Anti-ganglionic acetylcholine receptor antibodies in functional neurological symptom disorder/conversion disorder, 2023, Nagata et al

[Hutan]

https://www.frontiersin.org/articles/10.3389/fneur.2023.1137958/full
Open access

Team from Kagoshima, Japan

Objective: Autoimmune autonomic ganglionopathy (AAG) is a rare disorder characterized by autonomic failure associated with the presence of anti-ganglionic acetylcholine receptor (gAChR) antibodies; however, several studies have reported that individuals with anti-gAChR antibodies present with central nervous system (CNS) symptoms such as impaired consciousness and seizures. In the present study, we investigated whether the presence of serum anti-gAChR antibodies correlated with autonomic symptoms in patients with functional neurological symptom disorder/conversion disorder (FNSD/CD).

Methods: Clinical data were collected for 59 patients presenting with neurologically unexplained motor and sensory symptoms at the Department of Neurology and Geriatrics between January 2013 and October 2017 and who were ultimately diagnosed with FNSD/CD according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition. Correlations between serum anti-gAChR antibodies and clinical symptoms and laboratory data were analyzed. Data analysis was conducted in 2021.

Results: Of the 59 patients with FNSD/CD, 52 (88.1%) exhibited autonomic disturbances and 16 (27.1%) were positive for serum anti-gAChR antibodies. Cardiovascular autonomic dysfunction, including orthostatic hypotension, was significantly more prevalent (75.0 vs. 34.9%, P = 0.008), whereas involuntary movements were significantly less prevalent (31.3 vs. 69.8%, P = 0.007), among anti-gAChR antibody-positive compared with -negative patients. Anti-gAChR antibody serostatus did not correlate significantly with the frequency of other autonomic, sensory, or motor symptoms analyzed.

Conclusions: An autoimmune mechanism mediated by anti-gAChR antibodies may be involved in disease etiology in a subgroup of FNSD/CD patients.

 

[Hutan]

Hard to know where to place this one, dealing as it does with FND/conversion disorder, but suggesting an autoimmune mechanism for a subgroup.

It's a shame there was no control group, with a blinded evaluation of antibodies. (I haven't read the paper yet.)

The paper was first posted about on another thread, with a link to a twitter thread about it.

 

[RedFox]

What if ME and FND could have similar pathologies? Perhaps FND causes mostly overt neurological symptoms because the pathology only affects specific regions of the brain, where ME affects more of the brain and causes problems in other parts of the body.

 

[rvallee]

The conversion disorder stuff simply appears to be stacked on because reasons. Criteria were for neurological symptoms and a lack of diagnosis, it's just that the DSM criteria for "conversion disorder" are circular and basically apply to everyone with a neurological condition, the only exemption being a diagnostic. You could basically label this "not blessed by a medical priest" for all that it's relevant.

So basically, those are people with mostly dysautonomia. Shows how blatantly useless the FND labeling is. At this point, it's probably reasonable to think this is simply because FND is very marketable and will give the paper more prominence, but you could just as well apply criteria for demonic possession, or whatever.

Reading the symptoms list, huge overlap with ME. This may actually be somewhat relevant, despite the unnecessary marketing element. For sure this could be some LC cohort with some arbitrary criteria. Damn is medicine arbitrary when they don't have the biology nailed down, just all over the place with no concern for coherence or validity.

Invariably, when I see discussion in the wild about FND that finds anything biological, you will find a form of this reply: "so, it's not functional, then?" By which of course they all mean the magical generation of any and all symptoms by way of some imagined emotional distress that actually only means "not gonna bother with you". Or whatever.

 

[MSEsperanza]

Just incredible. Researchers in neurology find that 88.1% of their pts have an identifiable ANS issue, & 27.1% have anti-gAChR antibodies signifying AAG, a supposedly v rare neuropathy.

All those pts were originally dxed with FND/"conversion disorder".

There's something with this tweet I have been wanting to ask on the 'basic questions on research metholodolgy' thread for a while now -- even if it's more about language/ wording of study reports.

I wonder which is a large enough sample to report in percentages instead of natural numbers.

To me percentages, at a first glance, always appear to report representative figures.

I find it misleading to report only percentages in the abstract if you have a sample that's not large enough to be representative.

To be fair, the quoted paper does report the total number (and reports the subgroups in natural numbers) in the abstract and reads less spectacular than the Tweet. I think the Tweet is also misleading as the important info that the whole sample were patients with a FND diagnosis is postponed. I first read it as 88 percent of all patients in a neurological clinic not 88 percent of patients diagnosed with FND.

So of 59 patients diagnosed with FND in a particular neurological department the sample was taken from, 52 patients "exhibited autonomic disturbances" and 16 patients had anti-gAChR antibodies.


Paper's abstract:

Objective
Autoimmune autonomic ganglionopathy (AAG) is a rare disorder characterized by autonomic failure associated with the presence of anti-ganglionic acetylcholine receptor (gAChR) antibodies; however, several studies have reported that individuals with anti-gAChR antibodies present with central nervous system (CNS) symptoms such as impaired consciousness and seizures. In the present study, we investigated whether the presence of serum anti-gAChR antibodies correlated with autonomic symptoms in patients with functional neurological symptom disorder/conversion disorder (FNSD/CD).

Methods
Clinical data were collected for 59 patients presenting with neurologically unexplained motor and sensory symptoms at the Department of Neurology and Geriatrics between January 2013 and October 2017 and who were ultimately diagnosed with FNSD/CD according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition. Correlations between serum anti-gAChR antibodies and clinical symptoms and laboratory data were analyzed. Data analysis was conducted in 2021.

Results
Of the 59 patients with FNSD/CD, 52 (88.1%) exhibited autonomic disturbances and 16 (27.1%) were positive for serum anti-gAChR antibodies. Cardiovascular autonomic dysfunction, including orthostatic hypotension, was significantly more prevalent (75.0 vs. 34.9%, P = 0.008), whereas involuntary movements were significantly less prevalent (31.3 vs. 69.8%, P = 0.007), among anti-gAChR antibody-positive compared with -negative patients. Anti-gAChR antibody serostatus did not correlate significantly with the frequency of other autonomic, sensory, or motor symptoms analyzed.

Conclusions
An autoimmune mechanism mediated by anti-gAChR antibodies may be involved in disease etiology in a subgroup of FNSD/CD patients.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9968745/

Edited to add:

The author's conclusion in the paper:

"More than 80% of our FNSD/CD patient cohort had autonomic symptoms, and more than 25% of the cohort were positive for serum anti-gAChR antibodies, whether or not autonomic symptoms were present.

"To clarify the relationship between this psychiatric disorder and anti-gAChR antibodies, further investigation of clinical symptoms and the establishment of a measurement system for antibodies against the anti-nAChR subunit are needed."

 

[Sean]

Fair points, @MSEsperanza.

But at the very least it raises a serious question about the diagnostic reliability, relevance, and validity of FND, which seems important given what is at stake, and requires urgent and robust clarification.

 

[SNT Gatchaman]

So of 59 patients diagnosed with FND, 16 patients had anti-gAChR (no control group).

Which is an important finding when the formulation of FND, as secured by positive rule-in signs, means that there should be no further medical tests - and that doing more tests is both an unnecessary waste of scarce resources and will undermine the patient's recovery.

 

[MSEsperanza]

Yes, @Sean and @SNT Gatchaman --

Even if only one patient in this group had significant test results or could actually be diagnosed with another disease than FND, that would be an important finding.

Also, to be fair I haven't read the paper and have no idea how the 'diverse autonomic disturbances' were identified and whether the found antibodies (and their positive or negative correlation with some of the diverse autonomic symptoms) could actually point to something meaningful.

From the abstract, it isn't clear to me whether the presence of the found antibodies lead to an actual diagnosis of Autoimmune autonomic ganglionopathy in any of the patients -- also have to admit I never heard of this disease and only saw the Wikipedia article indicating that it "needs additional citations for verification".

It's just the way these results are hyped in the tweet without giving further details that I don't find helpful.


I share the hope though that the actual findings might eventually be helpful.


Apologies for repeated edits -- also edited my original post to add the authors' conclusion in their paper that I think justifies both cautiousness with interpreting the findings and hope that these could prove meaningful.

 

[Hutan]

Functional neurological symptom disorder/conversion disorder (FNSD/CD) is a neurological disorder of voluntary movement or sensory function with no medial or neurological cause; and is described in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5); as a long-term impairment that significantly impairs quality of life and requires assistive and supportive services (1). Because the etiopathogenesis of FNSD/CD is unknown and abnormalities in clinical tests are rare, FNSD/CD is generally considered to be a psychological disorder (2, 3).

Yet again we find people who use the FND label tripping over themselves. 'These are neurological disorders, but because we don't know what's causing them, they are generally considered a psychological disorder'. God of the gaps, the bin for stuff that's too hard.

Diagnosis of FNSD/CD in patients with non-specific motor-sensory symptoms can be difficult, and some are ultimately determined to have tumor-associated neurological syndrome or autoimmune encephalitis (3–6).In addition, elevated blood inflammatory markers have been reported in some FNSD/CD patients (7, 8), leading to the hypothesis that FNSD/CD symptoms may correlate with immune dysfunction.

I think more accurately, it's the tumour-associated neurological syndrome and the autoimmune encephalitis and something that might explain the elevated blood inflammatory markers that the doctor had trouble diagnosing. Diagnosis of FNSD/CD on the other hand was a piece of cake, a walk in the park, an 'oh, I don't know, this will do'.

To avoid misdiagnosis, physicians are recommended to not assign a diagnosis of psychogenic reactions to neurological symptoms that are difficult to explain, such as dystonia or atypical seizures. Indeed, DSM-5 and International Classification of Diseases, 11th Revision (ICD-11) no longer supports the term psychogenic factors as a cause of symptoms of neurological disorders such as involuntary movement.

I'm not too sure what this is saying. I think it's referring to the now abandoned requirement for there to have been childhood trauma, or just trauma. But, as for suggesting that FNSD/CD isn't a psychogenic reaction - well, I think there needs to be a bit of consultation among the FND crowd. Last time I looked, conversion disorder was very definitely a psychogenic reaction, and we've certainly seen a lot of definitions of FND that suggest that it can be fixed with better thinking. Like said above, this field is a mass of contradictions. I suppose at least these people are looking for a medical explanation.

 

[MSEsperanza]

It's a shame there was no control group, with a blinded evaluation of antibodies. (I haven't read the paper yet.)

As I edited my original post, I thought I'll add the section about how they measured/ assessed the antibodies compared to the control sample:

From the paper:

"Serum antibodies against gAChR α3 and β4 subunits were quantified using a LIPS assay (13, 19), in which specific antibodies are bound to a Gaussia luciferase-tagged antigen and the bound antibody is quantified by measuring luciferase activity with a luminometer.

"The results are expressed as relative luminescence units (RLU).

"Serum was considered positive for anti-gAChR α3 or β4 antibodies if the RLU of the test sample exceeded a cut-off value of three standard deviations (SDs) greater than the mean RLU of the control sample (sera obtained from healthy individuals). We evaluated the antibody levels as an antibody index (A.I.). A.I.= [measurement value of the sample serum (RLU)]/[the cut-off value (RLU)].

 

[Hutan]

Of those patients, 68 met the DSM-5 diagnostic criteria for FNSD/CD (1). Medical records were retrospectively reviewed for clinical symptoms and blood and cerebrospinal fluid (CSF) test results. After exclusion of patients with concomitant autoimmune neurological disease including Sjögren's syndrome, myasthenia gravis, systemic lupus erythematosus, chronic inflammatory demyelinating polyneuropathy, a total of 59 patients were included in the final analysis set

Just noting 68 patients attending the clinic appear to have been diagnosed with FNSD/CD. 9 of these had other conditions that surely might have produced some movement (this includes weakness) or sensory symptoms (this includes pain), I mean "chronic inflammatory demyelinating polyneuropathy"? And yet they still got a diagnosis of FND.

This paper only looks at the remaining 59 people.

 

[Hutan]

Among the individual cardiovascular autonomic symptoms, POTS and orthostatic hypotension were both more commonly seen among the antibody-positive group, but only the frequency of POTS reached the level of statistical significance (50.0 vs. 9.3%, P = 0.002). The prevalence of POTS is 0.5–1.0% of the population, mostly female (female/male: 5:1), so the prevalence in our patients is high regardless of the presence of antibodies.

Of the total cohort of 59 patients, 16 (27.1%) were positive for anti-gAChR antibodies, and of these, 11 were positive for antibodies against the α3 subunit only, one patient was positive for antibodies against the β4 subunit only, and four patients were positive for antibodies against both the α3 and β4 subunits (Figure 2).

As @MSEsperanza noted, positivity was relative to the mean of healthy individuals. There isn't any further detail given in this paper but the 2015 paper talks about the 73 healthy controls that were used to create the reference level.
Autoimmune autonomic ganglionopathy: an update on diagnosis and treatment, 2018

Clinical Features of Autoimmune Autonomic Ganglionopathy and the Detection of Subunit-Specific Autoantibodies to the Ganglionic Acetylcholine Receptor in Japanese Patients, 2015

Autoimmune autonomic ganglionopathy (AAG) is an acquired immune-mediated disorder that leads to autonomic failure. The disorder is associated, at least in part, with autoantibodies to the gAChR. Antibodies to the gAChR that are found in the serum of 50% of patients with the acute or subacute form of AAG correlate with disease severity, and have been shown to be pathogenic [3,4]. Several studies have reported that these autoantibodies induce the internalization of cell-surface nicotinic gAChRs and thereby impair synaptic transmission [4,5]. Furthermore, it has been demonstrated that antibodies to the α3 subunit of the gAChR or AAG serum have been shown to directly cause autonomic dysfunction in experimental animal models of AAG [6,7]. Although these antibodies are proving to be useful serological markers of AAG, the positivity of gAChR antibodies in acute or subacute panautonomic failure remains around 50%. Cases of idiopathic pure autonomic neuropathy have been reported since 1975 in Japan, and 29 cases of AAG have been reported [8]. However, no assays are available that detect the antibodies to gAChR in Japan, and this has caused difficulty in the diagnosis of AAG. Furthermore, antibodies to non-α3 subunits, including the β4 gAChR subunit, have not been identified in AAG to date.

I've run out of energy. I'm not sure what I think about this yet and I haven't read enough. There looks to be some evidence that the autoantibodies cause problems, but I'm not sure how they diagnose someone with AAG in the absence of the autoantibodies. Is this mainstream stuff?

 

[MSEsperanza]

Just noting 68 patients attending the clinic appear to have been diagnosed with FNSD/CD. 9 of these had other conditions that surely might have produced some movement (this includes weakness) or sensory symptoms (this includes pain), I mean "chronic inflammatory demyelinating polyneuropathy"? And yet they still got a diagnosis of FND.

I think investigating these 9 patients' illness / diagnosis trajectory, including reviewing the diagnosing clinicians' thoughts and decisions would be worth a paper too...