Sensory Receptors, Small Fibres and Neuropathy

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September 21, 2022 | 33 Comments


  1. I am posting a comment that I previously published on the Research Forum page, in the “Overview” section. Dr. Healy told me that it might be relevant to add it to this post. It would be interesting to have an informed opinion on such a study from neurologists or researchers who are familiar with the protein microassay technique. Please feel free to share this comment. Here is the comment :

    I am writing to introduce a potential study to assess autoantibodies in people with PSSD using protein arrays. This technique allows us to assess the autoantibody profile of people with the disease. I also explain why the discovery of a “PSSD’s autoantibody fingerprint” would provide us with a potential diagnostic tool and aid in our future research.


    Autoantibodies are a hallmark of pathologies involving the humoral branch of the immune system. Autoantibodies play a causal role in several autoimmune conditions such as Hashimoto’s disease (anti TSH receptor autoantibodies), some forms of Addison’s disease (anti 21-Hydroxylase autoantibodies) or Graves’ disease (anti-thyroid-stimulating immunoglobulin (TSI) autoantibodies). Autoantibody testing is therefore a useful tool for diagnosing certain autoimmune diseases. However, limiting autoantibody testing to the diagnosis of autoimmune diseases is a misconception. Autoantibodies are present in many diseases even if their role in these diseases is not elucidated or if their role is not causal. Therefore, autoantibody profiling is even discussed as a diagnostic tool for diseases that are not directly related to immune system dysfunction.

    Some example :

    -A Protein Microarray Signature of Autoantibody Biomarkers for the Early Detection of Breast Cancer ( : “From these, 119 antigens had a partial area under the ROC curve (p 91% specificity. Twenty-eight of these antigens were confirmed using an independent serum cohort (n = 51 cases/38 controls, p < 0.05). Using all 28 AAb, a classifier was identified with a sensitivity of 80.8% and a specificity of 61.6% (AUC = 0.756)."

    -Using protein microarray to identify and evaluate autoantibodies to tumor-associated antigens in ovarian cancer ( : "An optimized panel of three anti-TAA (GNAS, p53, and NPM1) autoantibodies was identified to have relatively high sensitivity (51.2%), specificity (86.0%), and accuracy (68.6%), respectively. This panel can identify 51% of OC patients with CA125 negative. This study supports our assumption that anti-TAA autoantibodies can be considered as potential diagnostic biomarkers for detection of OC"

    -Exploring autoantibody signatures in brain tissue from patients with severe mental illness ( ) : "Among the detected autoantigens, higher IgG reactivity in subjects with schizophrenia, as compared to psychiatrically healthy subjects, was found against the glutamate ionotropic receptor NMDA type subunit 2D (anti-GluN2D)."

    – A very interesting study regarding small fiber neuropathy (SFN). In this study they isolated some potential auto antibodies that could serve as a potential biomarker for SFN. Novel Autoantibodies in Idiopathic Small Fiber Neuropathy ( : "Nine autoantibodies were screened with statistical significance and pFC criteria in both cohorts, with at least 50% change in serum levels. Three proteins showed consistently high fold changes in main and validation cohorts: MX1 (FC = 2.99 and 3.07, respectively, p = 0.003, q = 0.076), DBNL (FC = 2.11 and 2.16, respectively, p = 0.009, q < 0.003), and KRT8 (FC = 1.65 and 1.70, respectively, p = 0.043, q < 0.003). "

    (caveat: some diagnostic tools, even if they have high specificity, may lead to overdiagnosis. If a large population is screened with a diagnostic tool that has low specificity, it will yield many false positives. This leads to overdiagnosis and therefore overtreatment. All touted diagnostic tools or biomarkers must be carefully considered and the benefit/risk ratio carefully assessed. Screening is not harmless. The pharmaceutical industry is known to push screening. The above study should be read in the light of this warning).

    As we have seen, autoantibodies may represent a fingerprint of a specific disease. Therefore, it would be interesting to assess the "autoantibody fingerprint" of PSSD. Assessing the autoantibody fingerprint of PSSD may have several advantages: First, it could provide us with a potential biomarker (thus a diagnostic tool). Second, it could be useful to guide us in further research, as a specific set of autoantibodies may suggest some type of dysfunction.


    There are several techniques to evaluate the existence of antibodies against a specific antigen:
    – ELISA: A specific antigen is coated on a well and probed with serum. By using a labeled antibody specific to the idiotypic determinant of human antibodies, it can be verified whether or not antibodies have bound to the self-antigen being evaluated.
    – Western blot: A mixture of self-antigens is separated by electrophoresis. The separated bands of known antigens are then probed with the sample suspected to contain specific antibodies for one or more of these antigens. The reaction of radiolabeled antibodies specific for the human idiotypic antigen determinant is detected.
    – Bead-based assay: The antigens of interest are bound to beads. The beads are probed with sera. A secondary antibody (antibody specific for the human idiotypic determinant of human antibodies) is used.

    Other techniques also exist. However, none of these techniques can screen the entire human proteome. To overcome this problem, a protein microarray composed of the entire human proteome can be used. The Baylor study used DNA microarrays to assess gene expression relative to a control. The same can be done using a protein microarray, except that the wells of the microarray are made up of proteins and serum antibodies are probed, not labeled cDNA from patient RNA. This will allow for the screening of a wide range of potential autoantigens. Depending on the microarray used, it may cover the entire human proteome.


    A case-control study can be performed. A group of people with PSSD can be compared to a group of healthy volunteers. Serum from each participant will be collected. The serum will be added to all microarray wells (each well contains a specific protein). We wash the microarray plate to remove antibodies that did not bind to the proteins. Using a radiolabeled secondary antibody specific to human antibodies, we detect the autoantibodies that have reacted with the proteins in the well. We compare the result of the case group to the control group. The size of the cohort must be carefully considered in order to achieve statistical significance.


    As mentioned above, such a study can provide us with a biomarker for PSSD and thus a diagnostic tool. Depending on the autoantigen and autoantibodies found, it could guide future research because a specific set of autoantibodies or autoantigens could be specific for a certain type of dysfunction. In addition, if relevant autoantibodies are found, they could be evaluated in another study among people with PFS or PRSD (using ELISA or western blot because protein arrays are very expensive). This would provide further evidence that PSSD, PFS, and PRSD are the same disease, even if accordding to the symptoms it seem obvious.

    The Baylor study also had a drawback, their biopsy was very localized in one specific area. They did a scrotal biopsy. Gene expression is of course very dependent on the tissue being evaluated. This is less the case if we collect serum. Also, it is much easier to collect a blood sample than to do a biopsy. This represent an other advantage of this study.


    One limitation of this study is its cost. I have not made a thorough estimate of the cost of such a protocol, but some of the materials needed may be expensive. A protein microarray plate costs about $1500. Suppose we recruit 60 patients (30 with PSSD, 30 healthy volunteers), it would cost about $90,000 just to obtain the microarray plate. Serum collection is actually very cheap. Other equipment would be needed. So we can estimate that such a study would cost about $110,000. We also need to find a research team that can conduct a protein microassay experiment and is willing to perform such a study.

    We also need to consider the sensitivity and specificity of a diagnostic tool that looks for autoantibodies. If the specificity is low (e.g., 96%), it cannot be used as a diagnostic tool because it would produce many false positives.


    Finding a "PSSD autoantibody fingerprint" may represent a great achievement. It could provide us with a diagnostic tool and guide us to interesting new leads. Thank you for reading, let me know what you think.


    This website went up just today.

    It is full of motivated PSSD sufferers, who are trying to find answers for PSSD, and expose the reality of PSSD to the world.

    Check out the photo campaign. They are going to add more and more photos over time.

    • Have just taken a look at the new website, Spruce. Its appearance is attractive with well-planned information and is easy to navigate.
      The idea of have pictures with stories is particularly good – gets the human touch without actually seeing the full face. It seems that a problem that many sufferers have is that of being “found out”. In the way that this has been overcome here, their story is out but part of their identity is still their own. I hope that more and more sufferers will add their messages and photos there. I also like the lack of colour – gets the gravity of the subject across by just having the black and white.
      I will make sure that members of our Withdrawal Group have access to this website.
      I wish the group all the best of luck with their new venture.

  3. I hope that the Finnish group publish a paper about this ASAP! A neurologist I spoke to said that the majority of neurologists reject PSSD and its sister conditions as plausible neurological conditions as nerve conductance tests usually show no abnormality. Obviously, such tests are not useful in detecting SFN.

  4. This is a great post, so intriguing to hear of the Finnish PSSD group and the positive SFN biopsy results and to see the possible overlaps in all the conditions mentioned. I have tingling in my legs which started whilst reducing Seroxat. 3 years off I still have it. It can be intense at times and becomes incredibly uncomfortable. I also have palpitations, fatigue, exercise intolerance, tinnitus, dizziness and odd heat sensations across different parts of my body (amongst other things) As I’m sure others can relate to it’s very difficult to try to describe some of these things when people can’t see them. An aunt with long covid has some similar symptoms, her referral to a long covid clinic gave no clues for any useful treatments for her.
    Things like PoTS, Fibromyalgia and Dysautonomia have interested me as withdrawal seems to bring about similar symptoms. Sometimes people end up with a Fibromyalgia or CFS diagnosis, both of which can also have links with SFN.

    The one thing that has always made sense to me is Dysautonomia. When I’ve researched this I feel my experience maps somewhere within the broad scope of Dysautonomia symptoms but it’s very difficult to get this recognised. A fast heart rate led to a ECG and 24hour holter monitor. My ECG was normal. I’ve been asked several times if I’ve ever had Covid and had the usual blood checks for Diabetes, Glandular Fever, Thyroid, and B12 which again have been normal. I have chronic fatigue syndrome now written on my notes. I’m fascinated to see where these links to skin and nerves could lead and whether people who have been unable to get answers elsewhere could learn more through the tests mentioned here.

  5. Please note that sexual dysfunction symptoms like ED, lack of arousal, lack of lubrication as such are long known symptoms of autonomic system neuropathy. Many pssd etc syndrome sufferers also have other common autonomic neuropathy symptoms: constipation, bladder, lack of sweating, lack of appetite, even sleep issues. This is what lead me to be convinced long ago that pssd and alike involve autonomic neuropathy. I am surprised the research has not made this connection before.

    David: l hope you add these pieces of info to your good article here. People need to understand the whole range of autonomic neuropathy symptoms in this context (some have more, some less)

  6. There is a PSSD group in Finland of all places? And doctors who believe and support them? How can I get involved? I’m a local sufferer and wouldn’t mind going through a couple tests if it isn’t too expensive. But really, the hardest part is actually finding someone who knows about this and is willing to investigate it to such an extent.

  7. Can anyone help with some information about how one can access these tests? I’m in the UK and I think it’s unlikely that my GP will order anything that isn’t listed in a NICE guideline. Are there clinics that offer these tests privately? Thanks.

      • How do I volunteer? I have been s/b a Dorset neurologist – not interested enough to do any investigations after the predictable negative nerve conduction studies, autonomic screen, B12, HbA1c and etc.
        Told ‘idiopathic’ – no point in further Ix as there is no Px.

  8. I have been consistently prescribed antidepressants, and regularly switched from one to another for the past 40 years. Prescribed for emotional distress, feelings of not coping, feeling very tired, brain fog, PMT, etc. etc. The underlying cause of my emotional distress i now understand to be ACE’s.
    I have suffered, and still do, with PSSD, tardive dyskinesia and brain fog. I have a diagnosis of small fibre neuropathy with extrene symptoms of fatigue, strange sensations like burning, stinging throughout my body, body weakness, and numbness and tingling in my hands and feet. The symptoms are getting worse, as i taper off VENSIR. I have tapered from 150mg to 96mg over approx the past 3 years. My tapers are now of 1mg at a time, to help minimise the withdrawal effects.
    I am now only able to work a few hours per week, due to the symotoms of, what i now understand to be ^some form of neuropathy” as quoted by a doctor, who also said”that your nerves arent working properly”.
    I had anothet nerve conduction test carried out 3 weeks ago and have a telephone consultation with a GP in just over a week to discuss the results.
    So i now have to deal with the damage caused by antidepressants, and i wonder whete i have been all my life.
    Not once as far as i can remember, until this year, did any medical proffesional ask me “has anything happened to you^?
    “What do you mean? I asked to which she replied “have you suffered any trauma”?. It has taken 40 years!!!! So now, as i taper, no doubt, my memory will become clearer. I dont care what happens now

  9. Can it still be Small Fibre Neuropathy if I don’t struggle with numb genitals but have other PSSD symptoms? Some emotional blunting as well

    • Anyone who has been on antidepressants and has withdrawal, autonomic or skin/neuro issues, should think about getting a skin biopsy done for SFN


  10. I am struggling to understand, and how to explain to the doctor, why I would request a skin biopsy, if a nerve conduction test has been carried out. Can you explain further please? Thank you

    • Nerve conduction tests look at the funtion of largely motor fibres. In this case the problem appears located in small fibres carrying sensory signals. A very large proportion of people with sensory neuropathy have normal nerve conduction tests.


  11. Also, how do I explain to the optician why I am requesting a Corneal Confocal Microscopy test please, if I have SFN?

    • An optician won’t do CCM tests. Its an ophthalmologist (and eye doctor) and especially a neuro-ophthalmologist who can. There are a host of vision problems linked to SSRIs. See recent RxISK vision post and downloadable article. With CCM there is no biopsy – its looking at nerve fibre endings under microscopy


  12. Im a psychologist in the US and I have made numerous attempts to discontinue antidepressants only to experience significant withdrawal symptoms. I’ve been on antidepressants for 25 years at this point and have made four unsuccessful attempts at tapering. I have come to learn that most doctors have absolutely no clue how to taper and have no understanding that withdrawal is a reality that can be severe and long lasting. After making an attempt to taper off of Effexor last year, I once again began to experience withdrawal symptoms which were mostly sensory in nature. When I started to experience autonomic nervous system symptoms, I then took it upon myself to find a neurologist to do a skin biopsy to determine if I had small fiber sensory neuropathy. She also sought to rule out MS (which I didn’t suspect). Of course, my brain and spine MRIs were normal as was my EMG. The skin biopsy was positive for small fiber neuropathy which was upsetting but did not come as a surprise. I have significant reduction in the small nerve fiber density. Symptoms, of course, were relieved by the reintroduction of the medication. As far as I know, at this point I don’t have PSSD. My question is: Is it the process of withdrawal from the antidepressant that causes the small fiber neuropathy or is it from the effects of the drug itself on the body?

    • Carol

      Thanks for this. My sense is the meds cause the neuropathy. Going back on can mask the symptoms again – just as going back on antipsychotics can mask the Tardive Dyskinesia the antipsychotics have caused. It might be worth it for the symptom relief but the bind is you remain on the drug that is causing the neuropathy.

      Some people can stop these drugs easily – just as some can stop antipsychotics. But others get TD on stopping antipsychotics and tapering is not a cure for this. In the same way, my sense is Protracted Withdrawal indicates neuropathy and it would be good if everyone with protracted withdrawal and enduring features after stopping could get tested for SFN. I imagine there would be a substantial positive rate.

      Small sensory fibres can regenerate. So we have to find ways to encourage them to do so. This is likely easier done off the triggering medicine than on it.


        • Am working on this. There is hope. It can be done. In the meantime it is worth you and others googling just this issue and seeing what you can find


  13. So following a routine eye test today, i was reminded that i have Astigmatism and dry eyes (both side effects from antidepressants).
    When i asked if i could be sign posted to an Opthalmatologist for a CCM test, and i explained, to help identify for small fibre degeneration, the Optician said that she could do this, and she identified no problem.

  14. Hi, I’m a severe PSSD case (close to 8 years). I did skin biopsy on ankle twice. Unfortunately (?) SFN not justified 10.5 nerves/mm. I have genital numbness and everything else.

    • J

      Thanks for this important comment. There will be a RxISK post about this next week – hopefully. It looks like some people with negative biopsies around the ankle have positive biopsies further up the leg. There will be a reference to this in the next post


      • Thank you Dr Healy! In that case I may go back to a 3rd one. It would be good to know the exact location and reference ranges for that.

        • J

          Post will be up tomorrow and will give you a downloadable link to the genital neuropathy article. The problem with doing a biopsy on the thigh is there are no reference ranges as there are for ankles.

          But as the sensory neuropathy post makes clear, standard reference ranges for ankles don’t take age into account – so I think there is a need for a degree of discretion in this area.


  15. To quote the study “Can VEGF reverse diabetic neuropathy in human subjects?”:

    “VEGF gene transfer 12 weeks after the induction of diabetes fully restored nerve function abnormalities studied in both large and small fibers. Furthermore, VEGF restored nerve blood flow and nerve vessel numbers to levels that were observed in nondiabetic animals, indicating that VEGF exerts its beneficial effects by promoting angiogenesis in the peripheral nerves”

    • For anyone getting a biopsy done outside of Sheffield, it would be good to get all of the tests listed in the post done along with anti-muscarinic and anti-ACE antibodies.

      In terms of a paper, at the moment it only makes sense to think about basing a paper on the cases done in Sheffield as they will have all been done in exactly the same way.

      But its important at the same time to have as many people tested as possible with some collection of the results in the same place to try and see what patterns there might be

  16. Thankyou so much.
    I finally managed to wean myself off high dose venlafaxine (600mg) & high dose trazadone (300mg)- it took years and had no idea of others doing so or awareness of groups dedicated to this.
    Since then, I have had persistent insomnia and have SFN – burning in my feet to the extent that I cannot wear shoes even in winter and use ice slippers, which need replenishing, through the night.
    I was referred to a neurologist here in the UK, who was not interested. Told me there was no point in doing skin biopsies as no treatment was available.
    Fortunately as far as ‘mental health’ is concerned, I am well and working -have been for years.

  17. I find a lot of what you say is interesting and evidence-based/seeking, but the throw away comment “PSSD is a lot worse than Long-Covid” appears to me misinformed and unqualified. Firstly, I am unsure of the value in comparing conditions in this way and where both cause such serious impacts on px QoL – why seek to minimise one set of pxs experiences over the other? Secondly, does the literature support your statement? I do not believe it does, but would be interested to hear your thoughts.

    Here are five peer-reviewed papers in respected journals and which cover topics such as dysautonomia, SFN, POTs, and erectile dysfunction in long-covid. The weight of evidence seems to stand against your statement.

    Additionally, your closing plea invites those with long-covid to join in with the conversation… “Finding out what is preventing recovery is most likely to happen where there is liaison between the enduring sexual dysfunction groups, the withdrawal community, and the vaccine injured.”, however I believe you risk alienating the long-covid px population by your earlier stating “PSSD is a lot worse than Long-Covid”. Your statement minimises the experience of millions of long-covid pxs – despite many of facing (very) similar challenges to those with PSSD.

    The long covid population deserves actively engaging – as does the PSSD population. However, the long covid pop. will doubtless receive significant funding in the immediate future given the known size of affected populations. Perhaps there is scope for a collaborative study looking at post-covid sexual dysfunction and which includes study of PSSD. Like you say, PSSD and Long-covid may prove to have similar underlying drivers (e.g., SFN, dysautonomias, auto-antibodies).


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