Revised November 2023
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 fings 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
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
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. 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
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 details of which are being worked out.
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.
Figure 1: 3D Reconstruction of Head and Neck Vasculature courtesy Dr Zane Sherif.
Figure 2: 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