Pervasive Arousal Withdrawal Syndrome (PAWS)

I have previously written about Pervasive Refusal Syndrome: Afvisningssyndrom eller ME?  (In Danish, but quotes and references in English)

A new name for Pervasive Refusal Syndrome is suggested in this arcticle: Pervasive refusal syndrome (PRS) 21 years on: a re-conceptualisation and a renaming. The new name is Pervasive Arousal Withdrawal Syndrome (PAWS).

A neurobiological model is proposed to explain PAWS. The autonomic nervous system is divided into the parasympathetic nervous system and the sympathetic nervous system. The model in PAWS is a breakdown in the normal relationship between the sympathetic and parasympathetic nervous systems. Normally there is a balance between the to systems, but in PAWS there is both sympathetic hyper-arousal and parasympathetic hyper-arousal. The two systems, sympathetic and parasympathetic are in a deadlock.

Then the authors of the article write: "Testing of this model could include: (1) exploring biological markers of arousal of both arms of the autonomic nervous system...."

PAWS is not a WHO diagnosis. And this paper on the new name PAWS is the only one I could find. So perhaps a little further testing of the model is good idea. I look forward to an article with test of the autonomic nervous system - including auto antibodies involved in dysautonomia.


The limited amount of literature on PRS is confirmed in this paper by Carl-Magnus Forslund and Björn Axel Johansson:

Pervasive refusal syndrome among inpatient asylum-seeking children and adolescents: a follow-up study:

15 articles (24 cases) identified in this review by Jaspers et al.

and

a search at PubMed.com (August 2012), using the term ‘‘Pervasive Refusal Syndrome’’, revealed 7 additional articles (10 cases) published after 2009.

So Forslund and Johansson have counted 34 cases. And they state:

"No evidence-based treatment for PRS is known."

But they mention that "Mean period of inpatient treatment was 5 months." 

PRS has not been identified among adults.

Immunological findings - overview

ME/CFS

References	Immunological findings
Charakterisierung des phänotypischen und funktionellen Immunstatus bei Patienten mit Chronischem Erschöpfungssyndrom	Examined CFS patients: 11% autoimmune thyroiditis 31% immunoglobulin deficiency, including: ·         5%   IgA deficiency ·         6%   IgG main group deficiency ·         10% selective IgG3 deficiency ·         10% selective IgG4 deficiency ·         8%   elevated IgM 32% T-cell-activation at an increased expression of activation markers CD11a, CD28 og CD57 på CD8 + - T-lymphocytes. 5% had an elevation in CD11a and a decrease in CD28 at CD8 + T-lymphocytes. 33% had elevated CD57 + T-cell-activity CFS patients could be divided into 4 groups: ·         high IL-2 ·         high IL-5 ·         decreased cytokine respons and predominantly T-cell activation and lymphopenia ·         26% no annormal cytokine production 22% had EBNA IgG deficiency 15% had leukopenia 25% had lymphopenia 6%   had low hemoglobin 25% had elevated MCHC niveau
Natural killer cells in patients with severe chronic fatigue syndrome	Severely affected CFS patients characterized by significant decreases in NK lysis and increases in KIR3DL1, IL4, TNF-α, and IFN-γ
Screening NK-, B- and T-cell phenotype and function in patients suffering from Chronic Fatigue Syndrome	·         Increased levels of T regulatory cells (CD25+/FOXP3+) CD4 T cells. ·         CD8 T cells showed significantly lower activation and frequency of effector memory cells. ·         NK cells displayed higher expression of NKp46 and CD69 but lower expression of CD25 in all NK subsets defined. ·         Overall, T cell and NK cell features clearly clustered CFS individuals.
Immunological abnormalities as potential biomarkers in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis	Impaired ·         cytotoxic activity of Natural Killer Cells ·         cytotoxic activity of af CD8+T celler  ·         number of CD56bright NK cells Upregulation of IL-10 IFN- γ TNF-α CD4+ CD25+  T-cells FoxP3 expression VPACR2 expression
Longitudinal investigation of natural killer cells and cytokines in chronic fatigue syndrome/myalgic encephalomyelitis	baseline  = T1,     6 months = T2,      12 months = T3 ·         NK cytotoxic activity was significantly decreased at T1, T2 and T3. ·         Significantly lower numbers of CD56brightCD16- NK cells at both T1 and T2. ·         Cytokine secretion revealed significant increases in IL-10, IFN-γ and TNF-α at T1. ·         Overall cytotoxic activity significantly decreased at T3 compared to T1 and T2. ·         CD56brightCD16- NK cells were much lower at T2 compared to T1 and T3.
Altered functional B-cell subset populations in patients with chronic fatigue syndrome compared to Healthy Controls	CFS patients had: ·         greater numbers of naive B cells as a percentage of lymphocytes: 6·3 versus 3·9% in HC (P = 0·034) ·         greater numbers of naive B cells as a percentage of B cells: 65 versus 47% in controls (P = 0·003) ·         greater numbers of transitional B cells: 1·8 versus 0·8% in controls (P = 0·025) ·         reduced numbers of plasmablasts: 0·5 versus 0·9% in controls (P = 0·013)
Increased IgA responses to the LPS of commensal bacteria is associated with inflammation and activation of cell-mediated immunity in chronic fatigue syndrome	·         Serum IL-1, TNFα, neopterin and elastase are significantly higher in patients with ME/CFS than in Chronic Fatigue  patients. ·         There are significant and positive associations between the IgA responses to LPS and serum IL-1, TNFα, neopterin and elastase. ·         Patients with an abnormally high IgA response show increased serum IL-1, TNFα and neopterin levels, and higher ratings on irritable bowel syndrome (IBS) than subjects with a normal IgA response. ·         Serum IL-1, TNFα and neopterin are significantly related to fatigue, a flu-like malaise, autonomic symptoms, neurocognitive disorders, sadness and irritability.
Cytotoxic lymphocyte microRNAs as prospective biomarkers for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis	There was a significant reduction in the expression levels of miR-21, in both the NK and CD8(+)T cells in the CFS/ME sufferers. Additionally, the expression of miR-17-5p, miR-10a, miR-103, miR-152, miR-146a, miR-106, miR-223 and miR-191 was significantly decreased in NK cells of CFS/ME patients in comparison to the non-fatigued controls
Increased nuclear factor-κB and loss of p53 are key mechanisms in Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS)	Future research should examine p53 signaling in ME/CFS: ·         Inactivation of p53 impairs aerobic mitochondrial functions and causes greater dependence on anaerobic glycolysis, elevates lactate levels, reduces mitochondrial density in skeletal muscle and reduces endurance during physical exercise. ·         Lowered p53 and increased NF-κB are associated with elevated reactive oxygen species. ·         Increased NF-κB induces the production of pro-inflammatory cytokines, which increase glycolysis and further compromise mitochondrial functions. ·         All these factors together may contribute to mitochondrial exhaustion and indicate that the demand for extra ATP upon the commencement of increased activity cannot be met. ·         In conditions of chronic inflammation and oxidative stress, high NF-κB and low p53 may conspire to promote neuron and glial cell survival at a price of severely compromised metabolic brain function.
Chronic fatigue syndrome and/or fibromyalgia as a variation of antiphospholipid antibody syndrome: an explanatory model and approach to laboratory diagnosis	Chronic Fatigue and/or Fibromyalgia have long been diseases without definition. An explanatory model of coagulation activation has been demonstrated through use of the ISAC panel of five tests, including, Fibrinogen, Prothrombin Fragment 1+2, Thrombin/ AntiThrombin Complexes, Soluble Fibrin Monomer, and Platelet Activation by flow cytometry. These tests show low level coagulation activation from immunoglobulins (Igs) as demonstrated by Anti-B2GPI antibodies, which allows classification of these diseases as a type of antiphospholipid antibody syndrome. The ISAC panel allows testing for diagnosis as well as monitoring for anticoagulation protocols in these patients.
Transcriptional control of complement activation in an exercise model of chronic fatigue syndrome	Complement activation resulting in significant increases of C4a split product may be a marker of postexertional malaise in individuals with chronic fatigue syndrome (CFS).
Complement activation in a model of chronic fatigue syndrome	Exercise challenge induced significant increases of the complement split product C4a, but not C3a or C5a, at 6 hours after exercise only in the CFS group (P <.01), regardless of allergy status.
Differential heat shock protein responses to strenuous standardized exercise in chronic fatigue syndrome patients and matched healthy controls	These preliminary findings suggest an abnormal or defective adaptive response to oxidative stress in CFS, and raise the possibility that HSP profiling may provide a more objective biologic marker for this illness
Chronic fatigue syndrome combines increased exercise-induced oxidative stress and reduced cytokine and Hsp responses.	The response of CFS patients to incremental exercise associates a lengthened and accentuated oxidative stress, which might result from delayed and insufficient Hsp production.

Antibodies in ME/CFS

References	ME/CFS Antibodies
In myalgic encephalomyelitis/chronic fatigue syndrome, increased autoimmune activity against 5-HT is associated with immuno-inflammatory pathways and bacterial translocation	·         The incidence of positive autoimmune activity against 5-HT was significantly higher (p<0.001) in ME/CFS (61.5%) than in patients with Chronic Fatigue (13.9%) and controls (5.7%). ·         ME/CFS patients with 5-HT autoimmune activity displayed higher TNFα, IL-1 and neopterin and increased IgA responses against LPS of commensal bacteria than those without 5-HT autoimmune activity. ·         Anti-5-HT antibody positivity was significantly associated with increased scores on hyperalgesia, fatigue, neurocognitive and autonomic symptoms, sadness and a flu-like malaise.
Autoantibodies against muscarinic cholinergic receptor in chronic fatigue syndrome	Human muscarinic cholinergic receptor 1 (CHRM1), mu-opioid receptor (OPRM1), 5-hydroxytryptamine receptor 1A (HTR1A) dopamine receptor D2 (DRD2) ·         The mean anti-CHRM1 antibody index was significantly higher in patients with CFS (p<0.0001) and autoimmune disease (p<0.05) than that in healthy controls, and positive reaction was found in 53.3% of patients with CFS. ·         Anti-OPRM1 antibodies, anti-HTR1A antibodies, and anti-DRD2 antibodies were found in 15.2, 1.7, and 5.0% of patients with CFS, respectively. ·         Anti-nuclear antibodies were found in 56.7% (34/60) of patients with CFS, but anti-nuclear antibody titers did not correlate with the activities of the above four autoantibodies
Reduction of [(11)C](+)3-MPB Binding in Brain of Chronic Fatigue Syndrome with Serum Autoantibody against Muscarinic Cholinergic Receptor	The present results demonstrate that serum autoantibody against the muscarinic cholinergic receptor (mAChR) can affect the brain mAChR without altering acetylcholinesterase activity and cognitive functions in CFS patients.
Anticardiolipin antibodies in the sera of patients with diagnosed chronic fatigue syndrome	Anticardiolipin antibodies (ACAs): ·         Immunoglobulin M isotypes in 95% of CFS serum samples tested. ·         The presence of immunoglobulin G and immunoglobulin A isotypes were also detected in a subset of the samples. ·         Future studies will focus on elucidating whether alterations to mitochondrial inner membranes and/or metabolic functions play a possible role in the expression of ACAs.
Infection, vaccination, and autoantibodies in chronic fatigue syndrome, cause or coincidence?	Antibodies testet in CFS. Antibodies in AIDs ·         Anti-dsDNA No ·         Anti-Sm No ·         Anti-RNP No ·         Anti-SS-A/Ro No ·         Anti-SS-B/LA No ·         Anti-Scl-70 No ·         ANA Yes Nuclear components ·         Laminin B1 Yes ·         68/48-kDa nuclear proteina Yes ·         p80-coilin nuclear proteinb Yes Phospholipid antibodies ·         Antiphosphatidylinositolc Yes Antibodies to CNS components ·         Serotonin Yes ·         ACTH Yes ·         CHMR1 Yes ·         MAP2 Yes Antibodies to diverse microorganisms ·         Gram-negative  enterobacteriaYes Coxiella burnetii (Q fever) Yes
IgM-mediated autoimmune responses directed against anchorage epitopes are greater in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) than in major depression	Serum IgM antibodies to the three anchorage molecules (palmitic and myristic acid and S-farnesyl-L-cysteine) and NO-phenylalanine were significantly higher in ME/CFS than in depression. The autoimmune responses to oxidatively, but not nitrosatively, modified self-epitopes were significantly higher in ME/CFS than in depression and were associated with fatigue and physio-somatic symptoms.
Antibody to Epstein-Barr Virus Deoxyuridine Triphosphate Nucleotidohydrolase and Deoxyribonucleotide Polymerase in a Chronic Fatigue Syndrome Subset	Antibodies to EBV EA(D) and neutralizing antibodies against the encoded-proteins EBV DNA polymerase and deoxyuridine triphosphate nucleotidohydrolase (dUTPase) were present in the EBV subset CFS patients. Of the sera samples obtained from patients with CFS 93.9% were positive for EA(D), while 31.6% of the control patients were positive for EBV EA(D). Serum samples were positive for neutralizing antibodies against the EBV-encoded dUTPase (23/52; 44.2%) and DNA polymerase (41/52; 78.8%) in EBV subset CFS patients, but negative in sera of controls.

Postural Orthostatic Tacycardia Syndrome, Orthostatic Intolerance, dysautonomia autoantibodies

References	POTS, OI, dysautonomi autoantibodies
Autoimmunoreactive IgGs from patients with postural orthostatic tachycardia syndrome	Forty unique proteins were identified and these include proteins that are associated with cardiac hypertrophy (mimecan, myozenin), cardiac remodeling (periostin), cardiomyopathy (desmin, desmoplakin), cell survival (laminin), structural integrity (filamin), chaperone proteins (crystalline, HSP70), mitochondrial enzymes, and channel proteins.
Autoimmunoreactive IgGs against cardiac lipid raft-associated proteins in patients with postural orthostatic tachycardia syndrome	The targets of autoimmunoreactive IgGs include proteins associated with caveolae structure, adrenergic signaling, calcium signaling, cytostructures, chaperone and energy metabolism. Multiple pathways were involved including those that regulate caveolae-mediated signaling, oxidative phosphorylation, fatty acid metabolism, protein ubiquitination, and cardiac β-adrenergic signaling. ·         Desmin ·         HSP70 ·         Cavin-1
Autoantibody activation of beta-adrenergic and muscarinic receptors contributes to an "autoimmune" orthostatic hypotension	Activating autoantibodies to β1/2-adrenergic (AAβ1/2AR) and M2/3 muscarinic receptors (AAM2/3R) are present in some patients with idiopathic OH compatible with an in vivo effect.
Agonistic autoantibodies as vasodilators in orthostatic hypotension: a new mechanism	We have identified the presence of autoantibodies to β2-adrenergic and/or M3 muscarinic receptors by ELISA in 75% (15 of 20) of patients with significant orthostatic hypotension. Antibody activation of vascular β2 and/or M3 receptors may contribute to systemic vasodilation.
Drug-like actions of autoantibodies against receptors of the autonomous nervous system and their impact on human heart function	Among the epitopes targeted are first and second extracellular loops of the β-adrenergic (β-adrenoceptor) and M2 muscarinic receptor. β(1)-adrenoceptor autoantibodies affect radioligand binding and cardiomyocyte function similar to agonists. In conclusion, such autoantibodies (Antibodies against cholinergic and adrenergic receptors) seem to cause or promote chronic human left ventricular dysfunction by acting on their receptor targets in a drug-like fashion.