Autoimmune Autonomic Ganglionopathy?

[~elizabeth~]

I've just spent 2 weeks in a specialist neurological hospital, trying to get to the bottom of what is going on. They seem to be sure that I have substantial small fibre neuropathy affecting both sensory, sudomotor and autonomic nerves affecting large areas, not just the peripheries. The small fibre expert there is into looking for underlying causes of these conditions, but they said that there a lots of things they know exist but can't test for. I'm guessing they mean autoimmune diseases against autonomic receptors. I asked about IVIG and plasma exchange, but they said they don't like using them, because of the risks of contracting something from blood products.

I really don't know what to think now. They are doing genetic testing to look for mutations that cause small fibre degeneration, as there is family history of problems, and also another rare autonomic problem (hereditary Holmes Adies). However, in other family members the problems are very mild, limited to mild sudomotor/parasympathetic involvement, without the degree of sympathetic/sensory involvement. I also have positive ANAs (last titre 1:160) and polyclonal gammopathy, plus longstanding autoimmune thyroid disease.

The sensory nerve pain/erythromelalgia I have is completely refractory to treatment, I spent 7 days receiving lidocaine infusion in hospital, which just seems to have made things worse. I don't know whether I should be insisting on trying immunosuppressive approaches to this, given that we are running out of options rapidly. They are looking at nerve blocks now, but given the burning pain is spreading across my whole body, including throat and thorax, even if particular blocks worked it wouldn't improve the overall pain situation much. I'm not really sure the neuros have come to any particular conclusion about what's wrong, they seem to keep changing their minds, as I'm such an untypical and complex case.

[andybonse]

immunosuppressive sounds ideal if it is antibodies to look into, you have a positive ANA and neruopathy which would highly indicate some autoimmune antibodies playing mayhem maybe, obviously an ANA can be positive in normal people, but with a neruopathy id like to rule other things out. Especially if you tried an immunodepressant and felt better, you would then be in a better position to fight for IVIG maybe?

[~elizabeth~]

At one point my rheumatologist in Swindon did diagnose me with undifferentiated connective tissue disease, but when she got the letters about the hypermobility and autonomic problems, she just said it was all beyond her expertise and dumped me, so I don't have a rheumatologist any more. When they thought it was UCTD, I was on hydroxychloroqine for a couple of years, I did feel better on it and eventually stepped it right down, which is when the problems suddenly got worse. That may have been a co-incidence though, upping it back to full dose certainly didn't help with the neurological problems once they'd started. However, hydroxychloroquine isn't an immunomodulatory drug they ever seem to use for these autoimmune ganglionopathies; they seem to use either prednisone and/or IVIG/plasma exchange. I got the impression I'd have be at death's door before they'd consider trying the latter though. I don't know if they can test for AAG antibodies there, I didn't get the feeling that they do.

[looneymom]

It sounds like autoimmune is in play. Are your doctors looking at some immune supressing drugs? If so research carefully. My son has the autoimmune stuff also going on. Our cardiologist had also thought about going the IVIG route but it can make things worse. My son already has severe headaches and scalp pain and some other issues that the IVIG could make worse. For these reasons and some of the reasons yours doctors have given you, my son is going to stay away from the IVIG. If they could test for AAG or neoplastic autoimmune antibodies, this might give you some more clues on what may be happening. Have you been checked for lyme or other virues by an immunologist? These I believe can cause a positive ANA. Look for another doctor or specialist that is willing to treat. Being dumped by a doctor is no fun, However, if they don't know how to treat it's best to move on and find another doctor that does.

[arizona girl]

Hi elizabeth,

What country are you in? I can only tell you my experience from a usa perspective, I know things can be different in other countries.

First though, your doctors have provided you with incorrect information about ivig and pheresis. I had pheresis and now get ivig going on 3 years now. I also have a similar diagnostic profile as you. My neuro who treats autoimmune neuromuscular disease first prescibed pheresis. Blood products are no longer used with pheresis in the usa they use albumin where the blood product used to be used to do the exchange. As for ivig it is safer then a blood transfusion as it goes through many levels of filtering and screening today. There is a small chance that some unknown antigen could be in it that they don't screen for, but the scrubbing process would usually kill anything like that as it does for the known antigens they test for. From what I understand though if you do have aag, ivig is the main treatment plan. So it is confusing what your doctors are saying. Often because of the expense involved some doctors don't like to prescribe it.

Also there are screening tests that must be done before ivig is put on board. If you ever get to that point let me know and I will get you the list of tests. Not everyone is a good candidate for it. As looneymom mentioned and posted in the past her child's tests showed it might not be a good choice for him and could harm him.

An excellent resource about ivig products is http://primaryimmune.org there is also a magazine called ig living. Also primary immune has a doctor referral resource to help you find a doctor in your area.

Your symptoms do sound like an autoimmune neuromuscular process, similar to mine.The treatments you've described sound only like they are trying to give you relief from symptoms not treating the cause of those symptoms. From my experience those treatment will not stop the progression of the disease process and things can get worse. I also am on plaquinel to address the uctd and it has bought my inflammatory markers down. For me it is a good drug as I can't take stronger immune suppressants because of my immuno deficincy and a mthfr gene defect. The ivig boosts my immune system and helps modulate the attack on my small fiber nerves. I also take thyroid meds for hashimoto and glumetza for hyperinsulinemia/pcos. I still don't feel great but I have slowly had improvements in my labs and some of my symptoms.

Do as much research as you can, in cases like ours information and documentation is power.

[~elizabeth~]

Thanks Arizona Girl, that's useful to know (I'm in the UK by the way). The person who told me that was part of the headache team (treating me for my facial erythromelalgia), it's possible they aren't completely up to date with stuff on the edge of their main specialism. I saw the small fibre guy for only a few minutes, but he kept on repeating 'we must find what is causing this'. He didn't seem particularly keen on taking me on though, he was only seeing me to give a second opinion.

I had a fairly full workup from the immunologist they work with last year. Apart from the ANAs and polyclonal gammopathy, he found elevated IgG4 with historical evidence of IgG antibodies against Epstein Barr, which was no longer active. I've always thought that my thyroiditis was triggered by the EBV infection I had 27 years ago, as that's when a lot of the odd symptoms started, but something seems to have activated again in the last few years. Thyroid antibody activity was zero, as evidently all thyroid tissue has now been destroyed, so it seems unlikely that any inflammatory activity can still be related to this. ANAs, IgG and the gammopathy did all decrease while I was on the hydroxychloroquine, so it must have been interfering with some active inflammatory process.

I'm inclined to ask my GP about trying a course of prednisone, at least while I'm waiting to hear back from the neurological hospital again. They do perform IVIG and plasma exchange there, but only for a very limited range of conditions (Guillain Barré, demyelinating polyneuropathy, MG, I'm guessing they are only licensed for these conditions). I'm not sure they recognise AAG there. It doesn't help that the autonomic department is at odds with everyone else there, they are maintaining I don't have small fibre neuropathy and everything can be explained by vasomotor instability due to my hypermobility. I'm glad to say that none of the other neuros agree with any of this, one of the others said that was 'nonsense' but I it should be the autonomic unit that is looking into conditions like AAG for patients with signs of autonomic neuropathy with an inflammatory component. I did have quite a positive response to pyridostigmine in terms of increased muscle strength, which has been declining gradually for years. To me that sounds like something interfering with nicotinic receptors, if it was just EDS-related weakness, it wouldn't have had any effect. It hasn't helped my lack of sweating though, in fact I'm limited in how much I can take as it just seems to trigger worse thermoregulatory flushing/cholinergic urticaria in response to heat, I can only tolerate about 60mg a day, half of what I was told to take to help the POTS symptoms I was put on it by the previous head of the autonomic team there, I get the impression he's more open minded on this stuff (sadly now retired). Maybe I should see him again and ask him about his thoughts on AAG, he probably still has a fair amount of influence there.

[arizona girl]

Did you test positive for aag? I'm going to have to look up the poly gam, that might have another treatment course. Seems like your up on stuff so you probably already did that. I know the healthcare systems in our countries are different, there are some uk's on the site, maybe see if they can recommend someone to see in your area. Primary immune I believe is international so you could see if they are working with someone in your area.

I see why your caught in the middle between EDS and autoimmune causes, as they are treated very differently. I too have mild hypermobility, so I'm proof you can have autoimmune and EDS at the same time. The famous Dr. Grubb diagnosed me with it and hyperandrengeric pots/syncope. He actually put me on labetalol as it is a alpha/beta blocker, that is short acting form, so I can take it as needed. It has worked well. I'm not swinging so much now though because we are treating the other stuff, so there are days I don't need it.

I can also see why your neuro would like to try to find cause for the small fiber, as treatments vary depending on cause. I had the skin biopsy and that along with my failed tilt and symptoms proved mine. My neuro said the causes for it can be endless, and he tested me for a bunch of scary causes which were negative. It was after that and my positive response to the pheresis that we found the hypogamma and then the autoantibodies for hashi and skin biopsies for uctd and lichen then proved the autoimmune component and probably primary cause. I had very high to low ana's on and off for years. You are right that only certain conditions are approved for ivig, I do believe AAG has been added to the list in the USA as FDA approved. My neuro started with pheresis since he could get that through unchallenged, my positive response to pheresis and the plaquinel also prove the autoimmunity. My ivig was approved through insurance though because of the hypogamma/cvid, not the small fiber. He has me as polyneuropathy and they wouldn't approve it for that.

I know eds is considered a genetic defect but it does still effect the connective tissues as do some of the autoimmune disease. So I can see treatment being tricky for you. Even if you get the autoimmunity under control there is still the floppy vascular system that can cause the same type of symptoms, so you might still be symptomatic. The genetic doc I saw said that they are now treating eds with high dose vitamin c to help the connective tissue improve.

Well I hope that helps. I do feel for you and how difficult it is to get everyone on board and fight for what you think is right. Don't give up and take a mental vacation from it here and there, if it gets too stressful dealing with your healthcare system. Then go put your warrior hat back on and try again.

[~elizabeth~]

Thanks so much, that's very helpful. No, I don't think the do test for AAG here. It's annoying when they don't actually give you a proper breakdown of results on paper, so that you know what they've tested for, but I've never heard of anyone else in the UK being tested or diagnosed with it. I'm sure the EDS vasomotor instability plays a part, I have very high standing norepinephrine (which they don't ever seem to refer to as hyperPOTS here) so I'm sure hugely fluctuating catecholamine levels with changes of posture don't help. However, I've had low BP and floppy veins all my life, and the onset of these symptoms was very sudden and acute, so I'm sure there's an additional factor at play somewhere. I can't tolerate any POTS drugs, as they all seem to destabilise the pain in some way or other, I guess because the process of small fibre disease may have caused 'sympathetic pain', either due to sensitisation of adrenergic receptors on sensory nerves, or regrowth of sympathetic nerves entangling with sensory ones. I can't really test the 'floppy vein' vasomotor scenario because I can't tolerate drugs like midodrine, or anything else that mimics norepinephrine or affects catecholamine levels. Propranolol helped a lot with the POTS symptoms, but I had to come off it because I have histamine intolerance as it lowers your diamine oxidase levels, and I'm limited enough in what I can eat as it is. The more widespread your neurological deficits, the more difficult it become to treat any part of them without affecting something else adversely.

Yes, I'm having a 'holiday' for now, at least until the hospital gets back in touch. They are trying to all meet up with the pain team to discuss multiple sensory nerve blocks. I'm not sure about this, as I can't find much evidence they are effective for erythromelalgia (which undoubtedly has an autonomic element of some kind, which why be the reason it is usually refractory to all the usual sensory neuropathy drugs), plus when your face, ears, eyes, mouth, throat, feet and hands are affected, it's impossible to block the pain in all those areas. I'm looking into botox injections, which I feel might be more effective as it can block sympathetic vasodilator nerves, which personally I think may be the main culprit in erythromelalgia pain. I'll get back in touch with my private autonomic specialist and ask him if he can have a word in the right ear about AAG, as I'm sure he keeps up to date with latest developments in the US.

[diabeticgonewild]

I have AAG.

The only credible commerical laboratory that tests for the antibodies associated with AAG is the Mayo Clinic Laboratories in Rochester, Minnesota, USA. You may be able to use DHL Export Services to rapidly deliver the specimen to the laboratory. However, only 50-60% of those with AAG test positive for the antibody.

There is another test that involves norepinepherine levels that is diagnostically indicative of AAG, which can be read in this article (you may have to purchase it). Clinical laboratory evaluation of autoimmune autonomic ganglionopathy

Anyways, I wish you luck.

[E Soskis]

I have AAG

I started with IVIG and it worked well for almost 3 years then, not so much. I switched to plasma exchange (pheresis) and have been doing that for 3 years now. I'm up to once every 4-5 weeks and I manage pretty well.

I encourage you to get tested for AAG - I am told by my physicians that it is very rare but, I suspect it is not as rare as they think - people just need to be tested more. If that happened, I bet there would be a lot more research and development of AAG-specific treatments.

[~elizabeth~]

Thanks. DGW, the article you link to suggests that serum catecholamines are low in AAG, if that's true it seems unlikely in my case as my serum norepinephrine is high, both supine and standing.

I'm wondering if what I have may be some other kind autoimmune dysautonomia, triggered originally by the Epstein Barr virus. I don't know how to convince my doctors of this though. From my point of view, I am completely refractory to any symptomatic relief (either of pain or dysautonomia) due to the facial erythromelalgia, so the only way forward is to look for a treatable underlying cause. However, I can't convince them that my positive, mildly raised ANAs are significant; although polyclonal gammopathy is found in in conditions like CIDP, it's not clear whether its cause or effect of the condition (it is also a finding in non-immune neurological damage, e.g. stroke). The lead specialist has said he thinks its irrelevant, but then he also confidently predicted it was a sodium channelopathy, which seems to have been undermined by the failure of lidocaine to help at all.

I just think it's unusual to have such serious neuropathy mostly affecting both aspects of the autonomic system. I even think the pain is primarily autonomic, as it does not respond to any of the usual neuropathic painkillers, and is made worse by any drug that mimics or stops reuptake of catecholamines. Apparently sympathetic terminals can regrow around sensory nerves, sensitising them to norepinephrine, plus they can invade the dorsal horn of the spine, causing neuropathic problems. I think the fact that lidocaine infusion was so catastrophic for me suggests that the primary problem can't be sensory. I really don't know what to do, they are now suggesting even more invasive pain treatments without really having diagnosed what's going on properly in my view.

[Mermaid]

Elisabeth, I'm really sorry to read that you haven't found anything to help treat the pain of the erythromelalgia but pleased that at last you have a route to hopefully get somewhere with this. I can certainly understand your frustration with the team not looking wholeheartedly and flat out for a root cause, and with the autonomic team and neurologists there not being on the same page.

My situation has some similarities to yours although I do not have the extreme pain that you do. As you know I have seen the same (now retired) autonomic specialist as yourself who has said that the redness and 'venous engorgement' in my limbs with heat/warmth and also in the evenings whatever the temperature is 'suggestive of erythromelalgia which is a problem with the small nerves'.' He said also that a subset of POT/EDS patients have this vasomotor instability. This view seems similar to that of the autonomic team there. I really still am not sure, makes me wonder why there aren't more people on this forum with erythromelalgia and more people on erythromelalgia forum with POTs. I have been reading one forum and could only find two people, although I realise both are syndromes with a spectrum of symptoms.

I also have just had a positive ANA 1:400, the NHS rheumatologist that I have seen locally did a test for Lupus (double stranded DNA) which was negative and now seems to think that the positive test is caused by Venlafaxine. I have been trying a low dose of this since October to see if it would help regulate the autonomic nervous system. This is in spite of the fact that I do have lots of autoimmune symptoms as do many with POTs.

I was wondering whether you had come across the yahoo group for erythromelalgia? I'm sure that you have but thought I would mention it just in case. They seem pretty clued up on possible treatments.

I do hope that you hear back from the NHNN soon and that things move on positively. Wishing you all the best.

Barbara