Advances in Diagnosing Multiple Sclerosis

doctors discussing the diagnosis of a patient with ms
MRI is currently the most effective tool for making a diagnosis of multiple sclerosis.iStock

With multiple sclerosis (MS), it’s critical to be diagnosed as early as possible, so that treatment can begin and, ideally, stave off the progression of neurological damage and disability.

But this urgency presents a challenge for physicians, because there is currently no single test that results in a definitive diagnosis of MS. Add to that the fact that MS causes different symptoms in different people, and you’ll see that an accurate diagnosis is rarely straightforward and is largely a process of elimination.

In 2000, a set of criteria, known as the McDonald Criteria for the Diagnosis of Multiple Sclerosis, aimed to spell out what’s needed to accurately diagnose MS in people with clinically isolated syndrome (CIS), or a single episode of demyelination and the accompanying symptoms, which commonly include blurred vision or vision loss, numbness and tingling in the legs or face, and slurred speech.

Since then, the criteria have been refined to incorporate new research findings, expedite diagnosis, and avoid misdiagnosis. In late 2017, the fourth revision was published, appearing in the February 2018 issue of The Lancet Neurology.

It appears that the efforts to improve the process of diagnosing MS have paid off.

Changes to the diagnostic criteria for MS over the years coincide with a shorter average time to diagnosis and less progression to disability, according to a study published in October 2021 in Neurology.

Compared with study participants who received an MS diagnosis based on pre-McDonald diagnostic criteria from 1994, those diagnosed based on the 2017 revised guidelines saw a 77 percent reduction in time between CIS and their MS diagnosis, and an 82 percent reduction in time between CIS and starting MS treatment.

Over the entire study period, from 1994 to 2020, participants whose MS treatment began the earliest were 47 percent less likely to have an Expanded Disability Status Scale score of 3.0 or higher than those whose treatment began the latest.

Early Signs of Possible Multiple Sclerosis

MS is an autoimmune disease in which the immune system attacks the myelin sheaths that protect nerve fibers in the brain, spinal cord, and optic nerve — a process known as demyelination. The nerve fibers themselves may also be damaged or destroyed. This, in turn, slows or disrupts the transmission of nerve impulses from the brain, causing symptoms including fatigue, tingling and numbness, weakness, vision problems, and difficulty walking.

In recent years, there has been a fair amount of research documenting potential early warning signs of MS, before a person has any typical symptoms of the disease. These early signs and symptoms — for MS or any other disease — are known as a prodrome. Many diseases are known to have a prodrome, but the idea of an MS prodrome is based on somewhat recent discoveries. These signs and symptoms may occur during a “latent period” after demyelination has begun but before typical MS symptoms develop.

Two features of an MS prodrome that are widely recognized include having a single episode of MS-like symptoms, called clinically isolated syndrome, or having abnormal findings on an MRI but no MS symptoms, called radiologically isolated syndrome. These syndromes may or may not indicate that a person will develop MS. Researchers are still learning how best to predict the risk of developing MS when a person has one of these syndromes — or other possible features of an MS prodrome.

Clinically Isolated Syndrome (CIS) This refers to a first episode of neurologic symptoms that lasts at least 24 hours and is caused by inflammation or demyelination in the central nervous system (CNS). CIS can be monofocal, in which the person experiences a single neurologic sign or symptom — for example, an attack of optic neuritis — that’s caused by a single lesion. Or it can be multifocal, in which the person experiences more than one sign or symptom — for example, an attack of optic neuritis accompanied by numbness or tingling in the legs — caused by lesions in more than one place.

Right now, CIS is considered a minimum requirement for an MS diagnosis, although many people have multiple episodes of neurologic symptoms before MS is diagnosed.

Radiologically Isolated Syndrome (RIS) In this case, findings on an MRI done for other reasons reveal lesions indicative of MS, but the person has no symptoms. As with CIS, someone with RIS may not go on to develop MS.

“RIS, CIS, established relapsing-remitting MS, and secondary-progressive MS are better thought of as stages of MS through which patients evolve,” says Jeffrey Cohen, MD, director of the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic in Ohio, and co-chair of the international panel that developed the 2017 McDonald Criteria.

“RIS is an MRI highly suggestive of MS, but the person has no symptoms. CIS is the first attack. So, although one might suspect MS at the time of RIS and CIS, at that point the diagnosis is not yet certain,” Dr. Cohen says.

Other Prodromal Features The existence of features other than CIS and RIS that indicate an MS prodrome is still an unsettled topic, but there has been research pointing to other potential warning signs, summarized in an article published in June 2021 in Nature Reviews Neurology.

For example, people who go on to develop MS tend to seek out or require more healthcare services in general in the years leading up to their MS diagnosis. This is true for a wide range of health issues, including mental health problems, fatigue, pain, bowel problems, and bladder problems.

Studies have also shown that cognitive performance may be lower in people who go on to develop MS, and that men who develop MS are more likely to have anemia (inadequate red blood cells). People who go on to develop relapsing-remitting MS, in particular, may be more likely to see a dermatologist for skin problems in the years leading up to their diagnosis — possibly an indication of inflammation related to the MS disease process.

Tests Used to Diagnose Multiple Sclerosis

Several tests may be used to arrive at a diagnosis of MS, including:

  • Family and Medical History If other members of your family have had MS or another autoimmune disease, you are more prone to MS than the general population.
  • Neurologic Evaluation Your doctor will perform tests to evaluate your movement and coordination, vision, balance, and mental and emotional functioning.
  • Blood Tests While there is no definitive blood test for MS, certain tests can help rule out other conditions that may cause symptoms similar to those of MS, including Lyme disease, a group of diseases known as collagen-vascular diseases, certain rare hereditary disorders, and AIDS.
  • Magnetic Resonance Imaging (MRI) MRI scans use magnetic fields and radio waves to detect lesions in the brain that are indicative of MS. MRI is currently the most effective tool for making an MS diagnosis.
  • Cerebrospinal Fluid (CSF) Analysis For this test, a few tablespoons of spinal fluid are drawn from between the lower vertebrae with a syringe. The spinal fluid of people with MS usually contains elevated levels of certain antibodies, as well as a group of proteins called oligoclonal bands, which indicate there’s inflammation in the central nervous system. There may also be certain proteins that are the breakdown products of myelin. Not all people with MS have these CSF abnormalities.

Implications of the New McDonald Criteria

Given the importance of early diagnosis and treatment, “catching” CIS is important, and this is where the McDonald Criteria come in. The most recent changes to the criteria involve the interpretation of MRIs and CSF tests.

The standard criteria for making an MS diagnosis includes all of the following:

  • Evidence of damage in at least two separate areas of the central nervous system (CNS), which includes the brain, spinal cord, and optic nerves
  • Evidence that CNS damage occurred at different points in time
  • Ruling out all other possible diagnoses

The key changes in the new McDonald Criteria include:

  • Oligoclonal bands can substitute for CNS damage “occurring at different points in time”
  • Allowing both asymptomatic and symptomatic MRI lesions to be considered when determining the number of lesions and when they occurred
  • Including lesions in the brain’s outer layer, or cortex (called cortical lesions), as well as those next to the cortex (juxtacortical) when determining MRI criteria for how many lesions are visible

Cohen points out that even with the new criteria, MS remains a clinical diagnosis — not a laboratory or imaging-based diagnosis — and that researchers continue to pursue ways to improve upon the existing diagnostic tools.

“Current research is focusing on developing a blood test that would ideally turn up an abnormality found in people with MS,” he says. “We still very much need something like that so that we can make a definitive diagnosis.”

How Doctors Determine What Type of Multiple Sclerosis a Person Has

Just as with the initial process of diagnosing MS, there is no single test or measurement used to determine what type of MS someone has. In general, the type of MS is determined by observing patterns in symptoms and disability, although MRI findings can also be used to support this determination.

The main types of MS include:

  • Relapsing-Remitting Multiple Sclerosis (RRMS) In relapsing-remitting MS, symptoms tend to flare periodically, followed by stretches of complete or partial recovery. The vast majority — about 85 percent — of people with MS are initially diagnosed with RRMS.
  • Primary-Progressive Multiple Sclerosis (PPMS) People with primary-progressive MS experience steadily worsening symptoms with few or no recovery periods. Nerve damage is generally more focused in the spinal cord than in the brain, and it can cause more significant disability than is typical of RRMS. About 10 to 15 percent of people with MS are diagnosed with PPMS.
  • Secondary-Progressive Multiple Sclerosis (SPMS) Most people with RRMS eventually progress to secondary-progressive MS, which involves a consistent worsening of symptoms. Flare-ups (periods of intensifying symptoms, also known as relapses or exacerbations) may occur, but they are less frequent than with RRMS.

Tests and Biomarkers for Predicting Disability and Multiple Sclerosis Progression

One focus of MS research in recent years has been finding ways to better predict the course of the disease in a given person, using various functional and imaging tests as well as biomarkers (measurements of substances in the body or other observable signs).

The search for better biomarkers to predict MS progression involves looking at levels of potentially thousands of different proteins, other chemicals, and cell types produced by the body — and comparing these measurements in people with different levels of MS progression or disability to those in people without MS.

One area of tests that may be especially promising for predicting MS progression and disability — and detecting any improvement in nerve function — is known as evoked potentials. These tests look at how electrical signals are transmitted in a specific area of the nervous system, in response to an activity or outside stimulation. Some researchers believe that these tests should play a larger role in evaluating experimental MS treatments in clinical trials, as well as in selecting who is eligible for trials of potential treatments.

Many of the tests used to help diagnose MS — including MRI and cerebrospinal fluid (CSF) tests — may also be used to help predict or evaluate disease progression, and they are the subject of ongoing studies in this area. Other tests and biomarkers that may hold promise for predicting and evaluating disease progression and disability include the following:

  • Sensory Evoked Potentials This category of tests measures how electrical signals travel along nerve pathways in response to visual, auditory, or electrical stimulation. Delays in transmission of these signals can indicate damaged myelin in different areas of the body, which may help predict disability in these areas. A visual evoked response test can show damage to the optic nerves, which may affect vision. A brainstem auditory evoked response test can help detect brain damage, which may affect hearing and other functions. And a somatosensory evoked response test can point to spinal cord damage, which may cause numbness or functional limitations in your arms or legs.
  • Motor Evoked Potentials This category of test looks at how electrical signals travel along nerve pathways in response to physical activity, usually involving movement of the arms or legs.
  • Optical Coherence Tomography (OCT) This type of test provides images of the eye’s internal structures using light waves. A version of the test called spectral-domain OCT can provide especially detailed images of the retina, which have been shown to help predict worsening of general disability scores in people with MS, according to a study published in April 2021 in Neurology.

  • Neurofilaments These proteins are released when nerve damage occurs, and they can be found in CSF as well as blood. A practical blood test for neurofilament light has been developed only recently, and this measurement has been shown to correlate with both disability and brain atrophy in people with MS, as described in an article published in December 2019 in the Journal of Neuroinflammation.

  • Genetic Tests While many different genetic variants have been shown to affect immune system regulation, no single gene has been shown to correlate meaningfully with MS type or progression. Researchers are investigating how patterns of multiple genes may help predict the course of MS.

Additional reporting by Quinn Phillips.

Editorial Sources and Fact-Checking

Everyday Health follows strict sourcing guidelines to ensure the accuracy of its content, outlined in our editorial policy. We use only trustworthy sources, including peer-reviewed studies, board-certified medical experts, patients with lived experience, and information from top institutions.

Sources

  1. Diagnosis of Multiple Sclerosis: 2017 Revisions of the McDonald Criteria. The Lancet Neurology.
  2. Effects of Changes in MS Diagnostic Criteria Over 25 Years on Time to Treatment and Prognosis in Patients With Clinically Isolated Syndrome. Neurology.
  3. Multiple Sclerosis: A Treatable Disease. Clinical Medicine (London).
  4. Clinical Course of Multiple Sclerosis. Cold Spring Harbor Perspectives in Medicine.
  5. The Multiple Sclerosis Prodrome. Nature Reviews Neurology.
  6. CSF Oligoclonal Banding. Medline Plus.
  7. Association of Spectral-Domain OCT With Long-Term Disability Worsening in Multiple Sclerosis. Neurology.
  8. Molecular Biomarkers in Multiple Sclerosis. Journal of Neuroinflammation.

Resources

Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of Multiple Sclerosis: 2017 Revisions of the McDonald Criteria. The Lancet Neurology. February 1, 2018.

Tintore M, Cobo-Calvo A, Carbonell P, et al. Effects of Changes in MS Diagnostic Criteria Over 25 Years on Time to Treatment and Prognosis in Patients With Clinically Isolated Syndrome. Neurology. October 26, 2021.

Doshi A and Chataway J. Multiple Sclerosis, a Treatable Disease. Clinical Medicine (London). December 2016.

Klineova S and Lublin F. Clinical Course of Multiple Sclerosis. Cold Spring Harbor Perspectives in Medicine. September 2018.

Makhani N and Tremlin H. The Multiple Sclerosis Prodrome. Nature Reviews Neurology. June 21, 2021.

CSF Oligoclonal Banding. MedlinePlus. January 12, 2022.

Lambe J, Fitzgerald KC, Murphy OC, et al. Association of Spectral-Domain OCT With Long-Term Disability Worsening in Multiple Sclerosis. Neurology. April 20, 2021.

Ziemssen T, Akgün K, and Brück W. Molecular Biomarkers in Multiple Sclerosis. Journal of Neuroinflammation. December 23, 2019.

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