Clinically isolated syndrome (CIS)

Last updated Sept. 7, 2022, by Marisa Wexler, MS
Fact-checked by Ines Martins, PhD

Multiple sclerosis (MS) is caused by the immune system launching an abnormal response that targets and damages myelin, the fatty coating around nerve cells that helps in the rapid transmission of nerve signals. Based on how its signs and symptoms present and evolve over time, the disorder is classified into four types.

Most MS patients initially present with a relapsing-remitting course, characterized by flare-ups where symptoms suddenly worsen, followed by periods of remission when symptoms ease and are generally stable. Clinically isolated syndrome, or CIS, is the first episode of neurological symptoms suggestive of MS.

What is clinically isolated syndrome?

To be diagnosed with overt MS, a person must experience multiple episodes of symptoms attributed to inflammation and loss of myelin (demyelination) in the central nervous system, which includes the brain, spinal cord, and optic nerves.

CIS is defined as a first attack of MS-like symptoms lasting at least 24 hours and not explained by fever or infections. After that first episode, symptoms tend to disappear partially or completely.

Some people with CIS will go on to have further episodes of symptoms, at which point they may be diagnosed with true MS. However, for reasons that are not fully understood, not all people with CIS will go on to develop MS.

CIS can develop at any age, but it most commonly occurs in people between the ages of 20 and 40. It is two to three times more common in women than in men.

Symptoms of CIS

Every patient has a different experience with CIS, but symptoms of this disease stage are generally similar to what can occur in an MS relapse. Common symptoms include:

• fatigue
• dizziness, vertigo, or nausea
• numbness, tingling, or other abnormal sensations
• vision problems
• muscle weakness
• spasticity and muscle stiffness
• bladder and bowel problems
• impaired cognition

Depending on the disease symptoms experienced during the attack, CIS can be classified as monofocal or multifocal. As the terms suggest, monofocal typically references a single disease symptom, while multifocal describes the presence of more than one symptom.

In monofocal disease, a person experiences symptoms caused by lesions, or areas of nerve cell damage, in a single region of the central nervous system — for example, vision problems due to inflammation in the optic nerves, termed optic neuritis.

In multifocal CIS, on the other hand, multiple symptoms are present simultaneously, due to the presence of lesions in several areas of the central nervous system.

How long does CIS last?

Historically, more than 60% of people with CIS have progressed to clinically definite MS in the first decade, and 80% within 20 years of disease onset. However, not all CIS patients will go on to be diagnosed with MS, and the time to progression varies widely for reasons that are still not completely understood.

The likelihood of developing MS is greater in patients with brain lesions at the time of their CIS diagnosis (60%-90% chance), compared with those with clear MRI scans. Those with MRIs not showing a lesion have a 20% chance of progressing to MS.

Other factors that also have been linked with an increased risk of progression to MS from CIS include:

• female sex
• younger age at CIS onset
• smoking
• low vitamin D levels
• more brain and spinal cord lesions on MRI scans
• markers of inflammation in the blood and spinal fluid
• certain disease symptoms, particularly motor dysfunction, cognitive impairment, and fatigue

A number of disease-modifying treatments are now available to help delay the progression to MS. However, it is too soon to tell the degree to which modern therapies impact that transition.

Diagnosis of CIS

There is no single test to diagnose CIS, or to confirm the progression from CIS to MS. In addition to evaluations of symptoms, neurological examinations and tests like MRI scans and lumbar puncture may be helpful in establishing the diagnosis and ruling out other potential causes of symptoms.

The formal guidelines used to diagnose MS, called the McDonald criteria, state that for people living with CIS to be diagnosed with MS, they must show evidence of inflammatory myelin damage that fulfills two diagnostic criteria:

• dissemination in space, meaning damage that affects multiple parts of the central nervous system
• dissemination in time, or inflammation that occurs at multiple points in time

Someone who experiences only one episode of neurological symptoms is generally considered to have CIS unless or until doctors find more evidence of definite MS. This evidence can come in the form of a second relapse, but additional flare-ups aren’t always needed for patients with CIS to be diagnosed with true MS.

In fact, a diagnosis of MS can be made right away in someone initially suspected of having CIS if brain imaging reveals signs of older and new lesions in different areas of the central nervous system. Such evidence would indicate there was a previous relapse affecting a different region.

This also is true if patients test positive for oligoclonal bands in their spinal fluid. These bands are inflammatory proteins found in the liquid surrounding the brain and spinal cord and are a well-defined risk factor for future relapses in people with CIS.

Under the recently updated McDonald guidelines, more people now are being diagnosed earlier with MS, and fewer are receiving a diagnosis of CIS, according to research.

Treatment of CIS

In many cases, the initial episode of disease symptoms that define CIS is mild enough that patients don’t require immediate treatment. Indeed, many individuals recover completely without therapeutic intervention. If symptoms cause substantial problems in daily life, however, glucocorticoids that help resolve the inflammation may be given to speed the resolution of the attack. These hormones have powerful anti-inflammatory and immunosuppressive properties.

Although CIS cannot be cured, a number of DMTs are available that can reduce the likelihood of new relapses or brain lesions and delay the progression from CIS to other relapsing forms of MS. These therapies also can reduce the severity of subsequent relapses in patients who do progress.

DMTs approved for CIS in the U.S. include:

• Aubagio (teriflunomide)
• Avonex (interferon beta-1a)
• Bafiertam (monomethyl fumarate)
• Betaseron (interferon beta-1b)
• Copaxone (glatiramer acetate injection)
• Extavia (interferon beta-1b)
• Gilenya (fingolimod)
• Kesimpta (ofatumumab)
• Mayzent (siponimod)
• Ocrevus (ocrelizumab)
• Plegridy (peginterferon beta-1a)
• Ponvory (ponesimod)
• Rebif (interferon beta-1a)
• Tecfidera (dimethyl fumarate)
• Tysabri (natalizumab)
• Vumerity (diroximel fumarate)
• Zeposia (ozanimod)

Because not all people with CIS will go on to develop MS, a decision about whether or not to receive disease-modifying therapies requires careful consideration and conversations with a person’s care team.

Patients should be educated about their likelihood of conversion and about the potential risks and advantages associated with starting DMTs early on in the disease course. Considerations about costs and the need for long-term treatment also are recommended.

Outlook of CIS

The prognosis of CIS varies from person to person — some people with CIS will quickly progress to MS, while others may go years or even decades without experiencing another attack or having evidence of new lesions.

When a person is diagnosed with CIS, it’s recommended the individual talk with doctors and other healthcare providers to develop a treatment and care plan. In addition to DMTs, which can reduce the risk of progressing to MS, this may include medication to manage individual symptoms, and lifestyle changes like adjusting diet, quitting smoking, or exercising frequently.

Multiple Sclerosis News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.