Applegate was diagnosed in 2021 after extensive testing, including brain and spinal MRIs and a spinal tap that found about 30 lesions. She later suffered numbness, tingling, pain, tremors, incontinence, fatigue and the loss of her ability to walk, and she spent long stretches largely bedridden. She described the new information as "earth shattering" and "life changing" and said she was in a "state of shock." She recalled being told, "Congratulations, you don't have MS."

The diagnosis had given her a "reason as to why my day sucked every day," Applegate said. She called the reversal "weird" and "unnerving" and said she was now "back at square one." Through the podcast she had become a prominent voice in the MS community and has been described as the "poster child for MS."

Dr. Marwa Kaisey, an associate professor of neurology at Cedars-Sinai in Los Angeles, told the podcast that MS misdiagnosis is "fairly common." No single test can confirm the disease, so doctors work from a list of criteria, some of them subjective. Common symptoms such as fatigue and brain fog also show up in many other conditions, which makes it hard to rule out the disorders that mimic MS.

In Applegate's case, a brain MRI showed white lesions and a lumbar puncture showed "three bands" of oligoclonal bands. Kaisey said those bands can point to inflammation from causes other than MS.

Estimates of how often MS is misdiagnosed vary widely. Studies have put the rate anywhere from 5% to 36%. A 2019 study led by Kaisey found that 18% of 241 patients referred to two academic centers in Los Angeles had been misdiagnosed, often because migraine or other conditions had left white matter spots on their MRIs. A 2024 analysis found that 15% of 1,621 patients diagnosed with MS did not have it. Other research found misdiagnosis in nearly 30% of patients referred for confirmation in a 2017 study, and in 50% of patients at four academic centers in a 2016 study.

Dr. Richard Ransohoff, a neurologist on the board of directors of the American Brain Foundation, said migraine, lupus, stroke and neuromyelitis optica spectrum disease can all produce symptoms that resemble MS. He pointed to the "central vein sign," a newer MRI finding that helps tell MS lesions apart from other white matter spots. Diagnostic criteria were revised in 2025 to include it, though not every hospital can check for it.

Kaisey and Ransohoff both urged patients to seek care at specialized MS centers. The disease has no distinct biomarker, and its symptoms overlap with conditions including migraine and fibromyalgia. Cheryl Herbert of the National Organization for Rare Disorders said an accurate diagnosis of such conditions often takes five years or more on average.