Christina Applegate’s recent revelation that she was misdiagnosed with multiple sclerosis is raising questions about how the disease can be confused with other conditions — even after years of treatment.
The actress, 54, shared the news during an Oct. 20 episode of her podcast, “MeSsy,” alongside co-host Jamie-Lynn Sigler, saying she was in a complete “state of shock.”
Applegate was first diagnosed with MS in 2021 after experiencing debilitating symptoms and undergoing extensive testing, including brain and spinal MRIs and a spinal tap. She said doctors found dozens of lesions on her brain.
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After years of treatment, her doctor decided to stop her regular infusions and monitor her B cells.
“And my B cells didn’t change. They didn’t go higher, they didn’t go lower, they didn’t change, and she had never seen that. So I guess that began kind of a study into my diagnosis,” Applegate shared.
After additional brain scans, the doctor came into Applegate’s room and said, “Congratulations, you don’t have MS.”
The actress did not consider this to be good news, however.
“Because you don’t get misdiagnosed and then all of a sudden [you’re] better,” she said. “I haven’t gotten better … If anything, I’ve gotten worse in some ways.”
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Applegate noted that she has “every symptom” of someone with MS, adding that there are many conditions that mirror the disease.
She recalled that her MRIs clearly showed around 30 lesions, but said her neurologist identified a different feature — which she described as a “string” — that led to the conclusion that she did not have MS.
“So I’m back at square one [and] don’t know what’s going on with me.”
Dr. Marwa Kaisey, an associate professor of neurology at Cedars-Sinai in Los Angeles, said during a follow-up “MeSsy” podcast episode that misdiagnosis of MS is “fairly common.”
In a study of patients referred to MS clinics at UCLA and Cedars-Sinai, Kaisey — who has not treated Applegate — said she found that nearly one in five who arrived with an MS diagnosis ultimately did not have the disease.
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“Some [had been diagnosed] for decades,” she said. “And a majority of them were on medication to treat their MS.”
The primary challenge, according to the doctor, is that there is no single test for MS. “It’s not like we have something like a pregnancy test that says, yes, you have it, no, you don’t.”
Instead, Kaisey said, “It’s a list of criteria, some of which remain a little bit subjective.”
Most misdiagnosed patients did have some type of white matter spots, or lesions, on their MRI scans, Kaisey noted, but they had a different cause that was not MS.
Newer imaging techniques may help doctors distinguish MS lesions from white matter spots caused by other conditions.
Kaisey pointed to the “central vein sign,” an MRI finding that looks for small blood vessels running through the center of lesions, which is a characteristic associated with MS. The sign was incorporated into updated MS diagnostic criteria to help doctors determine whether white matter lesions are consistent with the disease.
Richard Ransohoff, MD, a Boston-based neurologist who sits on the Board of Directors for the American Brain Foundation, called the central vein sign “a real step forward” in distinguishing MS lesions from other abnormalities.
“Things are getting better, and even in the time that Ms. Applegate has been having her symptoms and her evaluation, things have gotten better,” said Ransohoff, who also has not treated the actress.
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Many of the symptoms of MS — such as tingling or numbness in the feet, fatigue and brain fog — are very common in other conditions as well, according to both neurologists.
“To distinguish MS from its mimics can be challenging, and doctors, even with the best intentions … can sometimes still get it wrong,” Kaisey said. “To diagnose MS, we need a symptom that’s kind of very specific to MS, and we also need the MRI that looks like MS.”
Kaisey said she has found that being “undiagnosed” with MS can be even harder than receiving the initial diagnosis, particularly when the disease has become intertwined with someone’s identity, family and community.
“So to suddenly take that away, I think it’s earth-shattering. It’s life-changing in a huge way.”
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The neurologist emphasized that patients should feel comfortable asking questions and getting a second opinion.
“Don’t be afraid to do that, especially if something inside is telling you that you need to dig a little deeper,” she advised.
Ransohoff reiterated that MS misdiagnoses are common. “It’s a tough diagnosis, and there is no single element in the diagnostic process that tells you with 100% certainty that it is MS,” he told Fox News Digital.
The neurologist said even after a diagnosis, doctors should “keep an open mind” and be willing to reconsider.
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“If things start going differently from your expectations, if the person begins to have symptoms that really don’t fit in with MS, or they don’t respond to treatment, then you really start to put on your thinking cap and say, ‘What else could this be?’”
“It requires the ultimate in humility as a physician. You simply have to say there are certain things we know and certain things we don’t know.”
Classic early MS symptoms tend to appear relatively quickly, persist for weeks and then recede, according to Ransohoff.
Anything producing a similar pattern can potentially mimic the disease. Some of those conditions may include certain strokes in younger people, neuromyelitis optica spectrum disease (a rare autoimmune disease of the central nervous system), MOG antibody disease (a rare autoimmune inflammatory disorder), lupus and migraine, he said.
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Migraine is one of the most common alternative diagnoses, both neurologists agreed.
Kaisey noted that migraine can also produce MRI abnormalities in the form of white spots, although they are usually smaller and in a different shape and location.
“If you’re not looking closely at the MRI or you don’t know exactly what to look for, you can confuse the two,” she said.
In some cases, reversing an MS diagnosis can actually provide a concrete alternative diagnosis and better-targeted treatment — but that did not happen in Applegate’s case, Ransohoff noted.
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“You have to have tremendous sympathy for her suffering in that context, because even when treatment is not going as well as you would like, it’s better to know what you’re dealing with,” he said.
“Facing the unknown when you feel crappy is a very tough road to go.”
To prevent misdiagnosis, Ransohoff recommends that everyone who receives a multiple sclerosis diagnosis is seen by a specialist at a specialty MS center, who has developed pattern recognition after many occurrences of seeing the disease.
The neurologist noted that MS treatment has advanced dramatically over the course of his career, growing from virtually no options to more than 20 medications today.
“You want to work with someone who has experience with all those medicines, with all the various patterns that MS can show, because every person’s MS is different,” he said.
If a treatment isn’t helping or is causing significant side effects, an MS specialist can reassess the approach and help identify a more appropriate medication, Ransohoff added.
The doctor emphasized that the outlook for people who do have MS has improved dramatically.
“The person who’s diagnosed with MS today is totally different from 40 years ago when I got started,” the neurologist said. “If the diagnosis is correct and the treatment is correct, then they should do pretty well with their MS.”