By David Tuller, DrPH
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It must be tough for investigators when a major study seeking to assess the effectiveness of an intervention for a challenging condition yields null results. That’s what happened in 2019 with a trial of rituximab for ME/CFS, published in Annals of Internal Medicine. Findings from earlier research had suggested that rituximab, a drug used to treat autoimmune diseases, might have an impact on ME/CFS. However, the trial results did not support the hypothesis, forcing the investigators to revisit their notions about the mechanisms driving the disease.
Last year, a large trial for functional motor disorder (FMD), a subcategory of functional neurological disorder (FND), reported similarly disappointing news. In a paper in The Lancet Neurology, published in July, the investigators of the trial, nicknamed Physio4FMD, reported null results for specialized physiotherapy on the primary outcome–self-reported physical function at 12 months. While those who received the Physio4FMD intervention had slightly better scores on this measure than those who received treatment as usual (TAU), the results were neither statistically nor clinically significant.
(The lead author posted a thread about the findings here.)
In such cases, investigators are often in the somewhat thankless position of having to publish further analyses, trying to find some silver linings even though their intervention has already failed its most important test. Since last month, the Physio4FMD team has published two additional papers: a look at factors predicting outcomes, and a cost-effectiveness analysis. (I might get around to looking at those in a subsequent post.)
FND, formerly called conversion disorder, is the current term for a category of neurological symptoms that do not fall within established disease categories. The sub-group of functional motor disorder includes arm or leg weakness and paralysis, gait disorders, and the like. These conditions, whatever their cause, can be chronic, seriously disabling, and resistant to treatment. In the past, they were generally viewed as psychiatric conditions. In recent years, FND experts have categorized them as “brain network” disorders. In reality, their etiology remains unknown.
This is the second time in recent years that a high-profile FND treatment trial produced null results for its primary outcome. In 2020, the CODES trial for psychogenic non-epileptic or “dissociative” seizures, another subcategory of FND, reported that cognitive behavior therapy was no more effective than standard care in leading to seizure reduction at 12 months. In that case, FND experts argued after-the-fact that seizure reduction was the wrong primary outcome and that “quality-of-life” measures were more important.
Just as CODES was the largest trial of dissociative seizures, this new FND study–“Specialist physiotherapy for functional motor disorder in England and Scotland (Physio4FMD): a pragmatic, multicentre, phase 3 randomised controlled trial”–represented a first for the field. Noted the paper: “To the best of our knowledge, Physio4FMD is the first fully powered randomised controlled trial of a physical therapy-based intervention for functional motor disorder and is the largest randomised study of people with functional motor disorder published to date.”
The trial’s primary analysis included 241 participants from 11 hospitals in Scotland and England, with 138 assigned to the Physio4FMD intervention and 103 to TAU. The latter consisted of whatever treatment the participants received, or didn’t receive, after referral to the local National Health Service (NHS) neurological physiotherapy service. The intervention included nine sessions over three weeks, with a final session three months later. (Recruitment began in 2018 but was interrupted by the COVID-19 pandemic. The paper goes to substantial lengths to explain how the team addressed these challenging circumstances, including in the statistical analyses.)
As described in the paper, the Physio4FMD intervention sought to focus on the factors presumed to be driving the symptoms, such as paying excessive attention to symptoms, and had three broad goals: “to help patients understand their symptoms; to retrain movement with redirection of attention away from focusing on their body; and to develop self-management skills.” The approach had undergone extensive development in the years before the trial. As noted, “the protocol builds on expert consensus recommendations for physiotherapy for functional motor disorder and was tested with promising outcomes in a prospective cohort study and a randomised feasibility study.”
The trial was unblinded and relied on subjective outcomes—a study design that generates an unknown amount of bias, for any number of reasons. In such cases, modestly positive findings are as likely to reflect the bias inherent in the design as any genuine impact of the intervention.
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Poor results on the primary outcome
In any event, the intervention did not produce the expected results. The primary outcome, the SF-36 physical function subscale, is a frequently used measure. As described in the paper, it “includes ten questions for participants to self-rate their degree of limitation when attempting vigorous activities (eg, running or lifting heavy objects), moderate activities (eg, moving a table or pushing a vacuum cleaner), carrying groceries, climbing stairs, walking various distances, washing, and dressing.”
Scores on the SF-36 range from 0 to 100. Higher scores represent better physical function. A score of 65 or below, for example, was considered disabled enough to be able to enter the PACE trial, which purported to prove that psycho-behavioral interventions could cure ME/CFS. In the Physio4FMD trial, the average scores at baseline were 26 and 31, respectively, for the intervention and TAU groups. That is very, very disabled. At 12 months, both groups averaged just over 37—still very, very disabled.
Besides not being statistically significant, the mean difference between the two groups at 12 months on the SF-36 was also, at 3.5 points, below the threshold considered clinically significant. On the SF-36, the threshold for a difference to be considered clinically significant is 10 points.
Among the many secondary outcomes, the Physio4FMD intervention arm scored better than the TAU arm on an overall rating of symptom improvement and on treatment satisfaction. But many other secondary measures had null results. As the investigators noted in the limitations section, given the number of secondary outcomes, some might have been found to be statistically significant by chance, and the analysis did not include the extra tests designed to minimize this possibility.
The rating of symptom improvement, called the clinical global impression of improvement scale (CGI-I), is much briefer than the SF-36. In the CGI-I, as the study explained, “participants rate their perception of improvement in answer to the question, ‘After physiotherapy, the problem with my movement is…’ with the responses either ‘much improved,’ ‘improved,’ ‘no change,’ ‘worse,’ or ‘much worse.’” The answers thus provide no indication of the respondent’s level of disability in relation to others—just in relation to their own prior subjective state.
Like the CGI-I, the SF-36 is self-reported and therefore subject to biases related to that status. Unlike the CGI-I, it covers a range of specific activities and requires the respondent to consider each one separately. With its 100-point scoring, the SF-36 allows for easy comparison of results with other populations. In the Physio4FMD study, no matter what participants reported on the CGI-I, they remained severely disabled overall, according to the primary outcome.
In summing up, the investigators concluded that,“taken together, the subjective improvements in symptom ratings along with the very high levels of satisfaction with treatment, suggest that specialist physiotherapy could be a valued and safe treatment option for some people with functional motor disorder.”
Suggesting that a treatment “could be” an option for “some” patients is not saying much. As for the reports on symptom improvement and treatment satisfaction, it shouldn’t be surprising that patients who receive care from compassionate clinicians are more likely to answer questionnaires positively than patients who don’t receive the same level of care. These responses should not therefore be interpreted to mean the intervention is effective–especially given the poor results for the more comprehensive and thorough assessment provided by the SF-36, the primary outcome.
The bottom line, per the SF-36 data, is that the patients in this trial remained extremely debilitated, whether they received the Physio4FMD intervention or physiotherapy at a local NHS service. That’s the take-home message here.
It sounds to me like the NHS won’t need to spend its all too stretched resources on specialized physiotherapy programmes for sufferers of functional motor disorder then and that treatment-as-usual will probably suffice. I suppose the substantial cost of conducting trials like this might perhaps be worth it if it saves the NHS from wasting more money, but I do wonder how much of the NIHR’s considerable spend per year goes on research like this and how many new hospitals could be built if the NIHR concentrated on funding good biomedical research and not on trying to prop up a failing biopsychosocial (physio-/exercise-therapy and/or psychotherapy) approach to healthcare. If savings are to made to UK healthcare spend, then I think the UK Government should look at the research that’s being publicly funded and assess how much of it leads to significant findings of patient benefit. Of course, it’s important to learn that treatments don’t work but, once that’s been established, shouldn’t that be the end of it? It’s pouring good money after bad that I have a problem with.
The situation with this study reminds me of a 2017 presentation about a primary care psychotherapy service for patients with medically unexplained symptoms (MUS), see here -https://www.youtube.com/watch?v=P_q3fzhGtUw at 29.20 mins. It’s suggested that patients value the service/have high levels of satisfaction with it but the outcomes don’t appear to match with those levels of satisfaction. I imagine that most people would like to talk and that most would appreciate some individual attention. Wouldn’t it be lovely if UK GPs could spend half an hour with each patient and consultants a good hour or more? I suspect that patients might be a lot less stressed if that was the case. But outcomes matter. If the treatment isn’t delivering on outcomes then patients surely deserve more than just the emotional boost/positive feelings they get from having individual attention? Also, I doubt that the NHS can afford for all of its patients to have individualized physiotherapy or psychological care just to deliver some emotional boost or a feeling of being supported.
What will the results of this study now mean for UK FND services? If some NHS services/neurology centres have been giving their FMD patients that individualized physiotherapy outside of the study, will it now be stopping? I’m not suggesting that FMD patients wouldn’t benefit from some physiotherapy but that they may not require the same level/degree of individualized therapy that they’ve perhaps been receiving from their services in recent years either as part of this study or outside it. We’re told that the NHS needs to make efficiency savings so it would seem sensible for it not to waste any money on services that bring no significant improvements in key patient outcomes.
As someone living with Functional Neurological Disorder, I find the tone and framing of this post not only disappointing but harmful. While it’s important to examine the results of trials like Physio4FMD critically, the piece seems more invested in undermining the legitimacy of the condition than in genuinely engaging with what the data means for patients.
The way FND is repeatedly portrayed, with loaded language like “failed,” “disappointing,” and “thankless”, reflects a wider dismissive attitude that those of us in this community know all too well. It disregards the growing body of research into FND as a brain network disorder, as well as the real value patients report from supportive, specialised care, even when statistical thresholds aren’t met.
The Physio4FMD study didn’t provide a definitive answer, but it offered insights that will shape future care and trials. That is how progress works. This constant need to discredit any positive movement in FND research helps no one, especially not patients who are already living with debilitating symptoms and navigating stigma in both the medical world and wider society.
What is most damaging, though, is the generalisation implied – that because this one treatment didn’t deliver statistically significant results on a primary outcome, the whole condition should be questioned. That is deeply irresponsible. Patients with FND deserve rigorous science, but also dignity, understanding, and belief. We are more than a disappointing headline.
I’ve read nothing in this post that undermines patients’ experiences and dignity. If I was an FND patient, I’d want to know that there was good evidence to back up the treatments that I was receiving. I wouldn’t want to waste my valuable time, money and energy on treatments that hadn’t been shown to be effective on primary outcome measures. I’d hope that medical researchers wouldn’t want that for their patients either.
I’d say that science thrives when it’s rigorously challenged. I think that all theories should be questioned – to me, that’s what good science is about. I’d go as far as to say that science is likely to stagnate or degrade unless scientific theories, research work and its reporting ARE sufficiently challenged. I’d be grateful if someone kept medical scientists on their toes in relation to a disease or condition that I was suffering from, whether they did that purely from an academic interest point of view or because they had sympathy/empathy for my suffering, or both. I’d welcome it with open arms – the more challenge to the ‘science’ the better as far as I’m concerned and I believe that it’s especially important when there are pressures on healthcare resources and when limited research funding needs to be directed at the most promising lines of enquiry.
Thank you CT for your engagement, though I’d like to offer a perspective from someone actually living with FND and who has been actively advocating for better care and research for over a decade.
No-one is arguing against rigorous science – quite the opposite. The FND community has been asking for higher quality, larger-scale research for years because for too long this patient community has been neglected. The Physio4FMD trial, while not showing statistically significant results on the primary outcome, is part of that much-needed research process. Understanding what doesn’t work is as important as finding what does. It’s disheartening to see such trials framed as failures rather than necessary steps in progress.
I must stress, there is a growing body of international research supporting the neurobiological basis of FND. It is now considered a disorder of brain network dysfunction – not a psychosomatic leftover from outdated medical thinking. So when FND is consistently bundled under a “wasteful biopsychosocial” label, it risks dismissing not only valid research lines, but the patients themselves – many of whom live with profound disability and stigma, despite meeting modern diagnostic criteria based on positive clinical signs.
I understand the concern for healthcare resources – we all share that. But what many don’t see is the cost of not treating FND well – frequent emergency attendances, unnecessary investigations, and long-term disability. If patients don’t receive evidence-based support, the system pays a price anyway – financially and ethically.
The suggestion that people with FND just receive an “emotional boost” from care is an oversimplification that doesn’t reflect the complexity of rehabilitation or of being a patient. Trust in your clinician and being believed is part of effective care, especially when navigating a condition long dismissed and poorly understood. That isn’t a placebo – it’s a foundation for engagement.
Lastly, I agree that science should be questioned, but with the aim to improve it, not invalidate patient experiences or the entire diagnosis based on one trial. Constructive critique is vital; so is nuance and empathy.
FND patients deserve to be part of these conversations as equals, not as subjects of debate whose lived realities are constantly up for question.
As another person living with FND who is disappointed by the results of the trial, I would not wish the lessons learnt to go unheeded. The case of Jamie Lacelle makes it plain that physio can restore near normal life to flailing limbs so its use should not be abandoned ..(even if the ‘usual’ will not suffice) but further investigated with greater nuancing. l also believe , but don’t have the breadth of evidence to confirm, that the NHS is far from wildly spending its resources on ‘physio4fmd’ or indeed on very much for FND as a whole, or why would there be a parliamentary petition to request more help for what the fnd guru Jon Stone has called ‘ disease apartheid’ when it comes to treatment for us? The NICE pathway is unfunded. FMD patients I know, myself included may have received a couple of sessions of ‘the usual’ neuro physio ..to very little effect. It’s all work in progress and we need progress asap
Who says I’m not living with FND, (whatever FND actually is)? I was diagnosed with MCI, and since FND proponents seem to have commandeered MCI and renamed it FCD, I think that, at least, should qualify me to comment on FND matters. I don’t doubt for one moment that patients diagnosed with FND have been badly neglected but I don’t think it’s a good idea to continue to flog a dead horse when a treatment has been found to have null results. I have no particular issue with the NIHR funding this trial (although at this juncture I’d probably have prioritized funding biological research into the cause above research into a specific physiotherapy approach) but I wouldn’t be happy if the NIHR continued to fund further research into the same treatment. I think I was clear about the importance of finding out what doesn’t work as well as what does.
And who’s saying that there isn’t a neurobiological basis of FND? David wrote: “In reality, their etiology remains unknown.” He didn’t suggest that it isn’t neurobiological.
I’d be delighted if the psychosomatic theory was consigned to history, but as recently as 2019 it appears to me to have been promoted and up for discussion in relation to dizziness/PPPD (see here -https://www.youtube.com/watch?v=DqDTAHUMnq4). I’m not sure if that was before or after the FND brain network theory emerged. I think it’d be great if UK-funded research concentrated on the biology, and the ‘psych’ aspects of diseases took a back seat for a while. (Not that they’re unimportant – I’m all too aware of the psychological and social impacts that diseases/conditions can have on patients – but for decades the psych angle seems to have been prioritized in order to paint patients as somatizers who just needed to view their illness in a different way to get better. In my opinion, that WAS stigmatizing. I think it’s high time that biology got a look in.
I’m not sure that the modern diagnostic criteria for FND are really all that modern though. As I understand it, some of the so-called positive signs have been around for a very long time and were historically used to exclude ‘organic’ disease. I fear that dispensing with diagnosis by exclusion and relying on the ‘positive signs’ will increase rather than decrease misdiagnosis of neurological conditions as other investigations might not be as thorough as they were in the past. What’s wrong with doing both? Just the cost, I imagine, but I think the cost of not identifying and managing chronic diseases/conditions well is likely to come back to bite with regards to lost productivity due to illness-related economic inactivity (as I have stressed in previous comments), whatever the disease/condition is – FND, ME/CFS, Long Covid or whatever.
In my comment above, I was referring to treatments generally that aren’t delivering on outcomes when I said about patients just getting an emotional boost/positive feelings from them. I was not referring to FND patients specifically, indeed the presentation that I linked to was in my mind when I wrote that. It is for researchers and doctors and healthcare funders to come up with well-evidenced care packages that are beneficial to their patients. I’m sure lots of patients would appreciate care packages that make them feel supported but money is pretty tight and clinical efficacy must be prioritized over that, I think.
As far as I can see, nobody was invalidating individual patient experiences on the basis of this trial, but the implementation of safe and effective medical treatments relies on findings being positive over a significantly large number of people. If that had been the case in this trial, then the physiotherapy programme in question would have had evidence to support its use, but that didn’t happen. Like with the rituximab trial for ME/CFS, that’s likely to leave some patients disappointed if they believe they might have gained from the treatment. Medical science can seem quite brutal and patients generally don’t have much of a say in it.
I hope that FMD patients will continue to receive physiotherapy from the NHS, just not from this specific programme. I may be wrong but it looks to me as though the NHS’s Walton Centre in Liverpool may have a dedicated physiotherapist for FND while patients with MS, Motor Neurone Disease, Neuromuscular disease and Neuromyelitis optica are seen by the centre’s team of physiotherapists for long-term conditions. Perhaps the FND physiotherapist was just there for the duration of the Physio4FMD trial though or transfers from the other team for FND sessions? I suspect that most consultants would like more money to be spent in their particular area of medicine. FND sufferers (and their supporters) are almost certainly not alone in campaigning and petitioning for greater funding and better services for what they believe to be an under-resourced condition; I’m pretty sure that ME/CFS patients could testify to that.
As anyone with a rare condition will know, getting funding for clinical trials for relatively small and underserved patient populations isn’t easy so I applaud Dr Neilsen for setting up and conducting this trial and for the follow up papers about costings (NICE really need to change their £20k yardstick, eh?) and predictions. My understanding (from someone in the HU FND Hub) is that the original intention was to provide 12 sessions of physio to those in this arm of the trial but that because of Covid, some people only received 8 sessions. It would be good to get clarification about this from Glenn, especially for those of us who don’t use twitter, possibly via a comment here.
I agree that some of the language used could be upsetting for people with FND and/or FMD but it was ‘guru’ Jon who referred to people with FND as ‘tiresome’ based on a few conversations with his colleagues rather than a mixed methods review. His ‘top trumps’ stuff probably didn’t help either and it’s erm, interesting that he says that the term ‘functional’ is being used because it’s the least offensive term, which could be offensive to people who are aware that this term was chosen partly because it’s ‘easily used with patients’. He’s also still using the dehumanising/dumbing down ‘software’ analogy (‘Do their computers have hormones or get weather related migraine attacks? Mine doesn’t and I’ve read ‘why your brain is not a computer’ and am aware of the controversies about the Bayesian brain construct’) even though he must know that a) many patients don’t like it and b) we now know that neurologists use this analogy to align their language with that of patients when making this diagnosis which won’t work because they are not mind readers so don’t know who’s read what so it has the whiff of medical gaslighting/hoodwinking. As does using the term ‘functional’ to aid diagnostic acceptance of FND because it doesn’t overtly point to a mental health disorder diagnosis yet some of us know that FND is in DSM (not that many people seem to get told that at the point of diagnosis, possibly because of all the ‘limits to truth telling’ malarkey).
We’re also in a situation (and this is clearly not Jon’s fault or responsibility) where people with rare conditions (mostly women, but not always) are being initially misdiagnosed with FND on the basis that they don’t have Parkinson’s and, if they question the diagnosis they get told that questioning the FND dx proves that it’s the right dx (it doesn’t). This can derail their diagnostic odysseys, sometimes permanently, or delay them which almost invariably causes iatrogenic harm. Again, not Jon’s fault but I was surprised that he didn’t publish this information when it was posted via his feedback button or comment on it in house, as it were, since he’s usually quick to try to bust myths about FND and I think/hope he knows that recording a FND misdiagnosis officially is fraught with difficulties so will want to challenge and remove the many barriers involved now that he’s getting slightly better at doing meaningful patient engagement.
However a bigger challenge for all involved with FND might be sorting out the fairly recent FND/DSM fiasco https://doi.org/10.1177/07067437241245957 which is detrimental to people with FND and detrimental to FND research. I wonder who’s going to step up to take responsibility for that or if they’re all going to be allowed to hide behind the non disclosure agreements.
As for whether I have FND or not – who knows? Some people seem to think that everyone with Mal de Debarquement Syndrome (we’re mostly women, as with FND) had FND and, therefore, we get automatic entry into DSM (usually without our knowledge and almost certainly without our consent), but others don’t. Either way, I am very lucky to be in remission from MdDS and although I still have medically induced ongoing complex traumatic stress (aka ‘a sane response to an insane situation’) from all the gaslighting etc, I know I’m in good company in that respect, at least.
Here’s some commentary about this clinical trial from someone in the FND Hub I’m in who felt they were ‘lucky’ to get into the cat c group (neurophysio) of the trial arm. I have their permission to post. I am not sure if they have a diagnosis of FMD as well as FND but am aware that the trial was about FMD.
Hi, I was on that trial as I was sent to neuro-physio by my neurologist and it was my therapist who suggested I may have FND. I was put on the trial and got neuro-physio rather than physiotherapy. I found it good in the fact it got me walking again and was 1to1 but Covid hit before it ended so could not finish, my therapist then moved and never heard anything so left in the dark really. It was good while it lasted, but didn’t get to the last part which was about the brain and memory ( which I suffer with). Maybe it was the Covid that had a factor? I also know from on here it’s a post code lottery who you get therapy wise, I find physio now is to hands off but hydro therapy was good but short (1to1) and neuro-physio was good had three weeks and then on trial was due to be 12 sessions but only got to do 8 . I was at kings London and they have a big neurological department.
With respect to PJM’s comment above:
I’d like to know who diagnosed the trial participant with FMD in the case reported there. Did the therapist diagnose FMD (in addition to suggesting it) or did they refer the patient back to their neurologist for further evaluation/diagnosis/confirmation of the diagnosis? I assume that to be recruited to the trial the participant should have already been diagnosed with FMD by their own neurologist?