Actor Christina Applegate — a longtime advocate and self-described “poster child” for multiple sclerosis — shared unsettling news this week: She does not have MS, after all.
In her return to “MeSsy,” the podcast she co-hosts with actor Jamie-Lynn Sigler, after a months-long hiatus, Applegate revealed that new testing had led a doctor to rethink her 2021 diagnosis. Meanwhile, her condition has “if anything … gotten worse, in some ways,” she said on the podcast, tearfully. Now, she’s “back at square one” with figuring out what’s wrong.
MS is an autoimmune disease that occurs when the immune system mistakenly attacks the central nervous system (brain, spinal cord and optic nerve), triggering neurological symptoms that may affect vision, balance and movement. A 2024 review of studies found that the frequency of MS misdiagnosis ranges from 5 percent to 41 percent — though it’s worth noting that these numbers often come from academic institutions, which typically see more difficult-to-diagnose cases, said Bruce Bebo, chief research and medical affairs officer at the National Multiple Sclerosis Society.
The challenge: There is no one single test that can say with certainty if a person has MS, said Daniel P. Kurz, Jr., a neurologist specializing in neuroinflammatory conditions and associate professor of neurology at UChicago Medicine. Rather, experts rely on “a constellation of different tests as well as a history from the patient and their symptoms,” he said.
Such an inherently imprecise process also poses the opposite problem of missed or delayed diagnoses — which may prevent people with MS from accessing treatment early in the course of the disease, when it’s been shown to help slow its progression. (The review above found that the rate of MS underdiagnosis ranges from 3 percent to 58 percent.)
We asked experts to explain everything that goes into an MS diagnosis and why a misdiagnosis might happen.
The complexities of an MS diagnosis
Bebo equated MS diagnosis to putting together the pieces of a puzzle: Only when you lock all the pieces in place does the picture become clearly visible.
The first piece consists of the symptoms. Typically, in MS, these follow an episodic pattern, waxing and waning over the course of days, weeks or months — or what MS specialists call relapsing-remitting, Kurz said. A smaller portion of patients have progressively worsening symptoms. These vary depending on where the disease is primarily harming the central nervous system and can include vision issues, numbness or tingling, tremors, muscle weakness, balance and coordination problems, brain fog and fatigue, said Tsedey Biru-Williams, a neurologist specializing in multiple sclerosis at UC Health, in Ohio.
Many symptoms can be tough to pin specifically to MS, Kurz pointed out — for instance cognitive dysfunction and fatigue are common in a lot of autoimmune conditions. There’s also a level of subjectivity: Patients might not easily recall how long a symptom lasted or when or how many times it struck, for instance, and doing so with brain fog can be even tougher, Kurz said.
Typically, a physician will also do a clinical exam to check for evidence of neurological deficits — for example a discrepancy in strength or sensation between the arms or the legs, faulty reflexes or eyes that don’t seem to track together, Biru-Williams said.
The next puzzle piece is magnetic resonance imaging (MRI) of the brain and spinal cord. When the immune system targets the central nervous system, it often leaves behind scar tissue, visible on an MRI as a plaque or lesion, Biru-Williams explained. The tricky thing is, other common conditions such as high blood pressure, diabetes and high cholesterol can harm the tiny blood vessels of the brain and create spots that mirror or obscure MS lesions, Kurz said. Over time, the brain can also “collect evidence of damage” from other conditions or injuries, for instance stroke, migraine, concussion or meningitis, Biru-Williams noted.
Parsing MS-related marks from others requires the radiologist to look for a specific pattern, Kurz explained. This leaves room for interpretation.
An MS diagnosis also requires that the plaques are in multiple regions of the nervous system, and evidence that MS activity has unfolded over time, meaning certain lesions appear newer than others, Biru-Williams said.
The burden of meeting all these parameters has pushed researchers to pinpoint MRI markers that can better help distinguish MS from everything else, Bebo said. Two of them, the central vein sign and paramagnetic rim lesions, were added to the most recent version of the diagnostic guidelines (published in 2025). But access to the kinds of MRI sequencing necessary to detect these isn’t necessarily widespread, Kurz said.
Ruling out other diagnoses is a final critical puzzle piece. The above imaging and clinical assessments can help with that, as can a spinal tap and blood testing to check for infections, vitamin deficiencies (insufficient B12, for example, can trigger MS-like spinal cord changes) and rare conditions that can mimic MS such as neuromyelitis optica (NMO) and myelin oligodendrocyte glycoprotein antibody disease (MOGAD).
Why a doctor may rethink an MS diagnosis
Having different, new or worsening symptoms while being treated for MS is the main catalyst for a clinician to reconsider a diagnosis, the experts we spoke with said.
Before reaching that point, your provider is likely to weigh switching your treatment. There are more than 20 disease-modifying therapies for MS, Bebo said, so figuring out the best one for you might involve trial and error.
Certain symptoms of MS can still evade current treatments. For example, ones related to neurological damage already done by the time of diagnosis. But if you’re having “breakthrough disease” that doesn’t follow a typical pattern, this can be a sign for your clinician to rethink treatment and possibly your diagnosis, Biru-Williams said.
Not only can the wrong treatment not improve symptoms (and delay effective care), it can also cause unnecessary side effects. Because most MS therapies suppress the immune system, you may be more prone to illnesses like a cold or the flu, as well as urinary tract infections and “more dangerous opportunistic infections, such as hepatitis B and tuberculosis,” Kurz said. Certain immunotherapies for MS may even worsen MS-mimicking conditions such as NMO, he added.
Neurologists also monitor MS patients with imaging and testing over time, and look out for certain signals that may suggest a treatment isn’t working as planned, Kurz said.
Applegate said on “MeSsy” that her doctor chose to pause her treatment “to see something” and was inspired to reevaluate her diagnosis when Applegate’s B cells (a type of immune cell implicated in MS) didn’t change in the expected way for someone with the disease. This led to further testing that ultimately led her doctor to conclude she had been misdiagnosed.
Preventing or managing misdiagnosis
It’s not only okay but encouraged to take an active role in your own diagnosis of MS, the experts said. If you’ve been evaluated and diagnosed, consider asking your provider how they arrived at that conclusion. Biru-Williams said she often walks her patients through their imaging, pointing out their lesions and how they do or don’t meet the criteria for MS.
If you don’t feel comfortable with the explanation or the treatment plan, it’s worth seeking a second opinion — common practice in the MS world — ideally from a neurologist who specializes in MS.
The uncertainty involved can be difficult to navigate on an emotional level, Kurz acknowledged. “Just like adjusting to the diagnosis in the first place, there can be an adjustment or even a grieving that happens around this big change [in diagnosis] and what often becomes part of identity.”
Learning you’ve been misdiagnosed can be really stressful, Biru-Williams said, because it leaves you with no answer for your symptoms and means you need to undergo more (sometimes uncomfortable) testing. Losing the mental closure that a label and a treatment plan provides can be especially destabilizing, she said, when you’re still grappling with symptoms that may limit your day-to-day functioning.
However, it’s important to recognize that losing a diagnosis doesn’t invalidate your symptoms. It can begin a new process with your doctor of uncovering what’s really wrong and finding a better solution, Kurz said: “A lot of us see a spectrum of neuroimmunological diagnoses, also specifically to help us capture when the puzzle pieces don’t fit as we once thought they did.”
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