The Common Phenotypes Hypothesis

A Clinical Thought Experiment

Emma had always considered herself healthy.

When she first began experiencing fatigue, she blamed her demanding work schedule. Like many people, she pushed through it. A few painkillers, an early night, and life carried on.

Then came the fateful morning.

She woke with severe vertigo and what felt like electric shocks running down the back of her neck. Over the next three years, her symptoms became increasingly strange and difficult to explain.

She was referred from specialist to specialist. Each ruled out a piece of the puzzle, but none could provide a satisfactory answer. Eventually, she found herself sitting in a neurologist's office.

The neurologist recognised a familiar pattern and diagnosed Functional Neurological Disorder (FND) on clinical grounds. Separately, an MRI was ordered along with a range of blood tests, but all results came back normal.

With a diagnosis finally in hand, a multidisciplinary treatment plan was put in place. Physiotherapists, occupational therapists, psychologists, psychiatrists, and other healthcare professionals became part of Emma's care team.

Months passed.

Despite her commitment to treatment, her symptoms continued to evolve. New symptoms appeared while existing symptoms worsened. During follow-up appointments, her neurologist remained relatively reassured. The progression was considered consistent with her diagnosis, and no further investigations were requested.

Eighteen months later, Emma suddenly lost vision in one eye.

An urgent assessment by an ophthalmologist revealed severe optic neuritis. A new MRI was ordered.

This time, the results were different.

Inflammatory lesions were identified on the optic nerve, within the brainstem, and along the spinal cord. Further investigation led to a diagnosis of Multiple Sclerosis (MS).

Treatment was started immediately. Steroids reduced the inflammation and disease-modifying therapies followed.

Over the following months, Emma's vision gradually returned.

Interestingly, many of the symptoms previously attributed to FND began improving as well.

Fictional Patient, A Real Dilemma

Emma is a fictional patient. Her journey, however, is constructed from scenarios described in the medical literature and patient reports, including cases in which an FND diagnosis preceded the later identification of another disease, cases in which FND was subsequently framed as a comorbidity of that disease, and reports of functional symptoms improving following treatment of the newly identified condition.Functional neurological disorder and multiple sclerosis: a systematic review (Walzl et al., 2022)Psychiatric Comorbidities in Functional Neurologic Symptom Disorder (Patron et al., 2022)FND and MS (Multiple Sclerosis Trust)

Her story is not intended to prove a conclusion, but rather to illustrate a diagnostic dilemma.

The Question

The question we are exploring is this: when a new condition capable of explaining the patient's symptoms is later discovered, what should happen to the original FND diagnosis?

Should it be replaced? Should it remain as a comorbid diagnosis? Or does the question itself reveal something important about how we understand FND?

Before attempting to answer these questions, we first need to understand how FND evolved from a diagnosis of exclusion into the positive, non-exclusionary, rule-in diagnosis that it is often presented as today.

To understand this evolution, we must first understand the problem modern FND was designed to solve.

The Problem of Infinite Regress

The biggest problem with a diagnosis of exclusion is that it can easily lead to infinite regress. There is always another test to order, another investigation to perform, another specialist to consult, or another rare disease to consider.

This is not merely a theoretical concern. As one neurologist commenting on this website argued:

"It's not appropriate to order test after test. Testing is based on your history and physical exam and should only be performed when indicated." FND Nope comment thread - Living in France, stuck in the FND Trap

Most clinicians would agree that this is neither practical nor desirable. Medicine cannot function on the assumption that every possible explanation must be exhausted before a diagnosis can be made.

At some point, a clinician must decide that sufficient evidence has been gathered to move forward.

The challenge is determining where that point lies.

If the threshold is set too high, patients may be subjected to endless investigations with diminishing returns. If it is set too low, there is a risk of prematurely closing diagnostic doors and overlooking conditions that have not yet revealed themselves.

Modern FND attempted to solve this problem by shifting toward positive rule-in signs rather than requiring endless exclusion of alternatives.

At first glance, this appears to be a sensible solution.

However, solving one problem may have created another. Neurosymptoms - Functional limb weakness and positive signs StatPearls - Functional Neurologic Disorder

The Trade-Off of Positive Diagnosis

By definition, positive rule-in signs are intended to provide evidence for FND rather than merely evidence against alternative diagnoses.

This has an important consequence. If the diagnosis is based on positive clinical findings rather than the exclusion of disease, then the later discovery of another condition does not automatically invalidate the original diagnosis. More commonly, the new finding is incorporated alongside it as a comorbidity.

This raises an important question:

What kind of evidence should cause an FND diagnosis to be reconsidered?

This is not merely a philosophical question. It lies at the heart of how medicine distinguishes between a diagnosis that is provisional and one that is considered established.

What Would Count Against an FND Diagnosis?

The challenge becomes apparent when we consider the range of possible outcomes.

• If symptoms improve, the diagnosis appears validated.
• If symptoms persist, the diagnosis may still be considered correct.
• If symptoms worsen, the diagnosis may still be considered correct.
• If another condition is discovered, the diagnosis can remain as a comorbidity.
• If no other condition is discovered, the diagnosis can remain as the primary explanation.
• If treatment succeeds, the diagnosis appears supported.
• If treatment fails, the diagnosis itself is not necessarily abandoned.

Taken individually, each of these positions may seem reasonable. Together, however, they raise an important question:

What observation, finding, or outcome would cause an FND diagnosis to be reconsidered?

Based on the current diagnostic framework, I struggle to identify what evidence would reliably falsify an established FND diagnosis. New conditions can be incorporated as comorbidities, while symptom improvement, persistence, or progression can all remain compatible with the diagnosis. Whether this reflects the nature of FND itself or limitations in our current understanding is an open question.

In other words, what evidence would count against it?

The Comorbidity Question

Comorbidity is perfectly reasonable. Patients frequently have more than one medical condition. However, if a newly discovered condition is capable of producing the symptoms originally attributed to FND, how do we distinguish between genuine comorbidity and a more complete explanation?

The question becomes even more interesting when viewed through the lens of Bayesian models and predictive processing. Are we observing functional fluctuations arising from prediction errors within the nervous system, or are we observing fluctuations that reflect an underlying disease process that the body is still struggling to repair or compensate for?

In other words, are the intermittent symptoms themselves the primary disorder, or are they a common response to an underlying condition that has not yet been fully identified or understood? Journal of Neurology, Neurosurgery & Psychiatry - Functional neurological disorder and predictive processing Assessment of Functional Neurological Disorders

Should Treatment Priorities Follow Diagnostic Hierarchies?

This raises another important question. In many cases, FND is treated as the primary diagnosis, while other conditions are framed as comorbidities. Yet reports within the literature frequently describe improvement in functional symptoms following treatment of these supposedly secondary conditions.

This observation does not prove causation. However, if treatment directed at the secondary diagnosis leads to improvement in the symptoms attributed to the primary diagnosis, should the secondary diagnosis remain secondary in our reasoning?

At the very least, this suggests that the relationship between FND and its comorbidities may be more complex than a straightforward hierarchy of primary and secondary disorders. Neurosymptoms - Common associated symptoms and comorbidity Assessment of Functional Neurological Disorders

The Common Phenotypes Hypothesis

One possible interpretation is that we may be looking at the problem from the wrong direction.

Rather than viewing FND as a primary disorder accompanied by a long list of comorbidities, it may be worth considering whether functional symptoms represent common phenotypes that can emerge from many different biological disturbances.

This would help explain why functional symptoms appear across such a diverse range of conditions, including autoimmune disease, infection, metabolic dysfunction, neurodegenerative disease, medication withdrawal, and structural neurological disorders.

Under this interpretation, the comorbidities cease to be a nuisance that must be explained away. Instead, they become clues that may help us better understand the phenomenon itself.

The Lesson of Dropsy

History offers an interesting parallel.

For centuries, physicians diagnosed a condition known as dropsy, a term used to describe abnormal swelling caused by fluid accumulation within the body. The diagnosis was not wrong. Patients really were swollen. The signs were real, and the suffering was real.

What physicians eventually discovered, however, was that dropsy was not a disease in its own right. Rather, it was a common presentation that could arise from many different underlying conditions, including heart failure, kidney disease, liver disease, malnutrition, and cancer.

The diagnosis did not disappear because it was false. It disappeared because it described a pattern rather than a cause.

This raises an interesting question for FND.

If functional symptoms repeatedly occur alongside autoimmune disease, infection, metabolic dysfunction, neurodegenerative disease, structural neurological disorders, medication withdrawal, and many other conditions, are we observing a primary disease entity, or common neurological phenotypes?

The question is not whether functional symptoms are real. They clearly are. The question is whether we are sometimes treating a presentation as though it were the explanation. Encyclopaedia Britannica - Dropsy NCBI Bookshelf - Edema

Naming Versus Explaining

This highlights an important distinction that is often overlooked: the difference between naming a phenomenon and explaining it.

Naming allows us to recognise a pattern. Explaining requires us to understand why that pattern occurs.

The diagnosis of dropsy successfully identified a recognizable clinical presentation, but it did not explain why the patient was swollen.

Similarly, identifying functional symptoms, positive signs, or characteristic patterns of presentation may help clinicians recognise a syndrome. Whether this also explains the underlying mechanism is a separate question entirely.

A diagnosis may successfully classify a presentation without fully explaining it.

Conclusion

This article is not an argument that FND does not exist. Rather, it explores the possibility that functional symptoms may sometimes represent common phenotypes that can emerge from many different underlying biological disturbances.

If that possibility is correct, then comorbidities may be more than conditions that simply coexist with FND. They may provide important clues about the processes driving the symptoms themselves.

Returning to Emma, should the discovery of MS have invalidated the original FND diagnosis, or should it have remained as a comorbidity? The purpose of this article has not been to answer that question, but to explore why answering it may be more difficult than it first appears.

This matters because the move toward positive, non-exclusionary diagnosis may lower the threshold for diagnostic closure in some cases. While this helps avoid endless investigation, it also creates the risk that emerging diseases may be overlooked or prematurely reframed as comorbidities.

The lesson of dropsy was not that the swelling was unreal. It was that naming a pattern and explaining a pattern are not the same thing.

If functional symptoms are common phenotypes, understanding the conditions that give rise to those phenotypes may ultimately lead to better investigations, better treatments, and a deeper understanding of the patients experiencing them.