Christina Applegate, an American actress, has been an outspoken advocate for patients with multiple sclerosis (MS) since her own diagnosis. She has been open about her “MS journey” in hopes that it will help others facing the same challenge. Recently, however, her journey took an unexpected turn – she apparently does not have MS. She reported on her recent podcast that her doctors informed her the diagnosis of MS made in 2021 is not correct. She lamented that now she is “back to square one”, without a specific diagnosis.

However, this does not invalidate her MS journey in my opinion. This is a very common aspect of that journey for many patients, up to 20% of which will turn out not to have MS even after an MS diagnosis. This is a great learning experience and there are several lessons worth pointing out. The first of which is that the fact that her diagnosis has changed does not mean that her neurologists did anything wrong or substandard. That seems to be everyone’s first reaction – a “misdiagnosis” means someone screwed up. This is not true, for very informative reasons.

A couple of background points before I push on. First, I recently retired from a 30 year career as a clinical neurologist. I was not an MS specialist, but I obvious know a lot about MS as a neurologist and was involved in the care of many MS patients. But MS diagnosis and treatment is extremely complex and should be done by an MS specialist, which we had in our clinic. Second, I have no inside knowledge of Applegate’s case, so I am basing my comments on publicly available information. Besides, most of my observations her are based on MS and clinical principles generally, not specifically her case. But it will put the news reporting into a useful perspective.

So how could Applegate have been diagnosed with MS when it turns out she does not have MS without this being a mistake? Diagnoses in medicine come in many different forms, and are based on different kinds of information. There are diseases, which generally result from a specific pathological process. There are also syndromes and disorders which may simply be a common clustering of clinical signs and symptoms. We use labels (diagnoses) for clinical entities that seem to exist in different patients, so that we can communicate about them, research them, and develop a body of knowledge about their natural history, diagnosis, and treatment. Some of these entities may be fairly iron-clad, based on objective definable pathology that can be documented unambiguously. At the other end of the spectrum are diagnoses that are simply symptoms that may have a typical demographic pattern and natural history, but without any known specific cause. There is also everything in between. There are also different types of data we can use – symptoms, signs on exam, blood tests, biopsy results, imaging studies, electrodiagnostic studies, response to treatment, and time course.

Many diagnoses are also probabilistic. Some diagnostic findings are what we call “pathognomonic” – a specific finding unique to and diagnostic of a specific disease. If you have that finding, you have the disease, period. But that is the happy exception (because it makes our life easier), not the rule. Many other finding have only a partial correlation to a disease. An antibody found in the blood may correlate only 60-80% of the time with a certain clinical syndrome. Or a finding may be present only a percent of the time. And some findings are not specific to one disease but may be found in many diseases, or may only be specific to a category of diseases but not a specific entity within that category.

MS is a particularly squirrelly disease to diagnose. It is a chronic autoimmune disease of the central nervous system. To establish the diagnosis you therefore need multiple lesions separated in time and space, meaning they occur at different times in different places in the central nervous system (brain, spinal cord, and optic nerves). You also need evidence that the lesions are inflammatory. Finally, you need to rule out other disease that can cause the same findings. But that’s it. Except for some specific subtypes of MS, there are no tests that definitively show that you have MS.

Further, and this is important to understand, medicine is all about risk vs benefit, and this extends to making diagnoses. This means we do not do everyone possible to establish a diagnosis, we do only what is necessary, what benefits the patient. For example, we can often do a brain biopsy to further establish or rule out a diagnosis, but it is often simply not worth it. The risk of the diagnostic procedure can be higher than the benefit of the information it will provide. We also have to ask – what is the purpose of a diagnosis? Does it affect treatment, prognosis, the need for further testing, or management in any way (or perhaps it’s just a placeholder, or a convenience for coding).

We have had effective disease-modifying treatments for MS since the 1990s, and they have become quite good. When that happens to a disease (the emergence of effective specific treatments) that can result in the diagnostic criteria shifting. Experts stop asking the question “does this patient have MS” and start asking the distinct question “should this patient be treated for MS”. In MS specific evidence-based criteria emerged to determine who should be treated for MS and with which treatment options. From what I am reading, Applegate met criteria for MS treatment, after a proper workup. In this way MS became the working diagnosis, even though it is understood that a percentage of those patients will turn out not to have MS. This is also not uncommon in medicine, the treat first approach, when time is critical and the consequences of treating someone who does not have the disease is much less than delaying treatment for someone who does.

What then happened was that Applegate did not respond to the treatment, which is unusual. This caused her doctors to question whether the initial diagnosis was therefore correct, so they repeated the workup, including some newer MRI technique, and after reviewing the new information (and in light of her lack of response to treatment) they determined that she likely never had MS. If anything this shows that her doctors were thinking nimbly and were able to shift gears in light of her continued disease course.

According to Applegate her doctor presented this as “good news”, but her reaction was negative, thinking that this deprived her of a specific diagnosis and set her back to square one. I also think this is a misconception, one that I had to deal with often with my own patients. The common assumption, often reinforced by medical dramas like Dr. House, is that the one and only path to effective treatment is through a specific diagnosis. But this is not true. Sure, we always prefer to make a highly specific diagnosis, and will take reasonable steps to do so. But that does not mean that is the only path to effective management. It also absolutely does not mean that you should prefer a bad diagnosis to no diagnosis (which is often how patients respond).

Another perfectly viable clinical pathway, and one fairly common in neurology, is to rule out anything active, progressive, or that would require specific treatments, and then treat symptomatically or non-specifically. Another way to frame this is that what we are really looking for anyway is not necessarily a specific diagnosis but rather things to treat. Is there an infection, active inflammation, something anatomical that can be fixed, a metabolic derangement or hormonal problem that can be adjusted, etc. Look for things to treat, treat what you find, and otherwise manage symptoms and physical issues. Keep in mind, a clinician may find something to treat (like a low B12 level), and they should treat it, but it is still unclear how that relates to the symptoms the patient is complaining about. None of this requires a specific diagnosis.

In fact, for many patients that I saw, ruling out the specific diagnoses that I can was highly desired. They did not want any of those diagnoses. They were far better off being left without a specific diagnosis – that meant there was nothing specific to find. This could mean that what they do have is something more subtle, or something non-progressive, that can be managed entirely symptomatically (while monitoring their clinical course). Or it could mean that whatever caused their symptoms has come and gone, and is no longer active. Now we just have to deal with the results. Both of those situations are better than knowing you have an active destructive process.

Explaining all of this nuance to patients can be challenging. It is also easy to underappreciate as a clinician how different our perspective can be, and how many assumptions, expectations, and false paradigms patients can bring into the clinic with them.

I of course wish the best for Christina Applegate, and I applaud her openness and willingness to confront a serious neurological diagnosis in the public eye in the hopes it will help others dealing with the same thing. I also hope she comes to appreciate that a change in diagnosis is often part of an MS journey, that many patients will face, and so she can still have a critical role to play in being an MS patient advocate. In fact this may be the most instructive part of her journey yet.