Revised April 2024
Research in COVID-19 has answered many of the questions that kept popping up in POTS, Fibromyalgia and similar conditions- how a virus (or trauma, mould, parasites, sustained stress) can activate threat receptors (Toll-like receptors, or TLRs) which then activate Mast Cells that are responsible for the cytokine storm that is what happens in COVID.
The inflammatory cytokines, especially Interleukins 6 (IL-6) and Tissue Necrosis Factor alpha (TNFa) cause microglial activation that is responsible for the characteristic Small Fibre Neuropathy (SFN) (and the characteristic pain of Fibromyalgia) and from this the autonomic instability of dysautonomia, POTS and Long COVID.
"Mast cell blockade” with H1, H2 and often H4 blockers, is usually, but not universally effective, and lack of improvement signals a need for deeper level of assessment of the patient, and hopefully this DNA breakthrough will enable clinicians to target the underlying problems rather than just recommending “acceptance” of the disease. The mast cell responses are vital in our immune system, so looking at whether the response is aberrant- inadequate or excess becomes part of the management. At present there is no simple way of assessing this.
It has been the “decoding” of the DNA assessments by Dr Valerio Vittone, https://www.drvaleriovittone.com/ that revealed common threads of DNA mutations that has allowed us to develop a simple, cheap management program that may improve the fatigue and cognitive impairment for Long Covid sufferers anywhere. The program has been developed utilizing methods from researchers such as Lawrence Afrin, Kjetil Larsen, and especially Griffith University Gold Coast, and used successfully in our clinic at Mermaid.
Dr Vittone uses a technique called genetic imputation, utilizing the ~750,000 SNPs on a chip in a sequencing machine in Germany and use this information to predict with over 99% accuracy level the patient's genetic variances. Once this process is completed the patients variances are then further analyzed against 83 million additional SNP variants.
These findings make it possible to recover most patients if not too badly damaged by the inflammatory and microembolic cascades that are typical of a SARS infection. Dr Vittone and I wish to share these findings and how "old-fashioned" techniques of a sound detailed history and family history can often expose the culprits in these conditions, which can often be improved by lifestyle changes particularly in diet and posture, along with appropriate physiotherapy to improve dysfunctional areas.
The DNA findings that Dr Vittone has unlocked briefly are:
TLR4 mutations- mutations in the "first responders" and likely to be the critical point which decides whether you have Long Covid or not.
Mast cell mutation- mast cell membrane and Dao and HNMT function
COMT- processing of catecholamines
TRMP3- critical in Natural Killer Cell and glymphatic function
Apo E4- a known major risk for Alzheimers, and affects lipid transport in the brain
Methylation mutations
PEMT and STAT3 and similar involved in vascular complications, neuro-degeneration and thrombo-inflammation, plus fatty liver
Oxidative stress and mitochondrial mutations
Other inflammatory mutations
These, and the protocols we are employing, are described in more detail in the Long Covid articles.
So What is Happening
Figure 1: Mast Cell, Microglia and Astrocyte Cross -Talk
Source: Carthy, Elliott & Ellender, Tommas. (2021). Histamine, Neuroinflammation and Neurodevelopment: A Review. Frontiers in Neuroscience. 15. 10.3389/fnins.2021.680214.
Around 30% of patients after a Covid infection continue to report an array of persistent symptoms after infection, with these changes up to and over 2 years and ongoing in roughly 1 in 8. Commonly reported symptoms range from fatigue and dyspnoea to “brain fog” with ongoing disability and disruption of work, social,
Long Covid is not one condition. From the first “Long Covid” patients, it was clear that the autonomic instability of Long Covid are presenting as POTS
The Covid may continue to be active /reactive months after contact (sustained inflammation for at least 8 months. There are no official biomarkers to be sure if the infection remains in your system.
Covid is a microembolic and inflammatory disease that may also add amyloid to fibrin with increased risk of thrombo-inflammatory disease including cardiac pathology, Alzheimers, Parkinsons, and other neurodegenerative disease.
Microemboli are a result of histamine receptor 1 (H1) induced fibrinogen. Increased TLR expression and TLR-mediated platelet activation during COVID -19 appears to enhance vascular and coronary thrombosis. PEMT mutations have been found to be involved, and these can only be seen through DNA. There are other DNA mutations eg APO E4 which affect lipid transport in the brain and can affect other blood vessels as well when the system has been compromised. This is activated via threat receptors on immune cells called Toll-Like Receptors, and for microglia, primarily TLR4.
Microglial activation 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. There is a variable degree of astrocyte damage that is reported
Very recent research has demonstrated the marked similarity between Long Covid cognitive impairment and other symptoms to the Gulf War Syndrome symptoms, which has led to the realization that the activation of another series of TLRs, the TLR2 receptors, activates astrocytes in the brain. The astrocytes then are not only directly damaged, but also these cells form the “paravascular channels” that are so vital in clearing “toxins” from the brain and maintaining pressure equilibrium between the CSF and venous or dural spaces in the brain.
Both the astrocytes and microglia “cross-talk” with each other and another vital cell, the mast cells in the body’s immune response.
Cytokine-induced central sensitisation (inflammatory activation of glial/microglial cells and neuropathic inflammation) is the key driver of the autonomic and inflammatory instability in POTS and the POTS-type of PACS patients.
Covid causes mitochondrial dysfunction and it may reactivate earlier problems eg EBV, shingles, HSV and stay in cell nuclei.
In the POTS research we found that the mast cells are the “first responders” in physical injury related autonomic instability.
Mast cell histamine is a regulator of proinflammatory, fibrotic, and thrombogenic processes, and exerts its biological actions through four types of histamine receptors H 1,2,3 and 4.
In the immune system, histamine is mainly stored in cytoplasmic granules of mast cells and basophils and is released upon triggering along with other mediators such as serotonin and tryptase.
Inflammatory microglial activation by IL-6 and TNFα is the most common brain pathology found in patients who died of COVID-19.
But it is the TLR2 and TLR4 threat receptors on Natural Killer cells rather than microglia, which are the "first responders" to brain injury. Most importantly, activation of mast cells has been shown to activate microglia, whereas stabilization of mast cells inhibits the CNS inflammation that would otherwise result from activation of microglia. TLR2-driven inflammation/ damage to astrocytes can cause impairment of the vital glymphatic function in the brain.
The microglial activation results in Small Fibre Neuropathy and neuropathic pain, and from this small fibre neuropathy it is believed comes the sensitisation and characteristic autonomic chaos that is POTS and POTS-like Long Covid, and this includes random symptoms such as the eye pain and anosmia in Covid.
Then there are various COMT mutations with their reduced ability to process catecholamines. Oestrogen also signals mast cells to release histamines via its ER receptor on Mast cells. This is a critical mutation in POTS.
COMT gene production is itself influenced by methylation (in the presence of SAMe a product of the methylation cycle), which in turn is affected by multiple mutations, some very common such as the MTHFR genes.
There is an association between COMT mutations with malignancy especially breast cancer, and also endometriosis and auto-immune disease. Then there are various oxidative stress and inflammatory mutations.
The TRP mutations found at Griffith affect Natural Killer cell function. The impaired Natural Killer Cell function following Covid increases malignancy risk.
Complicating this, SARS has evolved mechanisms to evade the antiviral function of Interferon-1 and SARS patients show limited Interferon-1 responses, while there was an increased expression of IL-6, TNFα and other chemokines.
Possible implications of this are in an increased malignancy rate, and severity of malignancy at presentation following SARS infections. But there is a glimmer of hope from this as well, as modern research into malignancy is targeting these very same TLRs.
POTS Breakthrough July 2023
Figure 2: 3D Reconstruction of Head and Neck Vasculature
Courtesy Dr Zane Sherif. Mermaid Beach Radiology
In July, we have, I believe, been able to ascertain the underlying mechanical causes of POTS, using a world-first Spectral CT looking at arteriography and venography in 1 scan, and when matched with brain spect scans and MRI brains, things like the causes of the ubiquitous "brain fog", especially when there is pressure is now largely understood.
Spect scans have been able to differentiate those with impaired brainstem perfusion from normal, and management of this is well under way.
Complicating vascular compression, both venous and arterial, we have found lymphatic obstruction associated with the neck-based vascular obstruction areas especially in the head and neck.
These techniques join the MRI brain, spects, the invaluable dynamic vascular ultrasounds as MALS and TOS in particular often can only be seen in different positions, and xrays of the cervical spine in normal, flexion and extension for loss of lordosis and flexion kyphosis. This has engendered a radical change in management.
The changing dynamics of POTS courtesy of Covid may provide a link to the difficult task of managing EDS and hypermobility in the neck in these patients. The numbers of the "rare" diseases Median Arcuate Ligament Syndrome and Nutcracker Syndrome MALS from Covid has been much higher. It is largely unclear if this is a change in collagen or symptoms now apparent from the microglial activation related sensitisation. Generally, both processes look to be occurring.
New research has answered a few more questions- fairly typical in POTS is the coat hanger pain from top of neck onto shoulders. This is hypoperfusion with muscle depolarization and mitochondrial dysfunction (mitochondria provide the energy source for cellular functioning.) In PEM Post-exertional malaise, which you have), if prolonged, the metabolism changes to one based on amino acids, so we see changes in areas where neurotransmitters may be affected.
The remarkable similarity of Long Covid to the Gulf War Syndrome has provided a springboard to further research, looking at dysfunctional amino acids and neurotransmitters. Dr Christian Allen has joined our research team, and he will be pursuing this pathway, in collaboration with Dr Valerio Vittone.
The microglia “cross-talk” with the astrocytes in the brain. Astrocyte not only regulate blood flow, but also transfer mitochondria to neurons, and supply the building blocks of neurotransmitters, which fuel neuronal metabolism. In addition, astrocytes can phagocytose synapses, alter neurotrophin secretion, and clear debris. Astrocyte “end feet” form the paravascular channels in the glymphatic system with its importance clearing “toxins” as the “brains sewer.”
Studies in impaired veterans from the Gulf War showed how metabolic changes in areas such as diet can improve pain and neurological functioning from glutamate excess. The complexity of associated metabolic dysfunction associated with histamine and other dysfunction with the various DNA mutations identified in POTS and Long Covid may not provide the desired level of metabolic control, so care must be taken when depending totally on one direction of management.
From TLR4 activation via cytokines that activate mast cells increasing cytokine release until a “cytokine storm” occurs. These sensitise microglial cells with consequent small-fibre neuropathy which in turn causes autonomic instability and other neuropathic symptoms. TLR2 signalling from COVID affects astrocytes, which is associated with dysfunctional levels of glutamate. There is also a “cross-talk” between microglia, astrocytes and mast cells as the body mounts its immune responses.
From this cross-talk we start to see the patterns that describe POTS and Long Covid.
Figure 3: The Glymphatic System
“The glymphatic systems in the brain and eye export fluid and solutes from metabolically active neural tissue. 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.”
Source: Mogensen et al. The Glymphatic System (en)during Inflammation
The Glymphatic System was discovered in 2013. It is basically the sewer of the brain, and dysfunction and obstruction to its flow is a major part of evolving work, not only in brain fog in POTS and Long Covid, but also in migraine, Parkinsons and Alzheimers Diseases.
The TRP mutations also affect glymphatic function, with a consequent reduced clearance of waste solutes from the brain causing fatigue and brain fog. Low dose naltrexone, a H4 blocker, and TLR4 modulator provides a therapeutic benefit here, but it is not a universal panacea, and at times hard to use.
Controlling mast cell activation is the first step to recovering a Long COVID, or a POTS and many other “obscure” neurological disorders. Management usually starts with H1 and H2 blockers- this alone significantly improves most fatigue in 4 to 5 weeks.
Diet is an important part of improving the mitochondrial dysfunction which is also critical in exacerbating fatigue and brain fog. Low histamine keto-based diets may be helpful to re-establish good mitochondrial functions essential for energy productions and cognitive functions that COVID undermine during infection. In patients known to have comorbidities in astrocyte/glutamate dysfunction, again diet is a suggested first step.
Lack of response to histamine blockade is a reason to look more deeply into a patient’s history, including mechanical causes as described in the POTS and fibromyalgia articles.
Patients not significantly improving require a more detailed assessment, as there are a number of other potential contributing causes. These may be mechanical, especially postural as with the fatigue, recovery programs are important. By taking a preventative approach in all facets of a person’s life, by taking a thorough family history, and using appropriate investigations, and using appropriate investigations including DNA testing where appropriate, POTS, Long-COVID, Fibromyalgia have a greater capacity for control.
Dr Graham Exelby