Distinguishing Pseudo-Relapse From True Relapse and Progression

Key Takeaways:

• An MS relapse is a monophasic clinical episode of new or worsening neurologic symptoms developing acutely or subacutely that is the result of new MS inflammatory activity
  With worsening MS symptoms, it is critical to rule out pseudo-relapse, a temporary worsening of prior or existing MS symptoms that can result from raised body temperature, fever, infection, or other metabolic disturbances.
• Progression independent of relapse activity (PIRA) represents gradual clinical worsening that occurs without new lesions or relapses, and diagnosis requires well-organized neurological examination and assessments over time.
• Identifying the underlying cause of worsening MS symptoms is critical as it determines the treatment and future plans.

Three clinically distinct events can result in the same report from the patient: my symptoms are worse. A true MS relapse reflects new inflammatory MS disease activity. A pseudorelapse reproduces or worsens established deficits without new inflammatory activity. Progression independent of relapse activity (PIRA) accrues steadily without evidence of new inflammatory activity. Each requires different management, and the difference is not always apparent at the moment the patient reports it.

Ruling out a pseudo-relapse first

A pseudorelapse is the temporary acute or subacute worsening of existing or prior MS symptoms caused by raised body temperature from infection, heat exposure, or exercise; by an underlying infection such as a urinary or upper respiratory infection; or by metabolic disturbance or other medical illness.¹ A pseudorelapse is not the result of new inflammatory MS activity and does not represent new neurologic damage, just transient worsening of symptoms from prior MS inflammatory activity. If the neurologic symptoms are a worsening of existing or prior MS symptoms, rather than new neurologic symptoms, this increases the likelihood that this clinical worsening may be a pseudorelapse.

Patients with acute or subacute worsening of MS symptoms should be evaluated for potential triggers of a pseudorelapse, including fever, infection, and other metabolic disturbances.¹ Ruling out a pseudorelapse has important treatment implications as a pseudorelapse is treated by treating the underlying fever, infection, or metabolic disturbance. It is particularly important to rule out an acute infection, as corticosteroids that are often used to treat MS relapses are immunosuppressive and may worsen acute infections.

Transient neurological worsening with raised body temperature affects a majority of patients with MS, with reported rates of 60 to 80 percent.² Infections, particularly urinary tract infections, and therefore pseudorelapses from these infections can be relatively frequent in some MS patients. In the 2026 Multiple Sclerosis In America survey of 2,302 respondents with relapsing forms of MS, 50.4 percent reported heat sensitivity and 64.4 percent reported bladder problems in the past month – 2 of the most common triggers and confounders that may result in a pseudorelapse.³

Confirming new inflammatory activity

UpToDate characterizes an MS relapse as a monophasic clinical episode developing acutely or subacutely, lasting at least 24 hours, with or without recovery, and occurring in the absence of fever or infection, with at least 30 days of stability or improvement required to separate 1 relapse from the next.¹

Where a true relapse is suspected, and a pseudo-relapse is ruled out, the diagnosis can be primarily clinical. A complete neurological history and examination is needed to assess any change in cognition, vision, strength, sensation, coordination, and gait, and findings should be compared against the baseline established at prior evaluations. While imaging may not be required when clinical suspicion of an MS relapse is high, an MRI can demonstrate clear evidence of new inflammatory activity thereby confirming the MS relapse. Specifically, in the setting of an MS relapse, an MRI will often reveal an enhancing and/or new lesion that correlates with the new or worsening neurologic symptoms.¹

Depending on the neurologic symptoms, treatment of a new MS relapse often involves a short course of corticosteroids to reduce the new inflammatory activity and help resolve symptoms faster.

Recognizing progression without relapses

A third way MS patients can have worsening of their MS symptoms is PIRA. The 2024 revisions to the McDonald criteria define this progression as steadily (not acute) increasing neurological disability independent of relapses, sustained for at least 12 months.⁴

A cohort study of 33,303 patients with relapsing-remitting MS found that 33.9 percent experienced at least 1 PIRA event under the study's reference definition. Estimates were highly sensitive to how PIRA was specifically defined: across 360 candidate definitions, incidence ranged from 0.141 to 0.658 events per decade and persistence from 0.753 to 0.919.⁵

The clinically useful point is not the numerator but the mechanism: disability accrues gradually in patients who have not had recent relapses or new lesions on an MRI. This means careful and comprehensive neurological examinations and neurological assessments that are comparable across visits, and not just quantification of relapses and MRI imaging, are required to identify PIRA.

Treatment follows the specific cause of symptom worsening

It is critical to accurately distinguish the underlying cause of a patient’s worsening MS symptoms, as each of these three potential explanations described above has distinct management and treatment implications. When the episode is a pseudorelapse, treating the trigger, such as the underlying infection, and reassessing neurologic status after resolution is the goal. When there is a new MS relapse with new inflammatory activity, acute treatment with corticosteroids is often implemented. In addition, if the patient is on a disease-modifying therapy (DMT), a new MS relapse may lead to the consideration for switching to an alternative or higher-efficacy DMT. Where neither applies, and there is gradual symptom progression, this may suggest PIRA. There are currently no FDA-approved therapies for treatment of PIRA, though there are several ongoing clinical studies testing novel therapies for PIRA.