You might want to create some (or more than one) schematic to show how this all fits together.
I got so far with that then overcomplicated it and gave up!
I have now further developed my working hypothesis to take account of further readings, and in particular the recent work of Dr. Rowe. I've improved the article structure, am in the process of tightening up the discussion and have better developed/simplified the theoretical linkages between the main disorders in the Hypothesis section, as well as begun to develop a generalised checklist for protocol design
Have now incorporated a little on this, via neuroendocrine stress
Thanks for your input, I looked into the role of ANG II in POTS (as per your sig) and have also had a stab at incorporating that too
PART VI: WOLFE HYPOTHESIS
1) Primary Disorders & Vital Pathogenic Pathways: Prior to onset, at least one of the following primary disorder factors (often comorbid) place the CNS under strain via neurodynamic and lymphatic drainage dysfunction induced central sensitisation:
A)
CNS Central Sensitisation Syndrome (CSS):
- Diminished neurodynamics e.g. dorsal defects, trauma, hypermobility
- Potential for neuromuscular strain e.g. certain connective tissue phenotypes
- Predisposition toward auto/hyper-inflammatory responses e.g. sensitivities
B) Structural impediment of lymphatic circulation:
- Idiosyncratic architecture of the spine (dorsal defects)
- Acute spinal trauma
- Other obstruction
2) Triggers and Onset: '
Fast onset' ME/CFS is triggered when, in the presence of (a) primary disorder factor(s), (a) sufficiently acute and long lasting stressor(s) e.g.
viral,
bacterial,
toxic,
psychological trauma, physical trauma, surgery, or dehydration, tip(s) a patient's immune system into a
chronic activation state
'
Slow onset' ME/CFS relates to the worsening of (a) primary disorder factor(s) over time, to the point where the patient enters a
chronic activation state. This slow worsening often relates to phasic hormonal/growth-linked and lifestyle changes e.g. adolescence. Exacerbatory factors include all sources of peripheral-central sensitisation e.g.
energy exhaustion and/or inadequate restorative
sleep, deleterious
eating and
drinking habits,
state of mind, and exposure to
allergens,
viral and
bacterial infection, and
toxins
More often than not PWME who self identify as '
fast onset' patients can retrospectively identify signs of a '
slow onset' prior to an acute trigger event if they ponder carefully enough; thus we do not believe that '
fast' and '
slow' descriptives are necessarily indicative of heterogenous disorders, or representative of particularly distinct sub-groups
3) Central Disorder Cascade:
- Worsening of primary disorder(s) e.g. with an acute 'trigger' event
- ≈ Chronic immune responses e.g. sustained B-lymphocytes/microglia activity
- ≈ Chronic Activation State e.g. epigenetic B-lymphocytes/microglia changes
- ≈ Chronic Systemic Inflammation e.g. thanks to inflammatory cytokines
- ≈ (+) i) Enhanced stress gearing of the neurogenic sensitisation loop
- ≈ (+) Chronic inflammation of the dorsal root ganglia
- ≈ Increased congestion of spinal lymphatic drainage points
- ≈ Concomitant increased volume of lymph passing through
- ≈ Thoracic ducts swell and become varicose
- ≈ ii) Lymphatic drainage dysfunction
i) Mounting central sensitisation ensues as afferent input from the increasingly irritable peripheral nerves becomes increasingly noxious. Increased resting muscle tone and aggravation of vascular and autonomic tone are a corollary of this nascent neurogenic disorder, which further modulates the (continued) impact of the onset 'trigger,' as well as that of any other complimentary pathogenic pathway e.g.
ii)
ii) Examples of direct impacts from
i) include the impact of increased muscle tone on normal on 4th ventricular flow of CSF, and (central) lymphatic drainage, theoretically including the drainage of the lymph into the blood stream at the left
subclavian vein e.g. a mild form of
Thoracic Outlet Syndrome, which would have serious implications for lymphatic flow (chronic impediment of the chief circulatory aid: vacuum induction)
4) Persistence:
i) The cumulative cytokine-linked
pro-inflammatory/sensitising effects of the above give rise to neuroendocrine disorder involving altered hormone metabolism, production, and removal leading to neurotransmitter disorder and associated dysregulation of the HPA & HPT Axes. Once dysautonomia takes hold many important systems break down e.g. normal inflammatory processes, metabolic functions, circulatory regulation and circadian rhythms
Further
Chronic Systemic Inflammation ensues, causing, for example:
- Heightened antigenic, pseudo-antigenic and sensory sensitivity/reactivity
- OI emerging/worsening, bringing feedback effects such as nerve and CNS blood supply deprivation/vasoconstriction, which ratchets up central sensitisation
If the emergence of a chronic health disorder is accompanied by a period of relatively significant inactivity, as is often the case, and/or by a period in which a patient encounters (sporadic) neuromuscular strain, then a
pro-inflammatory neurogenic sensitisation loop may take hold. This has the potential to up-rate severity of the primary factor: CSS, and hence the potential to determine the progression, and severity, of ME/CFS
ii) Reduced (deep, lymphatic stimulative) respiration in ill health may further enhance the strain on the lymphatics. Over time the unidirectional valves that regulate flow within the thoracic duct (negating back-flow) become dysfunctional under such duress. Reverse drainage of lymph occurs and the
CSF becomes polluted with
toxic substances. These make their way up to the blood brain barrier where they may permeate, acting on exposed portions of regions of the brain e.g. the basal ganglia, causing (further) dysautonomia. This has feedback effects, examples include:
Functional impairment of lymphatic circulation:
- High ANG II levels in low flow POTS
- ≈ Low bioavailability of nitric oxide
- ≈ Less relaxation of smooth muscle lining of thoracic ducts
- ≈ Functional impairment of Peristalsis of the thoracic duct
Under-stimulation of lymph:
- Shallow/chesty breathing
- ≈ Attenuated respiration induced lymphatic circulation
- Reduced regular medium to high intensity exercise
- ≈ Attenuated skeletal muscle induced lymphatic circulation
- ≈ Attenuated respiration induced lymphatic circulation
- Thoracic hypovolemia (relating to blood volume/flow dysregulation [OI])
Wolfe Hypothesis © John H Wolfe (2013)