Applegate, 54, revealed the news in October 2026 on “MeSsy,” the podcast she co-hosts with fellow actor Jamie-Lynn Sigler. Applegate announced in 2021 that she had been diagnosed with multiple sclerosis, commonly called MS, and spent years speaking publicly about the disease and its effects on her life. The revised diagnosis has brought little relief because her symptoms persist and, she said, have worsened in some respects.

“I was, like, not happy at all,” Applegate said on the podcast, recalling her doctor’s announcement that she did not have MS. She explained that other people reacted with happiness, while she was left confused about the cause of her ongoing health problems.

Reconsidering the Diagnosis 

Applegate said her doctors began reassessing the diagnosis after discontinuing an infusion treatment to observe how her B cells responded. When the cell count did not change, the findings prompted further investigation into whether MS was responsible for her symptoms.

Her initial evaluation included magnetic resonance imaging scans and a spinal tap. Applegate said the scans showed lesions on her brain, findings that contributed to the original diagnosis. However, MS does not have a single definitive diagnostic test. Doctors typically evaluate symptoms, medical history, neurological examinations, MRI findings and, when appropriate, spinal fluid results while ruling out other conditions.

Neurologist Marwa Kaisey, an associate professor at Cedars-Sinai Medical Center who appeared on the podcast, discussed the difficulties of diagnosing MS and the frequency of mistaken diagnoses. Published estimates vary, and the exact rate depends on the population studied and the criteria used.

Applegate said she continues to experience symptoms associated with neurological illness, including numbness, tingling, balance difficulties and severe mobility limitations. She has used a wheelchair for medical appointments and said she attends physical therapy three times a week.

“You don't get misdiagnosed and then all of a sudden I'm better,” she said, describing herself as back at square one.

She said her doctors planned further investigations to determine what has caused her symptoms since 2021.

From Sitcom Star to Award-Winning Actress

Applegate began working in entertainment as a child and rose to prominence in the late 1980s as Kelly Bundy on the Fox sitcom “Married ... With Children.” The role established her as a recognizable television star and helped launch a career spanning comedy, film, television and theater.

She later appeared in films including “Don't Tell Mom the Babysitter's Dead,” “The Sweetest Thing” and “Anchorman.” Her television work included the comedy series “Samantha Who?” and a guest role on “Friends” as Amy Green, the sister of Jennifer Aniston's character, Rachel. Applegate won a Primetime Emmy Award for that guest performance.

Her career reached another milestone with “Dead to Me,” the Netflix dark comedy in which she starred opposite Linda Cardellini. The series earned critical recognition and additional award nominations for Applegate, who played Jen Harding, a grieving widow whose life becomes intertwined with another woman hiding a secret.

In August 2021, during production of the show's third and final season, Applegate publicly disclosed her MS diagnosis. Production paused for several months while she began treatment and addressed her health. She ultimately returned to complete the series, which premiered its final season in November 2022.

In interviews, Applegate described struggling with balance and coordination during filming. She said the production adjusted aspects of the script to accommodate her physical limitations and that she used a wheelchair on set. Her determination to finish the series made its final season a significant chapter in her career.

How the Misdiagnosis Impacted her Career

After completing “Dead to Me,” Applegate indicated that continuing to work in front of the camera could be difficult because of her symptoms. In 2023, she said she might not pursue traditional on-camera acting roles again, although she did not rule out other forms of creative work.

Her career has not simply ended; rather, its direction has changed. Applegate has remained publicly engaged through interviews, advocacy, podcasting and writing. Her podcast, “MeSsy,” gives her a platform to discuss disability, chronic illness and the emotional realities of living with serious health problems. Her memoir, “You with the Sad Eyes,” also reflects on her life and experiences.

The revised diagnosis complicates that public role. Applegate said she felt as though she had let people down after becoming a prominent voice for the MS community alongside Sigler. Her experience, however, does not invalidate her previous account of living with disabling symptoms. It underscores the distinction between a person's symptoms and the medical explanation initially offered for them.

Legal implications

Applegate's disclosure raises questions about diagnostic accuracy, communication between physicians and patients, and the consequences of an incorrect medical diagnosis.

A mistaken diagnosis can affect treatment decisions, expose patients to unnecessary medication risks, delay identification of the underlying condition and create significant emotional and financial burdens.

The disclosure does not, by itself, establish medical negligence or demonstrate that a health care provider violated the law. Medical malpractice claims generally require evidence that a provider failed to meet the applicable standard of care and that the failure caused legally recognizable harm. The specific requirements vary by jurisdiction, and an incorrect diagnosis alone is not sufficient to prove liability.

Medical Re-Evaluation

A reassessment may be medically appropriate when new evidence emerges or a patient's condition does not follow the expected course. Patients with complex or unexplained symptoms can ask their physicians to explain the diagnostic criteria, discuss alternative causes and consider a second opinion from a specialist.

For Applegate, the immediate priority is finding an explanation for her continuing symptoms. She has said her medical team intends to investigate what has been happening since 2021.

Her experience highlights a difficult reality: learning that a serious diagnosis was incorrect does not necessarily mean a patient is healthy. For an actor whose career has been shaped by both major professional achievements and profound physical challenges, the search for answers continues.

Publication note: The discussion is general background knowledge, not a legal conclusion that malpractice occurred in Applegate’s case.