Introduction: Who Should Undergo Diagnostics and When

If you have been diagnosed with multiple sclerosis, understanding when you might be experiencing a relapse is an important part of managing your condition. A relapse, also called an exacerbation, attack, flare-up, or episode, happens when new symptoms appear or existing symptoms become significantly worse due to inflammation in your central nervous system.^[1] Not every change in how you feel means you are having a relapse, which is why knowing when to seek medical evaluation is so important.

You should contact your healthcare provider if you notice new neurological symptoms or a clear worsening of symptoms you already experience. These changes need to last for at least 24 hours without any signs of fever or infection before they can be considered a true relapse.^[3] The symptoms typically develop quickly, usually over hours or days, rather than appearing suddenly in seconds or gradually over many weeks.^[12]

Relapses are most common in people with relapsing-remitting MS, which affects about 80% to 85% of people diagnosed with multiple sclerosis.^[2] They can also occur in people with secondary progressive MS, though less frequently. People with primary progressive MS generally do not experience relapses, although they may notice day-to-day fluctuations in their symptoms.^[3]

When you first receive an MS diagnosis, it can be difficult to distinguish between a relapse and the normal ups and downs of the condition. Many MS symptoms naturally fluctuate from day to day, so not every change represents a new attack on your nervous system.^[4] With time and experience, you will develop a better sense of what is normal variation for you and what might signal a relapse requiring medical attention.

Several factors can temporarily worsen MS symptoms without actually causing a relapse. These situations, called pseudoexacerbations or pseudo-relapses, occur when old symptoms reappear or worsen due to external triggers rather than new inflammation in the nervous system.^[8] Common triggers include infections like urinary tract infections or sinus infections, fever, heat exposure, physical exhaustion, stress, and depression.^[2] Once the underlying trigger is identified and treated, the symptoms typically return to their previous baseline level.

Diagnostic Methods for Identifying a Relapse

The diagnosis of an MS relapse primarily relies on careful clinical evaluation by your healthcare provider. There is no single test that definitively confirms you are having a relapse. Instead, your doctor will gather information through several methods to determine whether your symptoms represent true new inflammation or another cause.

Clinical History and Symptom Assessment

Your doctor will start by asking detailed questions about your symptoms. For symptoms to be considered part of a true relapse, they must meet specific criteria. The symptoms should be new or represent a clear worsening of existing symptoms that you experience continuously.^[4] They need to have been present for at least 24 hours, though most relapses last for days, weeks, or even months.^[3]

Another important criterion is timing. At least 30 days should have passed since the start of your last relapse, meaning your MS symptoms should have been relatively stable for about a month before new changes occur.^[4] This helps distinguish a new relapse from ongoing symptoms from a previous attack that have not yet fully resolved.

Your doctor will also want to make sure there is no other explanation for your symptoms, such as an infection, heat exposure, stress, or other medical conditions.^[4] This is why identifying and ruling out pseudoexacerbations is such an important part of the diagnostic process.

Common symptoms that might appear or worsen during a relapse include vision changes such as blurry vision, double vision, or painful eye movement; tingling or numbness in various parts of your body; a sensation of squeezing around your chest or abdomen; fatigue; bladder or bowel problems; difficulty walking; muscle weakness or stiffness; and cognitive difficulties described as brain fog.^[2] It is common to experience a combination of symptoms during a relapse rather than just a single isolated symptom.

Physical and Neurological Examination

After discussing your symptoms, your healthcare provider will perform a physical and neurological examination. This examination looks for objective signs of neurological problems that correspond to the symptoms you are describing. The doctor will test various functions including your vision, eye movements, muscle strength, coordination, balance, sensation, and reflexes.

In the context of an established MS diagnosis, if your new symptoms are typical of those caused by MS and there are no signs suggesting another condition, additional testing may not be necessary.^[12] However, when symptoms are atypical or unusual for a relapse, further investigation becomes important.

Laboratory Testing

When your doctor suspects a pseudoexacerbation or needs to rule out other causes for your symptoms, laboratory tests become helpful. Basic blood work and urinalysis are commonly performed. A urinalysis with culture can detect urinary tract infections, which are common in people with MS and can cause old symptoms to reappear without representing a true relapse.^[12] A complete blood count can identify signs of infection or other systemic issues that might be affecting your symptoms.

If there is concern about infection contributing to your symptoms, your doctor may order additional tests such as a throat culture or sputum evaluation, depending on the suspected source of infection. These tests help determine whether treating an underlying infection will resolve your symptoms, which would confirm a pseudoexacerbation rather than a true relapse.

Magnetic Resonance Imaging (MRI)

An MRI scan is one of the most valuable tools for evaluating MS activity, though it is not always necessary when diagnosing a relapse. An MRI uses powerful magnets and radio waves to create detailed images of your brain and spinal cord. It can show areas of inflammation and damage called lesions or plaques.^[7]

During a relapse, MRI may reveal new lesions or changes in existing lesions that correspond to your symptoms. Some MRI scans use a contrast dye containing the chemical element gadolinium to highlight areas of active inflammation. These are called Gd+ enhanced lesions and indicate recent or ongoing immune system activity in your central nervous system.^[7]

Interestingly, not all inflammation visible on MRI causes noticeable symptoms. Some people experience what are called “silent relapses,” where new lesions develop without any perceived symptoms or disability, especially early in the disease.^[5] These can only be detected through periodic MRI monitoring. In fact, if doctors perform MRIs regularly looking for new lesions at the beginning of the disease, they often find that lesions occur much more frequently than clinical relapses.^[13] You could go years with lesions appearing on MRI without experiencing an obvious attack. It is only when a lesion develops in a particularly important area like the optic nerve, spinal cord, or brainstem where many nerve pathways are concentrated in a small space that symptoms become apparent.^[5]

Your doctor may recommend an MRI if your symptoms are unusual, if they do not respond to treatment as expected, or as part of routine monitoring to track your MS activity over time. The exact relationship between MRI findings and your overall health is not completely clear, but MRIs are commonly used to help you and your healthcare team monitor disease activity and make decisions about treatment.^[7]

Distinguishing Relapses from Other Conditions

Your healthcare team must carefully distinguish a true relapse from several other possibilities. As mentioned, pseudoexacerbations caused by infections, heat, or stress are common mimics of relapses. Certain temporary symptoms that occur in MS are not relapses but rather paroxysmal syndromes or transient phenomena related to existing nerve damage.

Examples include Lhermitte’s sign, which is an electrical sensation down the back or into the limbs when you bend your neck forward, or Uhthoff’s phenomenon, which is temporary visual blurring that occurs with exercise in people who have had optic neuritis.^[12] These symptoms do not represent new inflammation but rather temporary changes in how damaged nerves function under certain conditions.

Progressive worsening is another important consideration. In some people with MS, disability can gradually worsen over time independent of relapses, a process called progression. This most commonly presents as a gradually worsening walking difficulty due to spinal cord involvement.^[12] This can be challenging to diagnose because it happens retrospectively over time, and people experiencing progression may also have overlapping relapses.

Diagnostics for Clinical Trial Qualification

When researchers design clinical trials to test new treatments for MS or better ways to manage relapses, they use specific diagnostic criteria to determine which patients can participate. These standardized criteria help ensure that trial participants truly have MS relapses and that results can be reliably compared across different studies.

For clinical trial enrollment, a relapse is typically defined very precisely. It must be a monophasic clinical episode, meaning a single episode with patient-reported symptoms and objective findings typical of MS. The symptoms must reflect inflammation and demyelination (damage to the protective myelin covering of nerves) in the central nervous system.^[10] The episode must develop acutely or subacutely and have a duration of at least 24 hours, occurring in the absence of fever or infection.^[12]

Clinical trials often require documentation of specific relapse patterns. For example, participants may need to have experienced a certain number of relapses within a specified time period before enrolling, such as two or more relapses in the past two years. This helps researchers study people with active relapsing disease who are most likely to benefit from interventions aimed at preventing relapses.

MRI criteria are frequently used in clinical trials to provide objective measures of MS activity beyond clinical symptoms alone. Trials may require evidence of new or enlarging lesions on MRI, or the presence of gadolinium-enhancing lesions indicating active inflammation. These imaging markers help researchers understand whether a treatment is reducing disease activity even when clinical relapses might not tell the whole story.

Participants in relapse management trials typically undergo a thorough diagnostic workup at baseline, which may include detailed neurological examinations using standardized scales, comprehensive MRI of the brain and sometimes spinal cord, and laboratory tests to rule out other conditions. During the trial, regular monitoring with these same tools helps track whether relapses occur, how severe they are, and how well they respond to treatment.

Common relapse syndromes that trials look for include unilateral optic neuritis (inflammation of the optic nerve affecting one eye), focal brainstem or cerebellar syndromes (problems with balance, coordination, or eye movements originating in specific brain regions), and partial myelitis (inflammation in a portion of the spinal cord).^[12] These are considered typical patterns of MS relapses.

On the other hand, atypical symptoms would prompt further evaluation before someone could be enrolled in a trial. These include encephalopathy (confusion or altered mental state), complete ophthalmoplegia (total paralysis of eye movements), headache, or isolated fatigue without other neurological signs.^[12] These symptoms are less characteristic of typical MS relapses and might suggest other diagnoses.

The speed at which symptoms develop is also important in trial criteria. A typical MS relapse evolves over 24 to 48 hours and reaches its worst point within several days.^[12] Symptoms that appear much more suddenly, over seconds or minutes, or that develop extremely gradually over many weeks would be considered atypical and might not qualify as relapses for trial purposes.

Some clinical trials also use specific disability scales to measure the impact of relapses. These standardized assessments provide numerical scores that reflect how much a relapse affects someone’s ability to walk, use their hands, see, think, and perform daily activities. By using the same assessment tools across all participants, researchers can objectively compare outcomes and determine whether a treatment improves recovery from relapses.