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Complex syndromes of chronic pain, fatigue and cognitive impairment linked to autoimmune dysautonomia and small fiber neuropathy


Senior Member
Complex syndromes of chronic pain, fatigue and cognitive impairment linked to autoimmune dysautonomia and small fiber neuropathy

YehudaShoenfeldabVarvara A.RyabkovabCarmenScheibenbogencLouiseBrinthdManuelMartinez-LavineShuichiIkedafHaraldHeideckegAbdullaWatadahNicola L.BragazziiJoabChapmanaLeonid P.ChurilovbHowardAmitala


Autoimmune aspects of CFS, POTS, CRPS and SIIS are discussed.

The common denominators of anti-GPCR AAb and SFN are identified for these syndromes.

A new concept of autoimmune neurosensory dysautonomia is suggested.

Sjogren's syndrome can illustrate the suggested concept.


Chronic fatigue syndrome, postural orthostatic tachycardia syndrome, complex regional pain syndrome and silicone implant incompatibility syndrome are a subject of debate among clinicians and researchers. Both the pathogenesis and treatment of these disorders require further study.

In this paper we summarize the evidence regarding the role of autoimmunity in these four syndromes with respect to immunogenetics, autoimmune co-morbidities, alteration in immune cell subsets, production of autoantibodies and presentation in animal models.

These syndromes could be incorporated in a new concept of autoimmune neurosensory dysautonomia with the common denominators of autoantibodies against G-protein coupled receptors and small fiber neuropathy.

Sjogren's syndrome, which is a classical autoimmune disease, could serve as a disease model, illustrating the concept.

Development of this concept aims to identify an apparently autoimmune subgroup of the disputable disorders, addressed in the review, which may most benefit from the immunotherapy.


Senior Member
According to the paper, a subset of all the listed diseases have SFN. I wish they could figure out how SFN develops - might offer some big clues

the paper seems to favor a role of G-protein coupled receptors autoantibodies in the pathogeny of SFN (adrenergic/muscarinic receptors) at less in an auto-immune subset of SFN.

In this 2020 paper by Dr Oaklander, she says all non length dependant idiopathic SFN in non diabetic patients are likely auto-immune in nature, most commonly associated with Sjogren but not necessarily.
She add:

"A small case series documents the responsiveness of apparently dysimmune SFN to corticosteroids, with four larger series reporting efficacy of intravenous immunoglobulins (IVIg)"


Senior Member
interestingly another April paper linking fatigue to dysautonomia (in Parkinson)

The Dysfunctional Autonomic Function and “Dysfunctional” Fatigue in Drug Naïve Parkinson’s Disease

April 2020

Authors: Ahn, Jong Hyeona; b | Kim, Minkyeonga; b | Mun, Jun Kyua; b | Cho, Yoonsub | Kim, Ji Suna; b | Youn, Jinyounga; b | Kim, Joong-Seokc | Cho, Jin Whana; b; *

Affiliations: [a] Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Gangnam-gu, Seoul, Republic of Korea | Neuroscience Center, Samsung Medical Center, Gangnam-gu, Seoul, Republic of Korea | [c] Department of Neurology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea

Fatigue is a common and disabling non-motor symptom in Parkinson’s disease (PD). Autonomic dysfunction is suggested as the possible pathophysiology of fatigue, but it has not been investigated in drug-naïve PD patients.

In the present study, the relationship between fatigue and autonomic dysfunction in drug-naïve PD patients was investigated.

In the present study, 89 drug-naïve PD patients were analyzed.
The Parkinson’s disease fatigue scale (PFS) was used to divide the patients into fatigue (mean PFS≥3.3) and non-fatigue groups (mean PFS < 3.3).
The autonomic function test (AFT), Scale for Outcomes in Parkinson’s Disease-Autonomic (SCOPA-AUT), Unified Parkinson’s Disease Rating Scale (UPDRS)-I, -II, -III, modified Hoehn and Yahr (H&Y) scale, Montreal Cognitive Assessment (MoCA), Parkinson’s Disease Questionnaire-39 (PDQ-39), Parkinson’s Disease Sleep Scale (PDSS), and Beck Depress Index (BDI) were performed in all the participants. The AFT results and clinical scales were compared using multiple logistic regression analysis.

The prevalence of fatigue was 23.6% (n = 21) in drug-naïve PD patients. Total SCOPA-AUT score was higher in the fatigue group than in the non-fatigue group. The fatigue group had lower inspiratory:expiratory (I:E) ratio and Valsalva ratio. The prevalence of abnormal sympathetic skin response and orthostatic hypotension (OH) was 19% and 38.1%, respectively, in the fatigue group. Regression model analysis revealed that SCOPA-AUT and OH were the most related factor of fatigue in drug-naïve PD patients.

Autonomic dysfunction in drug-naïve PD patients was investigated using a subjective scale as well as objective tests. The results indicated that fatigue is associated with autonomic dysfunction, especially OH, in drug-naïve PD patients.


Senior Member
Autonomic dysfunction is associated with neuropsychological impairment in Lewy body disease

This study aimed to analyze the association of autonomic dysfunction with cognition, depression, apathy, and fatigue in Lewy body disease (LBD).

We included 61 patients [49 with idiopathic Parkinson’s disease, 7 with dementia with Lewy bodies, and 5 E46K-SNCA mutation carriers] and 22 healthy controls.
All participants underwent a comprehensive battery of neuropsychological and clinical measures, autonomic symptom assessment with the SCOPA-AUT, analysis of non-invasive hemodynamic parameters during deep breathing, the Valsalva maneuver, and a 20-min tilt test, and electrochemical skin conductance measurement at rest (Sudoscan). Student’s t tests were used to assess group differences, and bivariate correlations and stepwise linear regressions to explore associations between autonomic function, cognition, depression, apathy, and fatigue.

Compared to controls, patients who had significant impairment (p < 0.05) in cognition, higher depression, apathy, and fatigue, more autonomic symptoms and objective autonomic dysfunction, reduced deep breathing heart rate variability [expiratory-to-inspiratory (E/I) ratio], prolonged pressure recovery time, and lower blood pressure in Valsalva late phase II and phase IV, while 24.1% had orthostatic hypotension in the tilt test.

Autonomic parameters significantly correlated with cognitive and neuropsychiatric outcomes,
systolic blood pressure during the Valsalva maneuver predicting apathy and depression.

The E/I ratio was the main predictor of cognitive performance (17.6% for verbal fluency to 32.8% for visual memory).


Cardiovascular autonomic dysfunction is associated with cognitive and neuropsychiatric impairment in LBD, heart rate variability during deep breathing and systolic blood pressure changes during the Valsalva procedure are the main predictors of neuropsychological performance and depression/apathy symptoms, respectively.