Updated Hypothesis presentation:
PART VI: WOLFE HYPOTHESIS
1) Aetiology: ME/CFS is the descriptor applied to the symptomatological manifestation of Central Sensitisation Syndrome (CSS) associated with neuroendocrine disorder and arising commonly in relation to the predisposing factors:
- Neurodynamic restrictions e.g. dorsal defects, trauma, hypermobility, P53 inactivation
- Predisposition toward hyper-inflammatory responses e.g. sensitivities, asthma
'Fast onset' ME/CFS is triggered when (a) sufficiently acute stressor(s) e.g. microbial, toxic, psychological trauma, physical trauma, surgery, dehydration, tip(s) central sensitisation over some threshold chronicity level
'Slow onset' ME/CFS relates to the gradual worsening of central sensitisation over time, often in relation to phasic hormonal/growth-linked, and lifestyle/behavioural themes e.g. adolescence and the impact of related growth spurts, increased computer/desk usage induced hip and neck flexion, and (lumbar) spinal destabilisation/vertebral compression, on tension/sensitisation in the PNS. Other exacerbatory factors include energy exhaustion and/or inadequate restorative sleep, deleterious eating and drinking habits, state of mind, and exposure to toxins, antigens, and pseudo antigens
Most 'fast onset' patients can retrospectively identify signs of a 'slow onset' prior to an acute trigger event if they ponder carefully enough; hence, given the above, we do not interpret 'fast' and 'slow' descriptives as being indicative of heterogenous disorders
2) Pathophysiology:
a) Core Disorder Cascade:
- Worsening central sensitisatione.g. with an acute 'trigger' event
- ≈ Sustained immune responses e.g. B-lymphocytes/microglia activity
- ≈ Chronic Activation Statee.g. epigenetic B-lymphocytes/microgliachanges
- ≈ Chronic Systemic Inflammation e.g. thanks to inflammatory cytokines
- (+) ~ The impact of viruses that remain 'latent' in the dorsal roots (EBV)
- (+) ~ Nerve sensitisation arising from other sources e.g. toxic/behavioural
- ≈Escalation of the neurogenic sensitisation loop
- ≈Chronic inflammation of the dorsal root ganglia *
- (+) ~ Chronic Neuropathic Pain Disorder
- (+) ~ Chronic Systemic Arousal
- ≈ Dysautonomia
- ≈ Emergence of CSS **
- ~ 'Crosstalk', between sensory nerves and SNS
- ~ Neuroplastic changes
- ≈ Corruption of neural circuitry
- ≈ Sensory Processing Disorder
- ≈ Hypersensitivities
- * ~ Increased congestion of spinal lymphatic drainage points
- * ~ Concomitant increased volume of lymph passing through
- ~ Thoracic ducts swell and become varicose
- ~ Lymphatic drainage dysfunction
** Mounting central sensitisation ensues as afferent input from the increasingly irritable peripheral nerves becomes increasingly noxious due, in part, to altered nociceptive signaling, intra-neural blood flow, and neuromuscular tension induced inflammatory neuropeptide activity. This further modulates the impact of the onset 'trigger', as well as that of any other complimentary pathophysiologic pathway to chronification of central sensitisation (the emergence of CSS) e.g. chronic lymphatic drainage dysfunction (above)
b) Chronicity and Persistence:
i) Neuroendocrine Disorder: The cumulative sensitising effects of the above give rise to 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 immune/inflammatory, metabolic, circulatory and circadian rhythm processes
Further Chronic Systemic Inflammation ensues, causing, for example:
- Heightened antigenic, pseudo-antigenicand sensory sensitivity/reactivity
- ~ Potential for CSS escalation with continuing/future exposure to relevant agents
- Emergence or worsening of OI (hypotension/hypovolemia/'low flow POTS')
- ~ Reduced intra-neural blood volume/flow
- ~ Increased nerve sensitisation
- ~ Increased neurogenic sensitisation
If, as is often the case, the emergence of a chronic health disorder is accompanied by a prolonged period of relative inactivity, and/or by a period in which a patient encounters significant acute, or less significant ongoing, neuromuscular strain, then a
pro-inflammatory neurogenic sensitisation loop may take hold. This has the potential to escalate
CSS, and hence the potential to determine the progression, and severity, of ME/CFS
ii) Lymphatic Drainage Dysfunction: Examples of direct impacts of neurogenic sensitisation include the impact of increased resting muscle tone or 'tightness' on 4th ventricular flow of CSF, and lymph transit both to and, theoretically, from the lymphatic system e.g. a mild form of
Thoracic Outlet Syndrome at the left
subclavian vein
Behavioural factors such as reduced physical activity, and hence (deep) respiration, under conditions of chronic ill health may further enhance the strain on the lymphatics thanks to the resultant under-stimulation of lymph:
- Shallow/costal breathing
- ≈ Attenuated respiration induced lymphatic circulation
- Reduced regular exercise
- ≈ Attenuated skeletal muscle induced lymphatic circulation
- ≈ Attenuated respiration induced lymphatic circulation
Over time the unidirectional valves that regulate flow within the thoracic duct (negating back-flow) may become dysfunctional under such duress. Reverse drainage of lymph may then occur, causing contamination of the CSF and other fluids and tissues. Toxins may 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, most poignantly the hypothalamus, causing (further) dysautonomia. This has functional feedback effects, examples include:
- High ANG II levels in low flow POTS
- ~ Low bioavailability of NO
- ~ Less relaxation of smooth muscle lining of thoracic ducts
- ~ Functional impairment of peristalsis of the thoracic duct
- Thoracic hypovolemia (relating to blood volume/flow dysregulation [OI])
- ~ Attenuated arterial pulsation action on thoracic duct flow
3) Gender Bias: The female:male ratio in ME/CFS is roughly 4:1, we put this partly down to:
- Distinct hormonal profiles
- ~ Higher risk of ANS dysfunction (precise mechanisms unknown)
- ≈ Higher levels of relaxin, which allows joint mobility, in females
- ≈ Females are more likely than men to have hypermobile joints
- ~ Higher potential for diminished nerve mobility with puberty
- ≈ Females have inherently less stable sacrums
- ~ Higher potential for local neuropathic pain disorder
- Greater potential for development of sensitivities (e.g. allergic) with age in females (Kelly & Gangur, 2009; Wormald, 1977)
- Enhanced limbic systems in females
- Enhanced potential for emotionality under adverse/emotionally charged conditions
4) Fibromyalgia [FM]
:We propose that FM shares the same core aetiology and pathophysiology outlined above but, compared with PWME, FM patients likely experience:
- Greater mitochondrial dysfunction (Castro-Marrero et al., 2013)
- Greater neurological sensitisation e.g. of the somatosensory systemand SNS
- ~ Greater 'interference', or 'crosstalk', between sensory nerves and SNS
- Greater oxalate depositse.g. as a function of:
- High systemic calcium:magnesium ratio (a function of diet/deficiencies)
- High systemic oxalate (a function of diet/clearance abnormalities)
- Any other predisposition for relatively high oxalate aggregation
Wolfe Hypothesis © John H Wolfe (2013)