating immune system activity), presence of at least one spinal cord lesion consistent with inflammatory demyelination, or 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.^[1]

Additionally, there must be no historical account of relapsing-remitting or progressive clinical symptoms consistent with neurological dysfunction. MRI abnormalities or neurological examination findings must not account for clinically apparent impairments to the individual, and another disease process must not have been identified to better account for the central nervous system MRI abnormalities.^[1]

Because RIS is often asymptomatic, accurately diagnosing the condition can be difficult. Newer imaging methods that allow the medical team to see if blood vessels are running through the lesions, a distinguishing feature of multiple sclerosis, can help in making a more accurate diagnosis.^[2]

The patient’s medical team may also order a lumbar puncture, also known as a spinal tap, and cerebrospinal fluid analysis, as well as nerve function tests. Blood tests may be performed to rule out other conditions that have similar symptoms.^[2]

Relationship to Multiple Sclerosis

Although there is a strong association between RIS and multiple sclerosis, being diagnosed with RIS does not mean a patient will always be diagnosed with MS.^[2] Multiple sclerosis is a disease of the central nervous system (brain, spinal cord and optic nerve). This disorder causes destruction of the coating (myelin) that surrounds and protects nerve fibers (axons). As a result, the damage disrupts the normal flow of messages (nerve impulses) from the central nervous system, causing a reduction or loss of body function.^[2]

When followed over a two-year period, one third of patients with RIS develop a neurological event and are diagnosed with MS, one third develop a new finding on MRI without any symptoms, and one third show no change.^[2] A subset of patients with RIS will develop clinical manifestations of multiple sclerosis over time.^[1]

Longitudinal evaluation revealed that people with RIS had a 13.8% chance of converting to clinically definite MS within a 2-year time period, increasing to 34% at 5 years and 51.2% at 10 years.^[6]

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.^[1]

RIS currently represents the earliest detectable preclinical phase of multiple sclerosis. At the start of the first macroscopic change, a single focus of high-signal abnormality within the brain or spinal cord that is observable on MRI may follow in the absence of symptoms. The subsequent development of additional lesions may follow and be identified incidentally on MRI.^[10]

Treatment and Management

There is no cure for RIS and depending on the patient’s history, MRI results and condition, observation may be the only treatment necessary.^[2] Patients diagnosed with RIS will have routine checkups to see if their condition is progressing toward multiple sclerosis.^[2]

Substantial challenges exist in determining the best management approach. This mainly stems from the uncertainty surrounding which people with RIS will go on to develop clinical MS, because some of these individuals remain clinically asymptomatic throughout their lifetime.^[6]

There are no established consensus guidelines to assist clinicians in navigating the care of individuals with RIS, but two management strategies are often used: a strategy which includes regular MRI scans and clinical surveillance, and a strategy of early disease-modifying therapy (DMT) initiation.^[6]

Remarkable advancements have been recently made, including the identification of risk factors for disease evolution, revisions to the existing 2009 RIS criteria, and understanding of the impact of early disease-modifying therapy use in the prevention or delay of symptomatic MS from two randomized clinical trials.^[10]

Outlook and Prognosis

RIS provides a serendipitous window into early, preclinical disease and allows for prospective identification of at-risk individuals.^[6] However, having RIS does not necessarily mean a person will develop multiple sclerosis. It may be an early sign in some cases but not all. Scientists are still trying to understand how relevant RIS is to the diagnosis of neurological conditions.^[4]

The 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.^[1]

Patients may only partially meet diagnostic criteria. These individuals, despite not meeting the strict criteria for RIS, have MRI abnormalities suspicious for demyelinating disease and require careful clinical follow-up.^[1]

• Brain
• Spinal cord
• Central nervous system white matter
• Corpus callosum
• Periventricular regions