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  • Writer's pictureGraham Exelby

Fibromyalgia Syndrome and the Linking with POTS and Chronic Fatigue Syndrome- Part 1

Dr Graham Exelby February 2024


The large quantity of data with images is more than this website will allow in 1 document, so it has been broken into a number of parts, with separate documents on management and references


Introduction


Fibromyalgia Syndrome (FMS) is a chronic disorder that causes pain and tenderness throughout the body, as well as fatigue and sleep disorder. The pain of fibromyalgia is typically diffuse, migratory (moves from one joint to another) and may involves both muscles (myalgia) and joints (arthralgia). It affects both sides of the body, and above and below the waist.  Typically this can be associated with increased skin sensitivity even to touch. 

 

FMS is common at all ages and in all societies, affecting females more than males.    While most patients are middle-aged at presentation, it can be seen in children, teenagers and the elderly.  Second only to osteoarthritis as the most common disorder seen by rheumatologists, it is recognised that FMS is an under-diagnosed and undertreated condition, generally poorly recognized and treated, and often labelled incorrectly as a psychological disease.   

 

FMS commonly is first recognized around the menopause when the autonomic nervous system is unstable, although there are usually clues that may date back decades into infancy.   The symptoms of menopause especially the flushes and sweats are autonomic in nature, and reflect a dysfunction in autonomic stability, and menopausal dysautonomia may be the final factor that tips someone with pre-existing problems into a recognisable diagnosis.

It is not uncommon in children, although very difficult to diagnose accurately when they are very young.    Fibromyalgia coexists with a number of chronic illnesses, and in this setting the clinical features of fibromyalgia will contribute to and often confuse the assessment of these disorders.   With the increasing awareness of the underlying DNA mutations in FMS, there is an increasing ability to understand these associations.

 

Working out the things that are triggering the immune system -the role of activation of the body’s threat receptors (Toll-Like Receptors) and immune response via Mast Cells, affecting microglial and astrocyte function in the nervous system and the symptoms this causes, is critical to understanding and controlling fibromyalgia and its comorbidities.    But like Pandora’s Box, when you open this it can be very complicated with the multiple genetic factors, and various drivers to work out.   But each one you do control can improve the quality of life in someone with this immeasurably.

 

Environmental and genetic factors predispose individuals to develop fibromyalgia.   Symptoms usually start after a precipitating event such as injury or acute stress, although in some it is a cumulative series of traumas or “activators” which can include physical trauma, especially MVAs with neck and shoulder injuries, stress, parasites such as pro-inflammatory subtypes of blastocystis hominis, moulds, infections, or prolonged postural or rotational causes often occupational in origin.  Ehlers-Danlos Syndrome is a very significant factor both in increased predisposition and management.  The onset of menopause may precipitate FMS symptoms, as this is a time of autonomic instability.  Even the increasing breast weight of menopause can be problematic, adding to the dysfunctional autonomic changes.

 

Symptoms often disappear when stress is not present, so many people are considered to have only psychological problems, which is usually far from reality.   I often see unexplained anxiety and panic attacks driven by catecholamine-driven reactions to mechanical or dietary triggering as well as psychological causes, and most of these patients have a DNA mutation in one or more of the many COMT mutations so catecholamines produced mechanically or from psychological stress are not processed efficiently.   So much anxiety is driven by mechanical causes, especially to the shoulder and spine, as well as foods the body sees as a threat.    So many patients with underlying intra-abdominal vascular compression syndromes especially Median Arcuate Ligament Syndrome and Superior Mesenteric Artery Syndrome, both common in POTS and FMS, are labelled as “eating disorders,” a label that is hard to shake even when the others are confirmed.

 

What is Fibromyalgia Syndrome (FMS)

 

Fibromyalgia is a disorder of central pain processing or a syndrome of central neural sensitisation.  There is altered functional connectivity and chemistry in the pain-processing system of the brain.  While it typically presents in young or middle-aged women but can affect patients of either sex and at any age, including children.

 

Fibromyalgia is a syndrome, with many symptoms in addition to pain. When pain is not present, the patient you really can’t diagnose fibromyalgia,(1) but it does demonstrate how fibromyalgia symptoms are responsive to control of underlying inflammatory “drivers,” as symptoms will vary and the fibromyalgia may wax and wane.

 

The concept of central sensitization, wherein pain and altered sensory states may be due to changes in nerve synapses and membrane excitability in the CNS, as opposed to processes in peripheral tissues, has been around for more than 20 years. Research into long COVID has demonstrated that glial and microglial small-fibre neuropathy are the primary source of this sensitization, and confirms the inflammatory nature that underpins it, from cytokines IL-6 and TNFa from exaggerated immune responses started at the boy’s threat receptors, the Toll-Like Receptors (TLRs), mast cells in trauma.

 

Clauw (2) describes the syndrome as a diffuse problem of sensory “volume control” such that patients have a lower threshold of pain and of other stimuli, such as heat, noise, and strong odours.


Hypersensization in Fibromyalgia, where the characteristic pain is now known to be small fibre neuropathy had been felt to be part of threat receptor hypersensitivity as there appears to be an array of TRP and Acetylcholine receptor polymorphisms that results in nerve hypersensitivity, altered calcium influx and cellular function and even immune responses.    As a consequence of the aberrant mast cell activity, it now appears that the sensitization is caused by the microglial sensitization.   A subtle difference, but important in consequence as it enables an approach based on managing the aberrant mast cell responses.

 

Working through the problems leading to fibromyalgia, I have found that looking at the activators and drivers in these problems, combined with a solid family history as a minimum (or DNA ideally when there are multiple complex coexistent diseases) helps us take the next step forward towards recovery.   The process is complex in most people as so many processes are underway and all need to be sorted out.

 

Turning off the processes driving the threat receptors is vital to controlling the symptoms of FMS, whether it be physical or emotional stress, vascular and lymphatic compression, spine triggers, infections, and diet triggers which manifest as IBS.    Simply using medication to control symptoms will not fix the problem.     Taking narcotics to control the pain in reality increases the problem as morphine causes increased hypersensitivity to the already damaged nerves.    The work by Griffith University in Low Dose Naltrexone has been a major step forward for many FMS patients.

 

Sleep disturbance has been identified as a major factor, and recent studies have reproduced FMS symptoms by inducing sleep deprivation in normal, although unfit subjects. EEG studies have shown a reduced amount of deep, non-dreaming, non-REM sleep with interruption by alpha waves.   Increasing evidence shows that patients with FMS experience pain differently to the general population because of dysfunctional pain processing in the central nervous system.   But the sleep disturbance is also characteristic of the heightened triggering of the threat receptors, the innate immune system activated and increased sympathetic output keeping the body on a “high alert” basis.   Sleep disturbance is also a factor in glymphatic function, as this system requires sleep for normal function.

 

Fibromyalgia is not a psychiatric condition

 

Fibromyalgia Syndrome is not a psychiatric condition, which has been a widely held belief for years in medicine, and this belief still exists and hampers effective management.  It is characterized by widespread musculoskeletal pain, fatigue and cognitive difficulties.  It presents with autonomic and inflammatory symptoms, with strong associations with myalgic encephalomyelitis /chronic fatigue syndrome (ME/CFS).   FMS, along with Postural Orthostatic Tachycardia Syndrome (POTS) are also common presentations of post-acute sequelae of SARS-CoV-2 infection (PASC), commonly known as “Long COVID.”  Our findings of how autonomic instability, fatigue, neurotransmitter dysfunction, and inflammatory responses can be provoked by stress, infection (especially COVID-19), injury, or mechanical and dietary factors has given us a basis for working with FMS, POTS and their comorbidities. 

 

Attempts to reduce fibromyalgia to one or 2 causes or depend simply on anti-depressants, anti-neuropathic medication, or on management of dysfunctional mast cells for example, is usually fraught with failure as it is a summation of multiple metabolic, psychological, genetic, infective, traumatic, mechanical, dietary and inflammatory factors.  

 

Inflammation at the core of FMS

 

Inflammation is at the basis of most disease including fibromyalgia.  Inflammation, the immune response of body tissues to injury or infection, has been an important part of our innate immunity since we were cavemen.     Acute inflammation is a normal process that protects and heals the body following physical injury or infection. However, if the agent causing the inflammation persists for a prolonged period of time, the inflammation becomes chronic, which can cause a wide range of problems.

 

Research shows mechanical, biochemical, metabolic, and immunoregulatory abnormalities that substantiate the proposal that fibromyalgia can no longer be considered a subjective pain condition, and is not a psychiatric condition, although sustained stress and PTSD number among its “activators “and “drivers.”


Table 1: Signs and Symptoms of FMS


  • Persistent widespread pain over 3 months on both sides of the body, above and below the waist, including the axial spine

  • Muscle and joint stiffness

  • Fatigue; disrupted and unrefreshing sleep

  • Cognitive difficulties- problems with concentrating, thinking clearly, and memory (sometimes called “fibro fog”).

  • Tenderness to touch.

  • Numbness or tingling in the arms and legs.

  • Heightened sensitivity to light, noise, odours, and temperature.

  • Digestive issues, such as bloating or constipation.

  • Multiple other unexplained symptoms, anxiety and/or depression, and functional impairment of activities of daily living (3)(4)

 

Figure 1: Trigger Points in Fibromyalgia

 


Source: Torborg,L. Understanding myofascial pain syndrome and fibromyalgia. 2017. Mayo Clinic. https://newsnetwork.mayoclinic.org/discussion/mayo-clinic-q-and-a-understanding-myofascial-pain-syndrome-and-fibromyalgia/

 

Overlapping Conditions

 

At a clinical level, fibromyalgia is much more than widespread pain. It overlaps substantially with other syndromes.

 

Figure 2. Overlapping Conditions

 


 

Bragee (5) and Hulens (6) describe the overlap between Intracranial Hypertension, Fibromyalgia and CFS.   Tilt tests in CFS in small studies by Raj et al (7) confirmed POTS and CFS to have similar causes.   Research at our clinic confirm that whatever the ‘activation” many of the same physical drivers are present.   This may be seen in the recurring symptoms of Intracranial Hypertension.

 

There is no “solid” data on the percentage of these co-morbidities in Fibromyalgia.  Looking at early data from our work around 65% of POTS have accompanying FMS.  The current data analysis should confirm the actual figures.   All the diagnoses described as co-morbidities are seen in our ongoing POTS research, and many of the descriptions in this document are centered around POTS.   In Table 1, the common documented co-morbidities are accompanied by possible causes.

 

Table 2: Established Co-morbidities and Possible Underlying Causes


  • Chronic Fatigue Syndrome -see Table 3

  • Irritable bowel syndrome 

    • TLR4 / cytokine /microglial activation

    • Mast cell activation

    • autonomic dysfunction including Intra-abdominal Compression Syndromes

  • Chronic pelvic pain syndromeprimary dysmenorrhoea

    • TLR4 / cytokine /microglial activation

    • Mast cell activation

    • Pelvic congestion syndrome

    • Intra-abdominal compression syndromes (especially May-Thurner and Nutcracker Syndromes with probable effects from paravertebral and azygous vein dysfunction)

  • Temporomandibular joint pain

    • Upper cervical dysfunction

  • Post-Traumatic Stress Disorder (PTSD)  

  • Multiple chemical sensitivity

    • TLR4 / cytokine /microglial activation

    • Mast cell activation

  • Periodic limb movement disorderrestless legs syndrome

    • Central sensitization (an aspect of increased spinal cord excitability related to impaired modulation by dopaminergic pathways) (8)

  • Interstitial cystitis

    • TLR4 / cytokine /microglial activation

    • Intra-abdominal compression syndromes

    • Mast cell activation

    • Food intolerance

  • Migraine /tension headaches

    • Upper cervical dysfunction (especially C2/3)

    • Impaired glymphatic flow and activated microglia and astrocytes (9)

    • Central sensitization

  • Intracranial Hypertension

    • CSF flow obstruction (including lymphatics head and neck)

    • Intracranial venous obstruction (see below)

  • Postural Orthostatic Tachycardia Syndrome (POTS)

    • See Assembling the Pieces of POTS

 

Table 2 based on clinic assessments

 

The most common overlapping condition with ME/CFS is fibromyalgia.   In ME/CFS dominant patients, the fibromyalgia pain is not constant, but tends to appear when there is an additional injury or infection, such as an accident, a viral infection, or a surgical procedure, in keeping with the evolving recognition of activation of the immune system via threat receptors, especially Toll-Like Receptor 4 (TLR4), and subsequent activation of microglial cells in the nervous system.


The evolving work from COVID research shows FMS to be a complex activation of threat receptors (Toll-Like Receptors especially TLR2 and TLR4) with subsequent small fibre neuropathy, sensitization and autonomic and neurotransmitter dysfunction. 


FMS hypersensization where the characteristic pain from small fibre neuropathy had been felt to be part of threat receptor hypersensitivity as there appears to be an array of TRP and Acetylcholine receptor polymorphisms that results in nerve hypersensitivity, altered calcium influx and cellular function and even immune responses.    As a consequence of the aberrant mast cell activity, it now appears that the sensitization is caused by the microglial sensitization.   A subtle difference, but important in consequence as it enables an approach based on managing the aberrant mast cell responses.

 

Griffith University Gold Coast has been exploring calcium ion channels which then may influence monocytes differentiating into microglia to control brain blood flow.   The level of glial activation (inflammatory change) corresponds to the level of fatigue.    Increased levels of IL-6 and IL-8 in CSF and serum suggests symptoms are mediated by autonomic activity.

 

FMS coexists in unusually high frequency with certain illnesses characterized by systemic inflammation, such as rheumatoid arthritis, systemic lupus erythematosus.(3)  Endometriosis is a common accompaniment, with TLR4 induced inflammatory pathways.(10)  A thorough “work-up” for FMS includes exclusion of these and similar conditions.  Unfortunately, FMS has become a diagnostic “dumping ground” for practitioners not familiar with how to dissect symptoms, signs and histories.

 

Neuroimmune System, Glial cells, Cytokines and TLR triggering- the Immune Response -detail in Fibromyalgia Syndrome Part 2 The Immune Response

 

The innate immune system is the body’s first line of defense.   As well as cells that destroy invading virus it also activates the adaptive immune system which provides the body with long-lasting protection. The “Gate-Keepers” are the Toll-like Receptors (principally TLR4, TLR2, TLR3), the primary sensors of the innate immune system.  TLR 2 and 4, on the outside of the cells are the first “responders”.  TLR activation can trigger a dysfunctional immune response (especially when TLR4 mutations are present) via often dysfunctional Mast Cells provoking the excessive cytokine storm, in particular interleukin 6 (IL-6) and tissue necrosis factor alpha (TNFα), that sensitise microglia cells.

 

Figure 3: Toll-Like Receptors 2, 3, 4



Source: Yookji, CC BY-SA 3.0 <https://creativecommons.org/licenses/by-sa/3.0>, via Wikimedia Commons


Toll-like Receptor 4 (TLR4) is a protein receptor found on the surface of immune cells, including Natural Killer Cells (NK cells), which play a critical role in the innate immune response to viral infections and cancer.   When TLR4 on NK cells is activated, it triggers a signaling cascade that leads to the production of cytokines and chemokines, which help activate other immune cells to fight the threat.    

 

TLRs can be sub-divided based on cell location. TLR1, TLR2, TLR4, TLR5, and TLR6 are found on the cell membrane.  TLR3, TLR7, TLR8, and TLR9 are located inside (endosomal.)  In neuroinflammation, the innate immune system, including the microglia or astrocytes, can be activated by inflammatory mediators.   TLR4 can be activated by damage-associated molecules that were released from damaged or dying cells. The activated TLR4 then initiates intracellular signals on two distinct pathways such as MyD88/NF-κB and TRIF/IRF3. The TLR4 signalling pathway has been involved in major depressive disorders and peripheral neuropathic pain, and appears to play a major role in POTS, Long Covid as well as fibromyalgia. 

 

Figure 4: Glial Cells of the Brain

This image shows the four different types of glial cells found in the central nervous system: Ependymal cells (light pink), Astrocytes (green), Microglial cells (red), and Oligodendrocytes (functionally similar to Schwann cells in the PNS) (light blue).  Astrocyte endfeet shown lining vessels.



Source: Artwork by Holly Fischer, CC BY 3.0 <https://creativecommons.org/licenses/by/3.0>, via Wikimedia Commons

 

Cytokines are small proteins involved in cell signalling, the process by which a cell responds to threats through signalling molecules, or ligands on the surface and inside cells.  Cytokines are a family of secreted ligands critical for immune homeostasis.  These cytokines, interleukin 6 (IL-6) and tissue necrosis factor alpha (TNFα) sensitize microglial cells that results in small-fibre neuropathy (SFN).  The small-fibre neuropathy causes the sensitivity, pain and autonomic instability that is characteristic of POTS, long COVID, and FMS.   SARS-CoV-2, as with other threats to the body, interacts with threat receptors TLR2 and TLR4 on a cell surface.  While TLR4 activated cytokines are responsible for microglial activation which causes small fibre neuropathy, TLR2 activation may disrupt astrocyte function. 

 

Clough et al (11) describe: “Microglia are the resident immune cells of the Central Nervous System (CNS) and represent 5–20% of the adult brain. Microglia have the capacity to migrate, proliferate and phagocytize. Under physiological conditions, microglia exist in their “resting” state, however on exposure to a pathogen, microglia transition into an activated state and quickly mobilize to the site of injury to initiate an innate immune response.”  As the resident macrophage cells, they act as the first and main form of active immune defence in the CNS.

 

Microglia and astrocytes play essential roles in the central nervous system contributing to many functions including homeostasis, immune response, blood–brain barrier maintenance and synaptic environment.    Microglia robustly express a wide range of TLRs whereas astrocytes preferentially express TLR3 (and not TLR4) receptors. As the spike protein of SARS-CoV-2 enters cells TLR3 activation inside the cells (endosomal activity) occurs. 

 

The consequence of the microglial sensitisation that causes small fibre neuropathy is abnormal functioning of the autonomic nervous system, that controls everyday body activities- autonomic dysfunction or dysautonomia.  Symptoms of this include: lightheadedness, presyncope, abnormal heart rhythms, shortness of breath, dry eyes, loss of saliva, temperature dysregulation, excessive sweating, constipation or diarrhoea, nausea, unexplained anxiety, abnormal bowel and bladder function, and other symptoms.(13)  Many symptoms demonstrate a “cross-over” with mast cell activation (14)(15) and astrocytes with consequent neuroinflammatory pathology.(12)

 

There is cross-talk between microglia and astrocytes (Figure 6) to influence and coordinate with each other and their effects on the brain environment.   Astrocytes contribute to the pathogenesis of neurodegenerative diseases, inflammatory CNS disorders, injuries, and neuropathic pain. It is likely that the net consequence of astroglial TLR stimulation is context-dependent and influenced by the pathological environment in which the cells function.(16)

 

Astrocytes perform metabolic, structural, homeostatic, and neuroprotective tasks such as clearing excess neurotransmitters, stabilizing and regulating the blood-brain barrier, and promoting synapse formation.   Because astrocytes fulfill many essential functions, their dysfunction has implicated them in several neurological disorders.”(17)    In CNS pathology, astrocytes become reactive and proliferate at affected sites, exerting both beneficial and detrimental functions, contributing to the cause of neurodegenerative diseases, inflammatory CNS disorders, neuropathic pain, as well as neuroprotection.(18)

 

Blood flow in the brain is regulated by neurons and astrocytes, which are “a subtype of glial cells that make up the majority of cells in the human central nervous system.   They contribute to many key physiological and pathophysiological mechanisms in the CNS.(16)  Attwell et al (19) describe “It is now recognized that neurotransmitter-mediated signalling has a key role in regulating cerebral blood flow, that much of this control is mediated by astrocytes, that oxygen modulates blood flow regulation, and that blood flow may be controlled by capillaries as well as by arterioles.”   Astrocytes can promote the induction and progression of inflammatory states, which are significantly associated with the disease status or severity.(20)

 

Figure 5: A schematic summary of mechanisms by which Astroglial TLRs contribute to viral infections of the CNS.

Astrocytes sense and respond to various viruses that enter the CNS. In the early stage of viral infection, infected astrocytes mount an anti-viral response to protect the host. Exposure to viruses or viral components upregulates the expression of astroglial TLRs located at the cell membrane or endosomal compartments. The activation of TLR signaling, especially TLR3 signaling, facilitates the anti-viral response including prevention of viral dissemination, inhibition of viral replication, and production of anti-viral mediators. The TLR3-mTORC2 axis is among the pathways that mediate this response. TLR signaling also promotes the production and release of pro-inflammatory mediators and induces inflammatory responses in the CNS. These inflammatory responses can help the clearance of the pathogen but also cause degeneration and dysfunction of CNS cells. Astrocytes can also store, support the replication of viruses, and disseminate them to other CNS cells.(18)



Source: Lun Li, Cigdem Acioglu, Robert F. Heary, Stella Elkabes,. Role of astroglial toll-like receptors (TLRs) in central nervous system infections, injury and neurodegenerative diseases. Brain, Behavior, and Immunity, 2021.  https://doi.org/10.1016/j.bbi.2020.10.007

 

From Covid-19 research it is apparent that microglia are involved in both protective and damaging responses in the central nervous system.  The severe cytokine storm in COVID -19 is associated with increased serum levels of proinflammatory cytokines and increased blood brain barrier (BBB) permeability due to cytokine-induced damage, causing neuro-cognitive impairment.  SARS-COV2, the virus that causes COVID-19, can trigger a process in the body's cells that leads to their programmed death (apoptosis). This process is like a built-in self-destruct mechanism that starts within the cell's powerhouses, the mitochondria, and is a normal way the body gets rid of damaged or infected cells.

 

Figure 6:  Microglial/Cytokine Cross-talk




Source: Beardsley P. M., Hauser K. F., Fitting S., Dever S. M., Podhaizer E. M., Knapp P. E., CC BY 2.5 <https://creativecommons.org/licenses/by/2.5>, via Wikimedia Commons

 

Mast Cell /Astrocyte/Microglial Interaction

 

“Mast cells play a key role in homeostatic mechanisms and surveillance, recognizing and responding to different pathogens, and tissue injury.   An abundance of mast cells reside in connective tissue that borders with the external world (the skin as well as gastrointestinal, respiratory, and urogenital tracts.)   Situated near nerve fibres, lymphatics, and blood vessels, as well as coupled with their ability to secrete potent mediators, mast cells can modulate the function of local and distant structures (eg other immune cell populations, fibroblasts, angiogenesis), and mast cell dysregulation has been implicated in immediate and delayed hypersensitivity syndromes, neuropathies, and connective tissue disorders.”(10)

 

Mast cells are activated by cytokines from TLRs releasing cytokines, chemokines and include tryptase. Dysfunctional mast cell activation is implicated in the cause of FM pain.   Several symptoms of FMS are very similar to those following contact with an infectious agent, with its activation of inflammatory cytokines.  The complex nature of the immune response and mast cell activation in now an integral part of Long Covid pathogenesis.   The same microglial activation has been demonstrated in other conditions -CFS (22), ADHD (23), migraine and Endometriosis (24).

 

In FMS, neurotransmission and glial activation can occur with an increase in inflammatory cytokines.  Conti et al (25) showed an increase in the number of mast cells, as well as the production of corticotropin releasing hormone and substance P by the neurons, which in turn activate mast cells to release neuro-sensitizing proinflammatory substances, such as cytokines, secreted preformed mediators, and lipids, which can exacerbate low-grade inflammation. 

 

Figure 7: Interactions and mediators between mast cells, microglia and astrocytes in the brain.

Bidirectional interactions are demonstrated between each cell type with the mediators involved in boxes. Different mediators are released in response to cellular activation, which are shown for each cell type.

 

ATP, adenosine triphosphate; BDNF, brain derived neurotrophic factor; CCL5, C-C motif chemokine ligand 5; C5a, complement 5a; CXCR4, CXC chemokine receptor 4; GDNF, glial derived neurotrophic factor; IL, interleukin; MCP, mast cell protease; NO, nitric oxide; NT3, neurotensin 3; ROS, reactive oxygen species; TLR, toll like receptor; TNF-α, tumour necrosis factor alpha.(26)  This diagram also shows the histamine receptors on each cell, providing potential pathways for inhibition of excessive cytokine responses.




Source: Carthy, Elliott & Ellender, Tommas. (2021). Histamine, Neuroinflammation and Neurodevelopment: A Review. Frontiers in Neuroscience. 15. 10.3389/fnins.2021.680214.(26)

 

Mast cells are increasingly seen as important in the communication between peripheral nerve endings and cells of the immune system. Alim et al (27)  stimulated primary mast cells with glutamate and showed that glutamate induced the profound upregulation of a panel of glutamate receptors at both the mRNA and protein levels, and the binding of glutamate to glutamate receptors on the mast cell surface was confirmed.    Further, glutamate had extensive effects on gene expression in the mast cells, including the upregulation of pro-inflammatory components such as IL-6 and CCL2 and confirming glutamate as an effector of mast cell function.(27)

Theoharidis et al(28) also felt that thalamic mast cells contribute to inflammation and pain in FMS, by releasing neuro-sensitizing molecules that include histamine, IL-1β, IL-6 and TNF, as well as calcitonin-gene related peptide (CGRP), HK-1 and SP.  The importance of mast cell activation has been confirmed in COVID research.

 

Inflammatory microglial activation (IL-6 and TNFa) is the most common brain pathology found in patients who died of COVID-19: 42% are affected, and another 15% have microclots in brain tissue.(31)     Dong et al (30) demonstrated that brain inflammation plays a critical role in the pathophysiology of brain diseases. Microglia, the resident immune cells in the brain, play an important role in brain inflammation. 

 

Neurotransmitter Dysfunction and HPA Axis

 

There is a dysfunctional sympathetic nervous system and hypothalamic-pituitary-adrenal axis (HPA axis), with both hypo- and hyperactivity, with dysfunctional neurotransmitter systems in fibromyalgia.  In addition, all transmitter systems found to be altered in fibromyalgia influence the body's stress systems. (126)    The key symptom of FMS is chronic widespread pain. 

 

Serotonin, noradrenalin, substance P, and glutamate have been shown to be altered in fibromyalgia in ways that could explain patients' increased pain sensitivity, and CSF concentrations of substance P and glutamate have been repeatedly found to be increased in fibromyalgia patients.   CSF levels of dopamine and presynaptic dopamine function are reduced, and dopamine responses to acute pain are diminished in fibromyalgia patients. (133)

 

Figure 8: Altered neurotransmitters in Fibromyalgia

 

Source: Becker S, Schweinhardt P. Dysfunctional neurotransmitter systems in fibromyalgia, their role in central stress circuitry and pharmacological actions on these systems. Pain Res Treat. 2012;2012:741746. doi: 10.1155/2012/741746. Epub 2011 Oct 2. PMID: 22110944; PMCID: PMC3195783.(33)

 

“The important biologic elements here include proinflammatory cytokines, the HPA axis, other neuroendocrine axes, and the autonomic nervous system.” (3)   “Although normally adaptive, the stress response may become maladaptive in patients with chronic pain and fatigue syndromes such as fibromyalgia.  The 2 principal effectors of the stress response, the hypothalamic-pituitary-adrenocortical (HPA) axis and the sympathetic nervous system (SNS), are also activated.”(3)

 

A number of abnormalities in pain processing have been demonstrated in fibromyalgia.   Among them are the following:

  • Excess excitatory (pronociceptive) neurotransmitters (eg, substance P, glutamate levels in the insula)

  • Low levels of inhibitory neurotransmitters (eg, serotonin and noradrenalin) in descending antinociceptive pathways in the spinal cord

  • Maintained enhancement of temporal summation of second pain

  • Altered endogenous opioid analgesic activity in several brain regions known to play a role in pain modulation

  • Dopamine dysregulation (3)

 

The biochemical changes seen in the CNS, the low levels of serotonin, the four-fold increase in nerve growth factor, and the elevated levels of substance P all lead to a whole-body hypersensitivity to pain and suggest that fibromyalgia is a condition of central sensitization and abnormal central processing of nociceptive pain input. 

 

The most widely acknowledged biochemical abnormality associated with fibromyalgia is abnormally low serotonin levels.  Many studies have linked serotonin, a neurotransmitter, to sleep, pain perception, headaches, and mood disorders.(3)   Dopamine has also been studied.  While brain dopamine is best known for its role in pleasure, motivation and motor control, it is also involved in pain modulation, with an impaired response to pain stimuli.(32)

 

Serotonin and noradrenalin have been shown to have a mainly excitatory influence on acute stress responses and both are key in circadian rhythm of the HPA axis. Dopamine has excitatory influences on the basal tone of the HPA axis and enhances acute stress responses.  Another excitatory neurotransmitter in CNS stress circuits is glutamate even though glutamate is present also in inhibitory stress circuits, and elevated levels are usually found in fibromyalgia.(33) 

 

Research from Germain et al (34) demonstrated a shift in metabolism towards amino acids as an energy source as an association with Post-Exertional Malaise, with glutamate in particular involved.  The changing levels of amino acids are currently being explored in our clinic setting.

 

Substance P is a neurotransmitter that is released when axons are stimulated. Elevated levels of substance P increase the sensitivity of nerves to pain or heighten awareness of pain. Multiple studies have found that levels of substance P are 2 to 3 times higher than normal in the CSF of patients with fibromyalgia. These elevated levels cause fairly normal stimuli to result in exaggerated nociception. 

 

There is an interaction between substance P and dopamine in pain perception.(35)  Transmitters that regulate circadian rhythm and enhance acute stress responses such as serotonin, noradrenalin, and dopamine are reduced in fibromyalgia, while substance P, which inhibits basal tone and acute responses of the HPA axis, is increased.(33)

 

Studies of the neuroendocrine aspects of fibromyalgia have found dysfunction of the HPA axis. The HPA axis is a critical component of the stress-adaptation response. The sequence of HPA action is that corticotropin-releasing hormone (CRH) from the hypothalamus stimulates the anterior pituitary to release adrenocorticotropic hormone (ACTH). In turn, ACTH stimulates the adrenal cortex to produce glucocorticoids (eg, cortisol). 

 

Circadian regulation and the stress-induced stimulation of the HPA axis are, in part, regulated by serotonin. Dysfunction of the HPA axis may also exaggerate the effects of abnormal serotonin metabolism. Hypoactivity of the HPA axis may cause low central serotonin levels.(3) Sleep dysfunction is considered an integral feature of fibromyalgia. About 70% of patients recognize a connection between poor sleep and increased pain, along with feeling unrefreshed, fatigued, and emotionally distressed.   

 

Complicating this further, research from Hulens (6) and Bragee (5) describes the link between the “Empty Sella Syndrome, Fibromyalgia, and Chronic Fatigue Syndrome” with the commonly seen increased intracranial pressure can cause disruption of the normal HPA Axis. 

 

Figure 9. The hypothalamic-pituitary-adrenal axis, or HPA axis- the interaction between the hypothalamus, pituitary gland, and adrenal glands; it plays an important role the body’s response to stress. The pathway of the axis results in the production of cortisol.



Source: Guy-Evans, O. (2021, Sept 27). Hypothalamic-Pituitary-Adrenal Axis. Simply Psychology. www.simplypsychology.org/hypothalamic–pituitary–adrenal-axis.html (36)

 

Glutamate Dysfunction

 

Fibromyalgia with its impaired pain perception pathways, has notably been found to have higher concentrations of glutamate in regions of the brain implicated in processing pain information.(37) Glutamate is the predominant excitatory neurotransmitter in the central nervous system.  It has critical roles in multiple brain functions including memory formation and synaptic plasticity (the ability of neurons to change the strength of their connections, an important neurophysiological process in brain networks after any damage.)    


Glutamine synthetase is an enzyme in astrocytes that breaks down glutamate into glutamine.(38)  In excess glutamate has been linked to many neurodegenerative diseases eg Alzheimer’s Disease.  Glutamate toxicity has been associated with severe stress, and in the development of many psychiatric disorders including schizophrenia and bipolar disease. (33)

 

The N-methyl-D-aspartate (NMDA) receptor is a receptor of glutamate.   Plasticity in the function of N-methyl-D-aspartate (NMDA) subtype glutamate receptors is necessary for central sensitization to occur. Increased sensitivity of central NMDA receptors was implicated in earlier studies as playing a primary role in fibromyalgia. However, subsequent evidence has suggested that suppression of the normal activity of dopamine-releasing neurons in the limbic system is the primary pathology in fibromyalgia. While increasing evidence indicates that fibromyalgia may represent a dysregulation of dopaminergic neurotransmission,(3) it does appear to be more complex than this.


Activation of TLR2, the other immune system “first responder” appears to affect the astrocytes.   The astrocytes form the paravascular spaces thus dysfunction in the astrocytes can affect the glymphatic system function.  It is proposed that cerebrospinal fluid enters the brain via paravascular spaces along arteries, mixes with interstitial fluid, and leaves via paravascular spaces along veins.(39) This is complicated by astrocyte/ microglial “cross-talk” and neurotransmitter dysregulation.

 

The astrocyte/glutamate dysfunction has been found to be a major factor in the Gulf War Syndrome, where service personnel were plagued by a variety of medical problems caused by exposure to herbicides employed, including “neurodivergence.”  This glutamate association has also been seen in Fibromyalgia, ADHD, Autism Spectrum, migraine, visual snow and other neurological dysfunction. (45)(46)(47) The mechanism proposed by Guedj and associates in Long Covid,(43)(44) links these to astroglial/glutamate dysfunction (40)(41)(42). Astrocyte dysfunction, by affecting glymphatic function, is thought to play its role in fatigue and Intracranial Hypertension as “toxin” clearance in the brain via the glymphatic system is impaired.

 

The Glymphatic System

 

“The glymphatic system is a macroscopic system for waste clearance in the brain. It uses a system of perivascular channels, formed by astroglial cells, to promote efficient elimination of soluble proteins and metabolites from the CNS. Besides eliminating waste, the glymphatic system may also distribute non-waste compounds, such as glucose, lipids, amino acids, and neurotransmitters, as well as permitting the flow of fluid through the brain.   As the glymphatic system becomes less effective fatigue and brain fog begin to appear.  Fluids from both the brain and the eye drain via the cervical lymph vessels, which empty into the venous system at the level of the subclavian veins.”(48) discussed later, and detailed in Glymphatic System.

 

Figure 10: The Glymphatic System



Source: Mogensen, F.L.-H.; Delle, C.; Nedergaard, M. The Glymphatic System (En)during Inflammation. Int. J. Mol. Sci. 2021, 22, 7491. https://doi.org/10.3390/ijms22147491 (48)

 

The glymphatic system is equivalent to the brain’s “sewer.”  Mechanical factors eg neck posture can impact on clearance and the sustained use of phones and computers (especially laptops,) are considered detrimental.   Glymphatic function is affected in Covid via the TRP pathway (detailed in DNA Mutations in POTS and Long Covid.)

 

Coat hanger pain and chronic fatigue and relevance to post-exertional malaise (PEM)

 

At this stage of our research, it is upper cervical spine dysfunction and thoracic outlet / Internal Jugular Vein obstruction (both at stylohyoid and venous angle) that appears to be the most significant of the known “drivers” in FMS, and is reflected in the fatigue and “coat hanger pain” so often seen.   This combination is common after MVAs, and even more so when Ehlers-Danlos Syndrome is present, where progressive dysfunction occurs, and appears to be a primary cause of the increasing symptoms, in association with other “drivers” especially PTSD. 

 

“Coat hanger pain” is seen frequently in patients with dysautonomia, especially POTS, as well as fibromyalgia and CFS.   Community data suggests it may be associated with a much larger number of conditions.(51) Literature quotes varying figures between 50 and 90% incidence.   Our clinical studies would suggest around 70 to 90% association in fibromyalgia.

 

Humm et al (49) describes the typical ache usually began with standing or sitting, as discomfort and pain in the neck and shoulder, and research suggests this could result from reduced blood flow and oxygen delivery to the muscles in the affected areas.  They showed that muscle membranes in patients with orthostatic hypotension become progressively depolarized during standing, which they felt was most likely the result of muscle ischaemia, related to the drop in perfusion pressure caused by orthostatic hypotension.   

 

The theory on this was proposed over 16 years ago when pain could be induced by vasomotor dysregulation, and vasoconstriction in muscle, leading to low-level ischaemia and its metabolic sequelae. Vasodilatory influences, including physical activity, relieve the pain of FMS by increasing muscle perfusion,(37) confirming the importance of paced appropriate physical activity.

 

Hypoperfusion in the brainstem is a very common finding in brain SPECT scans in CFS.   Wirth et al (52) described reduced blood flow causing neurological symptoms including impaired cognitive function or “brain fog.”  Increased intracranial pressure, as proposed by Hulens (6) and Bragee (5) has also been frequently observed compounding problems (actual rates pending database analysis.)

 

The brainstem hypoperfusion seen in CFS Spect scans is believed to be part of the same process of hypoperfusion and mitochondrial dysfunction that underpins the coat hanger pain of FMS,(49) although an emergent  hypothesis of glutamate/astrocyte dysfunction by Guedl (43)(44) in Long Covid provides a possible explanation for some impaired glymphatic function through impairment of the paravascular space function and potential effects on symptoms such as fatigue, brain fog and head pressure.

 

Wirth et al (52) noted that reduced cerebral blood flow in CFS can lead to a range of neurological symptoms, including psychomotor slowing and impaired cognitive function in CFS. This hypoperfusion can impact both the global and local regulation of blood flow in the brain.   They also reported an increase in intracranial pressure has been observed in ME/CFS patients.   In “heads-up” tilt testing, CFS patients had a 26% reduction in cerebral blood flow (against 7% in normal.)   In the severe CFS, a reduction in blood flow from lying to sitting was 24.5%.  As a possible explanation for the orthostatic intolerance and the decrease in cerebral blood flow they proposed the presence of both a strong vasoconstrictor effect mediated by an elevated sympathetic tone and weakened vasodilator influences. Covid-19 seriously affects the endothelium and there is evidence of chronic endothelial dysfunction in the post-Covid-syndrome similar to that in ME/CFS.(52)

 

Similarly, Wirth et al (52) reported muscle mitochondrial dysfunction, as evidenced by higher levels of pyruvate and lower levels of ATP and phosphocreatine in muscles, suggesting an impairment in muscle energy metabolism, which is also observed in ME/CFS, indicating a likely overlap in the pathophysiological mechanisms of these conditions​​.

 

In early trials we found while investigating the triad of POTS and FMS “drivers”, loss of cervical lordosis, Internal Jugular Vein Obstruction at the venous angle and the Thoracic Outlet Syndrome, postural changes stopped the flow in the Internal Jugulars and did not recover immediately.   As well as the known postural change of venous flow from lying to standing, of the flow changing from predominantly IJV to vertebral, it suggested a sympathetic-activated vasoconstriction the source of which we hypothesis could be the baroreceptors in the Carotid Arteries, the Locus Coeruleus activation or sympathetics in the lymphatic walls.   Further studies are currently in place.   It does appear likely that impaired vertebral flow is a pre-requirement, whether this is traumatic, from EDS or simply postural.  

 

Long Covid research by Appleman et al, (53) has also shown post-exertional malaise (PEM), with associated fatigue, pain and local and systemic metabolic disturbances, severe exercise-induced myopathy and tissue infiltration of amyloid-containing deposits in skeletal muscles of patients with long COVID.    The impaired recovery from venous obstruction suggests vasoconstriction from noradrenergic activity as we have been finding.   The finding of amyloid in Long Covid is very suspicious of underlying DNA mutations.    As far as I am aware there is no evidence of amyloid in skeletal muscle in other causes of FMS other than Covid.  

 

Figure 11: Locus Coeruleus

Morris et al describe “The adaptive response to acute threat involves a rapid, coordinated response in order to prepare the organism for an acute physiological response and behavioural activation. This involves hypothalamus–pituitary–adrenal (HPA) axis activation, hypothalamic corticotrophin-releasing factor (CRF) release and production of cortisol, which reaches body tissues via peripheral vasculature. Rapid Locus Coeruleus (LC) activation and noradrenalin (NE) release also occurs, with NE targets throughout the cortex leading to global modulation of arousal and attention. Other NE targets in the amygdala (Amy) and medial prefrontal cortex (MPFC) mediate threat learning and reciprocally regulate the LC (red lines). (b) Chronic threat or stress leads to widespread changes in the central LC-mediated response to subsequent stressors. Chronic stress leads to LC hyperactivity, increased NE in LC, amygdala, hippocampus, MPFC and increased HPA axis activity via reduced HPA regulation. Excessive cortisol and NE relate to maladaptive physiological signs of hyper-arousal and reduced regulation of the LC by the MPFC (dotted red lines), which additionally contribute to reduced regulation of pathological anxiety. Grey lines indicate LC and HPA projections."(54)



Source: Morris, L, Charnet,D, Murrough,J, McGall, J. The role of the locus coeruleus in the generation of pathological anxiety. Brain and Neuroscience Advances. 2020 DOI:10.1177/2398212820930321 (54)

 

Potential sources of chronic fatigue are shown in Table 2.  These may include glymphatic and cardiac dysfunction, small-fibre neuropathy, as well as inflammatory changes affecting other areas (e.g., Hashimoto’s thyroiditis), but all these are a blur and management requires a holistic look at what is happening and manage the culprits, not the end result


Table 3: Potential sources of Chronic Fatigue

 

  • Hypoperfusion with mitochondrial dysfunction /oxidative stress (CFS and coathanger pain with progressive muscle depolarization)

  • Astrocyte /glymphatic dysfunction (TLR2-driven or crosstalk with microglia)

  • Neurotransmitter dysfunction -Dopamine/serotonin/glutamate pathways

  • Intracranial pressure abnormality with HPA axis dysfunction

  • Metabolic pathway abnormality/ DNA mutations /Dietary

  • Small fibre neuropathy

    • Autonomic instability eg POTS, dysautonomia, orthostatic hypotension

    • Impaired cardiac function

  • Cardiac preload failure

    • Locus coeruleus

    • Aberrant azygous anatomy/ sympathetic activation (currently being investigated)

  • Sensitization mechanically

  • Secondary to Thoracic /Lymphatic duct obstruction

  • Associated with Intra-abdominal vascular dysfunction

COVID

o   Reactivation of EBV and other viruses

o   Cardiac damage- pericarditis, myocarditis, reduced EF%

o   Lung and other organ damage-embolic, inflammatory, malignant 


Adding lymphatic compression with activation of the sympathetics that accompany them that are affecting locus coeruleus activity fuels the hypothesis that it is lymphatic as well as venous compression that may form the basis of CFS, FMS and POTS pathology.  Whether this is sufficient to cause cardiac “preload dysfunction” that is found especially in POTS with its characteristic shortness of breath is another source of investigation.  Potential sources include the above mentioned, and a dysfunctional Azygous venous system which may be associated with anatomical variants, mechanical and sympathetic activation from the Locus Coeruleus, the sympathetic pathways aligned with the lymphatics or whether it requires all, is simply not yet known.

 

Post-exertional malaise in FMS can also be linked to metabolic dysregulation. Molecular biologist Dr Valerio Vittone describes “the PEMT gene impacts choline metabolism and, consequently, muscle and nerve cell function, and this mutation could contribute to the exacerbated fatigue and pain following exertion seen in FMS patients.”  The DNA mutations he has found in POTS and Long Covid, in particular in PEMT and APO E4, which is concentrated in astrocytic process at the pial surface and around blood vessels, are both implicated in FMS as well as neurodegenerative disease are detailed in DNA Mutations in POTS and Long Covid.  Phosphatidylethanolamine N-methyltransferase (PEMT) is involved in the biosynthesis of phosphatidylcholine (PC) from phosphatidylethanolamine (PE), and likely to be the underlying culprit in persistent D-Dimer tests in Long Covid.  PEMT mutations are associated with fatigue, fatty liver, and increased neurodegenerative risk, yet is potentially treatable metabolically.  

 

Part 2 continues with Intracranial Hypertension -linking CFS, POTS and Fibromyalgia

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