Can Functional Neurological Disorder Be an Indication of Prion Disease?

By David Tuller, DrPH

A recent article in the Journal of Neurology presents a twist on the issue of functional neurological disorder (FND). The article, which was published in September, is called “Functional neurological symptoms as initial presentation of Creutzfeldt‐Jakob disease: case series.” Creutzfeldt-Jakob disease is a prion disorder that leads to dementia and death, usually within months.

But first, some background.

FND is a clinical entity with “rule-in” signs that are designed to distinguish it from recognized or standard neurological disease, according to the Diagnostic and Statistical Manual of Mental Disorders. Formerly, FND was commonly known as conversion disorder. Before that, hysteria.

Once a neurologist has rendered a diagnosis of FND based on these rule-in signs, further testing to identify hidden pathophysiological dysfunctions is considered inappropriate. The FND diagnosis itself is the explanation—even if the proposed mechanisms remain poorly understood. The literature is clear: FND is not intended as a place-holder or provisional diagnosis to be used while doctors search for a better explanation for a patient’s symptoms.  

Some confusion about the construct is apparent from the differing prevalence rates routinely highlighted by leading FND experts. As I’ve previously documented, these experts have cited the prevalence of the condition among neurology clinic attendees as being 6%, 16% and 31%–with all three rates being drawn from the same study of Scottish neurology clinics.

Only the lowest prevalence rate—6%–is based on rule-in diagnoses, according to an authoritative 2016 paper. However, FND experts have generally preferred to cite the prevalence rate of 16%, which allows them to refer to the condition as the second-most common presentation, after headache.

But this 16% figure is inflated. It includes many patients identified in the Scottish study as having “psychological” problems but apparently without the rule-in signs required for an FND diagnosis. FND experts have perpetuated this confusion rather than demonstrating any inclination to clear it up. Perhaps they believe that promoting pumped-up prevalence rates is an effective way of drawing attention to the issue.

Misdiagnoses of patients as having FND when they actually have known neurological disorders are said to be rare. But whether they’re rare or not, they can be disastrous when they occur. (The counter-argument is that that misdiagnosing someone as having a known neurological disease when they actually have FND can also cause harm.)

Last May, an Irish court ordered a hospital to pay a young man six million euros for having failed to diagnose a brain tumor, an error that delayed necessary surgery by months. Doctors had misdiagnosed his headaches, concentration problems and hand numbness as “psychological and functional” and referred him to “the mental health services and physiotherapy,” according to The Irish Independent.

Physicians can be quick to default to psychological explanations when they don’t understand what is causing a patient’s problems, noted Brian Hughes, a psychology professor at University of Ireland Galway, in a blog post about the case. “It would be nice if the doctors concerned could perhaps try to be a little less hasty, and a bit more humble,” he wrote.


Prion diseases masquerading as FNDs

The article in the Journal of Neurology is not the first report related to FNDs and prion disorders. In 2017, researchers at Rutgers University in New Jersey published an article called “A Case of Sporadic Creutzfeldt-Jakob Disease Presenting as Conversion Disorder.” According to the abstract, “The patient was a 64-year-old woman with no prior psychiatric history who was initially diagnosed with conversion disorder and unspecified anxiety disorder but soon thereafter was discovered to have Creutzfeldt-Jakob disease.

In 2019, BMJ Case Reports published an article called Gerstmann-Sträussler-Scheinker syndrome misdiagnosed as conversion disorder.” Gerstmann-Sträussler-Scheinker syndrome is a genetic prion disorder. Here’s part of the abstract:

We present a 40-year-old man without relevant medical or family history who developed progressive neurocognitive and behavioural symptoms over 3 years. Initial extensive diagnostic workup of his variable motor symptoms was unrevealing and he was diagnosed with conversion disorder. This diagnosis persisted for over 2 years, despite progressive neurocognitive symptoms. He eventually developed dementia and severe neurological impairment.

And from the text:

“The diagnosis of a psychogenic disorder was seemingly substantiated at a subsequent hospital admission for falls, when inpatient video monitoring revealed inconsistencies in his neurological examination…He continued to experience progressive neurocognitive decline and presented to the emergency department repeatedly for falls due to gait disturbance. However, given his diagnosis of conversion disorder, his symptoms were interpreted as psychogenic.”

In other words, the presence in the patient’s records of a diagnosis of conversion disorder—that is, FND—meant that doctors continued to mischaracterize and misinterpret his worsening symptoms as psychogenic in nature. The patient died three years after the initial diagnosis. “In retrospect, it was likely that the variable nature of the abnormal movements was due to dystonia,” noted the article.


Were these FND diagnoses an error or correct?

Both of these individual case studies presented the FND diagnosis as an error that was later clarified. The Journal of Neurology study, from a team of Spanish researchers, frames the matter differently.

Here’s part of the abstract: “We report a clinical series of three patients who initially presented positive signs of a functional movement disorder (FMD) and were later diagnosed with a Creutzfeldt-Jakob disease (CJD). All patients presented with unilateral functional tremor, two patients also had functional limb weakness.”

(The authors parrot the party line on FND prevalence. They write that FND “represents one of the most frequent referrals to general neurology clinics” while citing the same study of Scottish clinics that has been referenced to support three different prevalence rates.)

In all three cases, the FND diagnoses were based on the presence of positive signs considered confirmatory for the condition. But it didn’t take long for these initial diagnoses to be revealed as insufficient. “Later on, a rapid clinical worsening occurred, and patients developed clear parietal and cerebellar signs that prompted the diagnosis of a prion disease,” the authors write. All three patients died within months.

Yet they do not suggest that the FND diagnosis was wrong or inaccurate. On the contrary, they seem to view the FND as part of the ongoing prion disease process or pathway. The full clinical picture, they write, “suggests that perhaps early prion-mediated neuronal loss might result in the involvement of brain circuits that are implicated in the FND genesis…Diagnosis of FND should not become immutable and an adequate neurological follow-up is, therefore, crucial.”

In other words, the authors are suggesting that the rule-in signs used to confirm an FND diagnosis cannot easily distinguish between an FND diagnosis that is a precursor of a prion disease and an FND diagnosis that is not a precursor of a prion disease. Therefore, they argue, the diagnosis should be provisional and not “immutable.”

(The authors’ efforts to communicate the meaning of their findings is marred by a sentence in the abstract that seems to have parts missing: “A positive diagnosis of FND is essential as it is an adequate examination and a close follow-up of these patients in neurology clinics.”

What does that linguistically and grammatically challenged sentence mean? Free subscription to Virology Blog for the best interpretation!!)

The authors contextualize their findings with a discussion of the literature about FNDs as co-morbidities in the presence of Parkinson’s and other known neurological conditions. At the same time as they present the FND diagnosis as a kind of place-holder pending further developments, they also seem to indicate that it exists as an entity independently of the prion disease. Here’s what they write:

“We propose that initial precipitants such as mood disorders that can be present at the onset of prion diseases (Patient 2) or minor trauma (Patient 3) associated with subtle sensory abnormalities in our patients might have driven increased attention to self-movements and facilitate a conscious motor processing. This, along with parietal dysfunction in our patients, may have facilitated the genesis of the FND.”

I find this kind of confusing—especially because the first sentence in the above paragraph, like the sentence in the abstract, is somewhat challenging to untangle. (Note to researchers: Please copy-edit your articles before they appear!!)

The explanation seems to be that early markers or indications of the prion disease led patients to engage in heightened monitoring of their symptoms—one of the prominent factors said to be involved in generating FND. And that these patients, therefore, actually suffered from FND as well as their prion disorder. So FND was the right diagnosis after all.

At least, I think that’s what they’re saying. But I could be wrong.

What would leading FND experts make of this article, I wonder? Would they consider these FND diagnoses to be misdiagnoses, or diagnoses that were properly made at the time? And do they have suggestions for how neurologists can distinguish FND from early signs of prion disease other than waiting for patients to get worse and die?

(Originally posted on Virology Blog.)