Severe gastroparesis improved with IV high dose methylprednisolone 2019

[pattismith]

Steroid Responsive Gastric Dysmotility - Seronegative Autoimmune Autonomic Neuropathy
2784
Harris, Samar MD1; Greenan, Garrett MD2; Naina, Harris MD3; Harris, Adam4; Philip, Justin PA-C2; Phillips, Lauren MD2
Author Information
American Journal of Gastroenterology: October 2019 - Volume 114 - Issue - p S1538


INTRODUCTION:

Gastrointestinal motility disorders are complex conditions manifesting with a wide array of symptoms.

In recent years, the increasing discovery of autoantibodies targeting the nervous system has led to the recognition of new neurologic autoimmune disorders (NAD) which present with the subacute development of profound neurological impairment and gastrointestinal motility disorders which when promptly treated with immunotherapy, may show dramatic improvement.

CASE DESCRIPTION/METHODS:

A 32 year old woman with a history of undifferentiated connective tissue disease presented to establish care for known gastroparesis Her symptoms started following an upper respiratory infection the age of 15 years, which was followed by development of arthralgia, rash, raynaud's, tonic pupils, and distal sensory symptoms.

She also developed orthostatic intolerance and was diagnosed with severe gastroparesis with over 40 lb weight loss.

Her medications included Plaquenil and methotrexate, as well as Zofran.

She underwent extensive testing with autonomic function testing showing moderate sympathetic adrenergic dysfunction and distal sudomotor impairment which indicated a limited autonomic neuropathy and skin biopsy showed small fiber neuropathy.

Paraneoplastic antibody testing, GAD antibody and ganglionic Acetylcholine receptor (gAChR ab) was negative.

A trial of IVIg was started for suspected autoimmune GI dysmotility but this was complicated with pancytopenia.

On exam she was malnourished with a BMI of 15, normal reflexes, and decreased distal sensations.

She underwent repeat autonomic function testing which was normal.

A 4 hour solid gastric emptying was performed which showed delayed emptying at 4 hr of 80%.

She was underwent a 5 day infusion of IV Solumedrol at 1000 mg daily for suspected autoimmune dysmotility.

A daily GCSI-DD (gastroparesis cardinal symptom index- daily diary) score showed a >50% improvement in scores on Day 0 to Day 5 and normalization of 4 hour solid GES and was then started on IV Rituximab.

DISCUSSION:

This case highlights that importance of considering a diagnosis of neurologic autoimmune disorders which can present with as solitary GI dysmotility. Seronegative autoimmune autonomic neuropathy is a clinical entity which shows prominent sympathetic failure, sensory symptoms and is steroid responsive.

 

[Pyrrhus]

Does anyone else's head explode when they hear the words "seronegative autoimmune"?

By definition, a disease is "autoimmune" only if there are auto-reactive antibodies or T-cells. The word "seronegative" means that no auto-reactive antibodies or T-cells were found. So "seronegative autoimmune" sounds like quite the oxymoron.

Of course, it's possible that auto-reactive antibodies or T-cells exist, but could not be detected, just like there can be underlying viruses that can not be detected. But then you can't really call it either "autoimmune" or "viral".

I find it a bit disturbing how people in the medical field so casually use the word "autoimmune", with no understanding of the scientific definition of autoimmunity.

The fact that this woman's symptoms improved dramatically with corticosteroid treatment provides strong evidence that her symptoms are mediated by inflammation. But it does not distinguish between autoimmune inflammation and viral inflammation.

 

[andyguitar]

This paper might be of interest to @Howard

 

[pattismith]

Does anyone else's head explode when they hear the words "seronegative autoimmune"?

By definition, a disease is "autoimmune" only if there are auto-reactive antibodies or T-cells. The word "seronegative" means that no auto-reactive antibodies or T-cells were found. So "seronegative autoimmune" sounds like quite the oxymoron.

Of course, it's possible that auto-reactive antibodies or T-cells exist, but could not be detected, just like there can be underlying viruses that can not be detected. But then you can't really call it either "autoimmune" or "viral".

I find it a bit disturbing how people in the medical field so casually use the word "autoimmune", with no understanding of the scientific definition of autoimmunity.

The fact that this woman's symptoms improved dramatically with corticosteroid treatment provides strong evidence that her symptoms are mediated by inflammation. But it does not distinguish between autoimmune inflammation and viral inflammation.

This patient has Gastroparesis + SFN (SFN can induce Gastroparesis), and SFN is a frequent comorbidity of some auto-immune diseases like Sjogren or Lupus, MS, RA.
Some papers authors also consider Acute SFN as part of the Guillain Barre Syndrome (also auto-immune).
We can assume that some chronic/progressive SFN may be part of the Chronic Inflammatory Demyelinated Polyneuropathy (the chronic counterpart of th Guillain Barre), another auto-immune disease.

Idiopathic SFN has shown some association with some auto-antibodies that are not yet used for diagnosis, and Dr Oaklander showed IVIG is usefull in idiopathic SFN.

So yes, we can say more and more papers speak for an auto-immune nature of SFN.

 

[Pyrrhus]

Thanks for your response.

SFN is a frequent comorbidity of some auto-immune diseases like Sjogren or Lupus, MS, RA.

The main recognized causes of small fiber neuropathy (SFN) are infections, such as HIV, and diabetes, a metabolic cause. So the main recognized causes of SFN are not generally accepted to be autoimmune.

Sjogren's syndrome commonly occurs after infection with enteroviruses. It is assumed to be autoimmune, but auto-reactive antibodies or T cells have not yet been conclusively identified.

According to the National MS Society:
"The cause of MS is still unknown. However, several factors suggest that an infectious agent is involved in triggering MS." https://www.nationalmssociety.org/What-is-MS/What-Causes-MS/Viruses

Despite decades of research to identify reliable auto-reactive antibodies or T cells in MS, the autoimmune hypothesis for MS remains unproven.

We appear to be seeing an unfortunate trend of medical professionals using the word "autoimmune" as a synonym for "idiopathic".

Guillain Barre Syndrome (also auto-immune

It has been well documented that Guillain Barre Syndrome is triggered by infections. The secondary auto-reactive antibodies fade soon after the original infection resolves.

Chronic Inflammatory Demyelinated Polyneuropathy (the chronic counterpart of th Guillain Barre), another auto-immune disease

I myself have Chronic inflammatory demyelinating polyneuropathy (CIDP). We weren't sure exactly what was causing it until I tried antivirals that specifically targeted Enterovirus 71. Within days, I started to regain feeling in my feet, and then regained the ability to wiggle my toes. This is just one anecdote, but CIDP has not been demonstrated to be autoimmune.

Dr Oaklander showed IVIG is usefull in idiopathic SFN.

IVIG was approved to treat a variety of immune deficiency syndromes, not for autoimmunity. It is also used to treat infections such as parvovirus. Recently, some people have been trying it for "autoimmune" diseases, with mixed success.

I think we have to be careful when reading research papers, because it appears some writers are mistakenly using the word "autoimmune", when they really mean to say "idiopathic".

 

[kangaSue]

I assume that in having a known history of undifferentiated connective tissue disease, this patient would also have had a positive antibody finding in an ENA panel to suspect that autoimmune GI dysmotility could be the cause of gastroparesis.

Does anyone else's head explode when they hear the words "seronegative autoimmune"?

While not patently obvious in this article, "seronegative" in this context is specific for being seronegative to the condition Autoimmune Autonomic Neuropathy (now renamed as Autoimmune Autonomic Ganglionopathy - AAG) with there not being a positive result for the ganglionic acetylcholine receptor antibody. This particular antibody is absent in about 50% of cases of AAG but there will be other findings (such as UCTD in this case) to suggest there is still a possible autoimmune basis to it.

Incidently, Autoimmune Gastrointestinal Dysmotility (AGID) is a term coined for cases of AAG that have a lower titre of ganglionic acetylcholine receptor antibody and can just affect the GI tract. AGID and some cases of "idiopathic" gastroparesis may respond to oral steroid treatment though and worth trying where gastroparesis is refractory to all other measures.

I have tried oral steroid for idiopathic gastroparesis, tentatively and at low dose because I had a bad experience with steroids years ago when I was a "healthy normal", and even a low dose causes my (already low) bp to plummet into near-syncope territory so not game to push for trying a high dose IV steroid course.

 

[pattismith]

@Pyrrhus , I am really interested in this discussion, I thank you for bringing it, there isn't a definitive answer yet.
I think I do respond to high methylpred dose, but this is just one more anecdote and doesn't prove an initial infectious agent isn't still here in my body.

The main recognized causes of small fiber neuropathy (SFN) are infections, such as HIV, and diabetes, a metabolic cause. So the main recognized causes of SFN are not generally accepted to be autoimmune.

Of course I only meant that idiopathic SFN has often auto-immune nature, which excluded HIV and Diabetes SFN. It also excludes genetic SFN as well.

Sjogren's syndrome commonly occurs after infection with enteroviruses. It is assumed to be autoimmune, but auto-reactive antibodies or T cells have not yet been conclusively identified.

According to the National MS Society:
"The cause of MS is still unknown. However, several factors suggest that an infectious agent is involved in triggering MS." https://www.nationalmssociety.org/What-is-MS/What-Causes-MS/Viruses

Despite decades of research to identify reliable auto-reactive antibodies or T cells in MS, the autoimmune hypothesis for MS remains unproven.

We appear to be seeing an unfortunate trend of medical professionals using the word "autoimmune" as a synonym for "idiopathic".

It has been well documented that Guillain Barre Syndrome is triggered by infections. The secondary auto-reactive antibodies fade soon after the original infection resolves.

Many auto-immune diseases are the result of an initial infection or a vaccine shot, however that doesn't prove the disease is the result of a persistent infection.

Idiopathic just means the cause is unknown, I had not the feeling papers I read were making any confusion between idiopathic and auto-immune.

I will try to give you the papers references for an auto-immune nature of at less a subset idiopathic SFN.

I myself have Chronic inflammatory demyelinating polyneuropathy (CIDP). We weren't sure exactly what was causing it until I tried antivirals that specifically targeted Enterovirus 71. Within days, I started to regain feeling in my feet, and then regained the ability to wiggle my toes. My Sjogren's also cleared up, and I no longer needed regular eye drops. This is just one anecdote, but CIDP has not been demonstrated to be autoimmune.

I'm sorry to read you have CIDP, and I feel happy you got success with Enterovirus treatment. Did you get IVIG as well?
I too considered my disease could be the result of a persistent infection, and took antibiotics and also valacyclovir, but couldn't tolerate them, so had to quit (Valacyclovir injured my kidneys)

IVIG was approved to treat a variety of immune deficiency syndromes, not for autoimmunity. It is also used to treat infections such as parvovirus. Recently, some people have been trying it for "autoimmune" diseases, with mixed success.

IVIG is used in neuro-sjogren, as well as methylprednisolone, but I agree this doesn't prove the auto-immune nature:
https://forums.phoenixrising.me/thr...in-sjogrens-syndrome-2020.80344/#post-2278967

I have tried oral steroid for idiopathic gastroparesis, tentatively and at low dose because I had a bad experience with steroids years ago when I was a "healthy normal", and even a low dose causes my (already low) bp to plummet into near-syncope territory so not game to push for trying a high dose IV steroid course.

@kangaSue did you investigate why you get that problem with corticosteroids?
Did you get any some other immune suppressive treatment?
Do you have some evidence an auto-immune process could be involved in your dysautonomia ? (any other auto-immune disease like auto-immune thyroiditis or antibodies of the Celltrend panel or others?)

When I started methylpred, I noticed paresthesia always flared within minutes after the intake. I sticked to it because I also noticed other symptoms were improving in the same time (muscle pain and brain fog).

Now my paresthesia also improved as well but it took longer. My autonomic skin and heart function seem to improve as well as acquagenic wrinkles (they are back in my fingers and my heart arrythmia resolves).
However, the good effect fades when I stop or just lower the dose, so I don't know what will be the answer for my disease on the long run.

 

[pattismith]

@Pyrrhus

Cryptogenic small‐fiber neuropathies: Serum autoantibody binding to trisulfated heparan disaccharide and fibroblast growth factor receptor‐3
Todd D. Levine MD
First published:25 October 2019
Abstract

Introduction
Causes of small‐fiber peripheral neuropathies (SFN) are often undefined. In this study we investigated associations of serum autoantibodies, immunoglobulin G (IgG) vs fibroblast growth factor receptor‐3 (FGFR‐3), and immunoglobulin M (IgM) vs trisulfated heparan disaccharide (TS‐HDS) in cryptogenic SFN.

Methods
One hundred fifty‐five patients with biopsy‐proven SFN and no identified cause for their neuropathy were blindly tested for serum IgM vs TS‐HDS and IgG vs FGFR‐3.

Results
Forty‐eight percent of SFN patients had serum antibodies, 37% with IgM vs TS‐HDS and 15% with IgG vs FGFR‐3. TS‐HDS antibodies were more frequent in SFN patients than in controls (P = .0012). Both antibodies were more common in females, and with non–length‐dependent nerve pathology. Nintey‐two percent of patients with acute‐onset SFN had serum IgM vs TS‐HDS.

Discussion
Autoantibodies directed against TS‐HDS and FGFR‐3 suggest an immune disorder in otherwise idiopathic SFN. Serum IgM vs TS‐HDS may be a marker for SFN with an acute onset.

Heterogeneous presentation of caspr2 antibody‐associated peripheral neuropathy – A case series

;;;;;;;;

Anti‐plexin D1 antibody–mediated neuropathic pain
Takayuki Fujii

First published:31 March 2020


Abstract

Neuropathic pain (NeP) is an intractable pain caused by a lesion or disease of the somatosensory nervous system. NeP is often challenging to manage because most of the mechanisms remain to be elucidated. Recent investigations in the field of autoimmune neurology have demonstrated that specific autoantibodies against antigens in the somatosensory pathway can cause NeP.

Detection of pathogenic autoantibodies in NeP adds to the understanding of the mechanism of pain, which might aid in the development of novel immunotherapies.

Therefore, it is necessary to explore novel NeP‐related autoantibodies to improve the management of intractable pain. Recently, we screened serum autoantibodies that bound to pain‐conducting small dorsal root ganglion (DRG) neurons and their nerve terminals in the dorsal horns of NeP patients.

We detected a novel autoantibody that bound to unmyelinated C‐fiber–type small DRG neurons.

The positive rate in patients with NeP was 10%. We identified plexin D1 as the target antigen. NeP patients with plexin D1‐IgG developed burning pain and thermal hyperalgesia. The main comorbidities were allergy, collagen vascular disease, and cancer.

Plasma exchange and intravenous methylprednisolone pulse therapy are effective for NeP in patients with plexin D1‐IgG, indicating that these autoantibodies might be pathogenic in NeP. Indeed, our in vitro study demonstrated that plexin D1‐IgG induced the membrane hyperpermeability of DRG neurons. In this review, we describe the discovery of plexin D1‐IgG and discuss the association between plexin D1 and pain, allergy, and cancer.

Acute painful autoimmune neuropathy: A variant of Guillain‐Barré syndrome
Nobuhiro Yuki PhD

First published:01 July 2017

ABSTRACT
Introduction
We present a painful small‐fiber neuropathy variant of Guillain‐Barré syndrome characterized by antecedent infectious symptoms, hyporeflexia, and albuminocytologic dissociation.

Methods
Two patients received intravenous immunoglobulin, one corticosteroids.

Results
The patients subsequently improved. Immunoglobulin G (IgG) antibodies in their acute phase sera strongly bound to murine small nerve fibers, and the binding disappeared during the convalescent phase. Serum transfer to a murine nociceptive model induced transient alteration in thermal pain responses.

Discussion
Our case series suggest that an acute transient immune response can be directed against small nerve fibers, and that patients so affected can exhibit features of Guillain‐Barré syndrome

 

[Pyrrhus]

While not patently obvious in this article, "seronegative" in this context is specific for being seronegative to the condition Autoimmune Autonomic Neuropathy (now renamed as Autoimmune Autonomic Ganglionopathy - AAG) with there not being a positive result for the ganglionic acetylcholine receptor antibody. This particular antibody is absent in about 50% of cases of AAG but there will be other findings (such as UCTD in this case) to suggest there is still a possible autoimmune basis to it.

Thank you for the illuminating context that I was missing. I really hope you're right that this patient had, at a minimum, a positive ANA test. Otherwise, I feel this poor woman might have been grossly mistreated.

Of course I only meant that idiopathic SFN has often auto-immune nature, which excluded HIV and Diabetes SFN. It also excludes genetic SFN as well.

I understand. A perfectly fair point.

Many auto-immune diseases are the result of an initial infection or a vaccine shot, however that doesn't prove the disease is the result of a persistent infection.

Quite true. Many infections can trigger the production of auto-reactive antibodies or T cells. (I had one immunology professor who felt that any long-term inflammation, of any cause, would eventually trigger some auto-reactive antibodies or T cells, which usually go unnoticed!)

The question remains: How long do these auto-reactive antibodies or T-cells linger after the infection has been resolved? There is sufficient evidence that they can linger up to 6 months, and one case study claimed that it saw them linger for 18 months in one patient, but we really don't have a good answer to this question at this point in time.

I will try to give you the papers references for an auto-immune nature of at less a subset idiopathic SFN.

I don't for one second doubt that auto-reactive antibodies or T cells can significantly contribute to SFN. I don't doubt that, in some cases, immunosuppressive therapy might permanently resolve SFN. So no need to convince me on that point. But I always enjoy the case studies you post.

I'm sorry to read you have CIDP, and I feel happy you got success with Enterovirus treatment. Did you get IVIG as well?

Thank you. Unfortunately, the success only lasted a couple of months, before we discovered that the experimental drug caused liver damage, and we had to stop the drug. It was like being given a taste of normal, and then having it snatched away from you! (By the way, while I was taking the experimental drug, I also noticed my skin wrinkling in the bath, for the first time in years!)

My doctor encouraged IVIG, but since the posited enterovirus would also reside in the brainstem and basal ganglia, IVIG would probably trigger brain inflammation for me, so I declined the IVIG. (Theoretically, once the posited enterovirus has infected neurons in the central nervous system, only the innate immune system can help against the virus. Any response from the adaptive immune system would probably cause more damage than good. Remember that you can't just kill off infected neurons to resolve an infection in the central nervous system.)

By the way, there was an article in the Washington Post today about SFN:
https://www.washingtonpost.com/heal...a-8872-5df698785a4e_story.html?outputType=amp
I was uncomfortable about how they portrayed SFN as a disease in its own right, rather than describing SFN as a symptom of many different diseases. But at least the article should raise some awareness about SFN.

 

[pattismith]

Thank you. Unfortunately, the success only lasted a couple of months, before we discovered that the experimental drug caused liver damage, and we had to stop the drug. It was like being given a taste of normal, and then having it snatched away from you! (By the way, while I was taking the experimental drug, I also noticed my skin wrinkling in the bath, for the first time in years!)

Too bad this drug is so toxic for your liver, you had such an amazing result, did the aquagenic wrinkling stay after stopping this drug?

I noticed that my fingers started to wrinkle again in water some weeks ago, but not yet in my toes.

The thing is that I don't know how long for my aquagenic wrinkling was missing, because I just became aware of that some months ago when someone here on PR started a thread about it, and this is something you usually just don't notice when it's gone.
I think it was probably missing for years, because I would have noticed the fingers wrinkles otherwise.
Now my hands aquagenic wrinkles are so quick (about 5 min) that I wonder if the variant snp I have for cystic fibrosis may have some effect!

Did you ever consider low dose of antiinflammatory drugs (low dose corticosteroids, or even AINS as they have shown some interest in auto-immune diseases)?
I had initially an interesting result after two years with 10 mg Piroxicam a day, but my stomach didn't tolerate it well (and we know it's not good for kidneys)

 

[Pyrrhus]

did the aquagenic wrinkling stay after stopping this drug?

Unfortunately not. Everything went back to "normal" after I had to discontinue the drug.
(If you're interested in more about that experience, I posted about it here: https://forums.phoenixrising.me/thr...rom-ron-davis-video.62564/page-3#post-1022062 )

The thing is that I don't know how long for my aquagenic wrinkling was missing, because I just became aware of that some months ago

Me too. I actually thought that the aquagenic wrinkling was just something that happened to kids, since I had no memory of it happening as an adult! I reasoned that maybe kids haven't yet "grown into their skin". That's why I was surprised when I noticed the aquagenic wrinkling while taking the drug. Then I checked the literature and realized that it was actually an autonomic wrinkling response that I had been missing.

The same thing happened with my vision. For years, I was complaining that my glasses prescription had changed as everything was a little blurry. My eye doctor disagreed, saying that my prescription had not changed. I thought that maybe my eye doctor was incompetent, so I had the LASIK procedure to correct my eyes completely. But everything was still blurry, and I was perplexed. It was only when I tried the experimental drug, and my vision suddenly cleared up, that I realized that my blurry vision was actually due to an autonomic pupillary response that I had been missing.

Did you ever consider low dose of antiinflammatory drugs

I might consider that as a last resort. We're currently pursuing other avenues right now...

 

[kangaSue]

@kangaSue did you investigate why you get that problem with corticosteroids?

They did an ACTH stim test which was normal but also caused a drop in bp during the infusion. I have Nutcracker Syndrome though which causes increased venous pressures into the left adrenal and kidney among other things and morning cortisol is at the low end of the range and renin level is elevated a bit so I think the steroid reaction somehow ties in with Nutcracker Syndrome (NCS).
NCS is also known to cause autonomic dysfunction (POTS at its worst (in about 20% of cases) and low bp is very common, autonomic neuropathy crops up a lot too) but I haven't struck a doctor yet who knows that it can be a cause of these and even experts in the condition don't know the full mechanisms involved. There is also a subset of us who have gastroparesis from NCS alone (most people have SMA Syndrome along with NCS to cause their gastroparesis).

Do you have some evidence an auto-immune process could be involved in your dysautonomia ? (any other auto-immune disease like auto-immune thyroiditis or antibodies of the Celltrend panel or others?)

I don't have any established autoimmune conditions. I have symptoms that can fit for Sjogrens or Scleroderma but have had work-ups done by both an Immunologist and Neurologist and no positive antibodies found. Had bloods sent to the UK to test for AAG/AGID after I had a finding of a low titre of voltage gated calcium channel antibody (but considered in the "normal" range) but also negative.
I haven't had the Celltrend panel done.

 

[kangaSue]

We weren't sure exactly what was causing it until I tried antivirals that specifically targeted Enterovirus 71

@Hip was pondering recently if hydroxychloroquine and zinc may be an alternative combo for treating enterovirus, might be something to try that's less harsh on the liver.
https://forums.phoenixrising.me/thr...combo-also-work-for-enterovirus-me-cfs.80221/