Christina Applegate’s revelation that she was misdiagnosed with multiple sclerosis after years of treatment is drawing attention to the difficulty of distinguishing MS from other conditions. The actress, 54, shared the news during an Oct. 20 episode of her “MeSsy” podcast.

Speaking alongside cohost Jamie-Lynn Sigler, Applegate said the reversal left her in a complete “state of shock.” She was initially diagnosed with MS in 2021 after debilitating symptoms and extensive testing, including brain and spinal MRIs and a spinal tap.

Applegate said doctors found dozens of lesions on her brain. After years of treatment, however, her doctor stopped her regular infusions and began monitoring her B cells, which did not change as expected.

“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 said.

Following additional brain scans, Applegate’s doctor entered her room and said, “Congratulations, you don't have MS.” Applegate did not see the reversal as reassuring because her symptoms had not disappeared.

“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.”

Applegate said she has “every symptom” associated with MS and recalled that her MRIs showed around 30 lesions. She said her neurologist identified another feature, which Applegate 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,” Applegate said. Her experience reflects the uncertainty that can follow when a diagnosis is withdrawn without a clear alternative explanation.

Dr. Marwa Kaisey, an associate professor of neurology at Cedars-Sinai in Los Angeles, discussed the frequency of MS misdiagnosis during a later “MeSsy” episode. Kaisey, who has not treated Applegate, described such cases as “fairly common.”

In a study of patients referred to MS clinics at UCLA and Cedars-Sinai, nearly one in five people who arrived with an MS diagnosis ultimately did not have the disease, Kaisey said. Some had carried the diagnosis for decades, and most were taking MS medication.

The central problem is that no single test can definitively diagnose MS. Instead, doctors rely on multiple criteria, some of which remain subjective, Kaisey explained.

Most misdiagnosed patients had white matter spots, also called lesions, on MRI scans, but the abnormalities had causes other than MS. Symptoms such as tingling, numbness in the feet, fatigue and brain fog can also occur with other conditions.

Newer imaging techniques may improve doctors’ ability to identify lesions that are consistent with MS. Kaisey highlighted the central vein sign, an MRI finding involving small blood vessels running through the center of lesions, which has been incorporated into updated MS diagnostic criteria.

Richard Ransohoff, M.D., a Boston neurologist and member of the American Brain Foundation’s Board of Directors, called the central vein sign “a real step forward.” Ransohoff, who has not treated Applegate, said diagnostic methods have improved during the period in which she has experienced symptoms and evaluation.

Possible MS mimics include certain strokes in younger people, neuromyelitis optica spectrum disease, MOG antibody disease, lupus and migraine, Ransohoff said. Both neurologists identified migraine as one of the most common alternative diagnoses because it can produce white spots on MRI scans.

Kaisey said migraine related abnormalities are usually smaller and differ in shape and location from MS lesions. “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.

Kaisey encouraged patients to ask questions and seek a second opinion when they believe more investigation is needed. Ransohoff recommended that anyone diagnosed with MS be evaluated by an experienced specialist at a specialty MS center.

Ransohoff said MS treatment has advanced from virtually no options during the early part of his career to more than 20 medications today. Specialists can reassess treatment when it is ineffective or causes significant side effects and can help identify a more appropriate medication.

For Applegate, the withdrawn diagnosis has not produced an alternative answer or better targeted treatment. “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,” Ransohoff said.

The neurologist stressed that physicians must remain willing to reconsider a diagnosis when symptoms do not fit MS or treatment does not produce the expected response. “There is no single element in the diagnostic process that tells you with 100% certainty that it is MS,” he said.