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  • Writer's pictureGraham Exelby

POTS Meeting

March 16, 2024. Presenter: Dr Graham Exelby


To start, this is not mainstream medicine, and is not the “safe” “Cochrane Guidelines” that doctors work from.  But Cochrane does not cover all the tricky stuff you will see, and so dealing with it is based on experience with these problems and ongoing research.  Most of your patients will have been “gaslit,” told they have a “functional neurological disorder” or an eating disorder, or simply dismissed as a psychological problem.  It is definitely not a psychiatric disorder, although psychological disorders may co-exist, and chronic anxiety from prolonged catecholamine activation and depression over circumstances (and sometimes neurotransmitter dysfunction) is present.


Postural Orthostatic Tachycardia Syndrome or POTS is intolerance of postural change associated with tachycardia exceeding 120 beats per minute or an increase in the heart rate of 30 beats per minute from baseline within 10 minutes of changing the posture from a lying to standing position with absence of blood pressure drop, or 40 if between 12 and 19 years.


Symptoms such as headache, nausea, tremors, sweating, palpitations, syncope and near -syncope tend to occur in the upright posture and disappear on lying down.  POTS reflects symptoms caused by sensitisation of microglia and subsequent exaggerated responses to the autonomic nervous system.   The shortness of breath with postural change is part of Pre-load Dysfunction.


POTS is autonomic and inflammatory chaos, with strong associations with Chronic Fatigue Syndrome and Fibromyalgia. POTS is also a common presentation of “long COVID,” with very similar DNA patterns and symptoms including brain fog and chronic fatigue.   A Canadian study described over 70% of Long-COVID have cardiovascular autonomic disorder, 30% of these with POTS (Postural Orthostatic Tachycardia Syndrome).  While our clinic figures do not agree with this percentage, it remains a significant complication of COVID.


POTS should also be viewed as a central nervous system disorder, in keeping with the emergent knowledge of POTS, Long Covid, chronic fatigue syndrome, migraine and fibromyalgia all having "sensitisation" of the immune cells of the brain, the microglia, and  linked through intracranial pressure changes (both CSF and vascular) and dysfunction of the astrocytes.

The Immune Response

The innate immune system is the body’s first line of defence.   As well as cells that destroy invading virus it also activates the adaptive immune system providing long-lasting protection.  The ”Gate-Keepers” are the Toll-like Receptors (TLR4, TLR2, TLR3), the primary sensors of the innate immune system.  In Covid, the predominant source of POTS activation currently, SARS-CoV-2 interacts with threat receptors TLR2 and TLR4 (the first responders) on a cell surface, triggering a dysfunctional immune response that includes mast cell activation, provoking the excessive pro-inflammatory “cytokines,” the “cytokine storm.”  

Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a family of transcription factor protein complexes that controls transcription of DNA, cytokine production and cell survival.  Transcription is the first step in gene expression, copying a DNA sequence to make an RNA molecule.   Found in almost all animal cell types, it is involved in cellular responses to stimuli such as stress, cytokines, free radicals, heavy metals, UV irradiation, oxidized LDL, bacterial and viral antigens.   It plays a key role in regulating the immune response to infection.

Incorrect regulation of NF-κB has been linked to cancer, inflammatory and autoimmune diseases, septic shock, viral infection, improper immune development, and is implicated in processes of synaptic plasticity and memory.  NF-κB derived inflammation generates DAMPs and initiates a cycle of innate immune activation, which may drive organ injury.   The Interferon (IFN) response is critical for viral clearance.   As both pathways are active, a race between viral clearance and host injury ensues.    In severe disease, the balance is shifted toward injurious NF-κB derived inflammation

TLR2 acts as a sensor of SARS-CoV-2, triggering inflammatory responses that may exacerbate the severity of the infection.    TLR2 expression has been linked to COVID-19 severity, suggesting that its activation plays a role in the disease's progression.

TLR2 activation disrupts astrocyte function affecting CNS homeostasis.  Activation of TLR2 and other Toll-like receptors can lead to excess NF-κB activation.   Higher MyD88 signalling pathway activation relative to TRIF activation may result in increased NF-κB activation, leading to elevated inflammatory cytokine production.  Aberrant activation of NF-κB can cause chronic inflammation, oncogenesis and autoimmune disease.

The spike glycoprotein of SARS-CoV-2 binds to TLR4, leading to increased ACE2 expression, facilitating viral entry and causing hyperinflammation contributing to hyperinflammation and tissue damage.  TLR4-mediated NF-κB signalling leading to increased Tissue Factor Expression is implicated in COVID-19 pathogenesis.  DNA mutations at TLR4 and/or mast cell function can induce a dysfunctional immune response, provoking the excessive cytokine storm.

TLR4 activated cytokines in particular interleukin 6 (IL-6) and tissue necrosis factor alpha (TNFα) activate and sensitise microglia cells which causes small fibre neuropathy.  Microglial small-fibre neuropathy produces neuropathic pain and the autonomic chaos that is characteristic of POTS and POTS-like long COVID.

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.


Mast cell activation plays a central role in pathophysiology of EDS, Breast implant illness, collagen degeneration and can play an important role in POTS, where the association between Mast Cell Activation Disorder and POTS have been documented.

Mast cells are located perivascularly close to nerve endings and ANS sites eg carotid bodies and the adrenals, allowing them to potentially regulate and be affected by autonomic function.  They can be triggered not only by allergens but also by triggers from the ANS, releasing neuro-sensitizing, pro-inflammatory and vasoactive mediators.

Mast cells regulate the functions of immune cells such as dendritic cells,

monocytes/macrophages, granulocytes, T cells, B cells and Natural Killer (NK) cells.   They recruit immune cells to inflamed tissue by secreting chemokines and other mediators which locally increase vascular permeability.

Mast cells are activated by cytokines from TLR4.  They contribute to coronavirus-induced inflammation through mechanisms like degranulation and histamine release.  Mast cell mediators can disrupt connective tissue integrity. 

Proteases elastase, tryptase and chymase degrade extracellular matrix components including collagen. Prostaglandins and leukotrienes contribute to inflammation and pain


Microglia and Astrocytes


As a general rule in POTS, it is the microglial activation that causes the biggest issues with autonomic instability, but astrocytes cannot be ignored, again especially in Covid when these and neurons may be damaged by the viral assault.   Molecular biologist Dr Valerio Vittone has found DNA mutations in TLR4 and others  (described in DNA Mutations in POTS and Long Covid) that may provide answers to why COVID and other insults to the immune system progress to become symptomatic.  


The microglia “cross-talk” with mast cells and astrocytes in the brain.  Astrocytes not only regulate blood flow, but also transfer mitochondria to neurons, and supply the building blocks of neurotransmitters, which fuel neuronal metabolism.  In addition, they can phagocytose synapses, alter neurotrophin secretion, and clear debris.  Astrocyte “end feet” form the paravascular channels in the glymphatic system with its importance in clearing “toxins” as the “brains sewer.”    Astrocytes are damaged frequently in COVID, and changes can cause glymphatic dysfunction.


Fibromyalgia, ADHD, autism spectrum, migraine and others often have a dysfunction in the neurotransmitter- glutamate, which in excess is neuro-excitatory.  The astrocytes /glutamate pathway is more important when these co-morbidities are present. The regulation of glutamate and dopamine by serotonin in the brain is a vital connection.


Studies in impaired veterans from the Gulf War showed how metabolic changes in areas such as diet, removing in particular processed foods, can improve pain and neurological functioning from glutamate excitotoxicity.   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.


POTS Activators and Drivers


In all POTS patients, if you look carefully enough, there will be an activator (or series of activations), then there will be drivers that continue to drive the autonomic instability after the initial insult. It is easiest to explain activation by looking at how Covid can trigger this, but the same can apply after parasites, other infections, sustained stress, surgery, pregnancy, trauma, especially to the upper cervical spine and even sustained backpack use.


An exaggerated mast cell response can be a critical part of the immune response, and this can be very rapid, within minutes to a few days, and symptoms of exaggerated/ sustained mast cell activation can be severe.   Sorting out the people with abnormal mast cell activity is yet another area that requires dietary intervention.   And it doesn’t stop there, as there are other metabolic and dietary components can influence inflammatory processes, such as histamine, arachidonic acid, lectins, casein, and oxalates as well as infections, etc.   In people with trauma as their activator (not uncommon in upper cervical and coccygeal injuries) the mast cells are the first responders.


In POTS and Long Covid, Fibromyalgia and other co-morbidities there are common mutations in mast cell function, and aberrant mast cell response is most likely responsible for the collagen changes, as well as co-morbidities such as endometriosis suddenly developing, changes that are being seen in Long Covid. The dramatic increase in ADHD and ASD may be due to changes in astrocyte function, while collagen changes are mast cell-driven.  In management, decisions between tackling TLR4 modulation or mast cell dysfunction, or both may be needed.   Each patient is different, and management is seldom the same.


There are a large number of “activators”, most commonly these days associated with Covid, but there are still many from neck and spine trauma, repetitive occupational or sporting activities, mould, PTSD, other infections and parasites, and even heavy backpacks.  Then there are the drivers, most commonly easily correctable problems with diet, posture, phone and computer use.




A major breakthrough in investigations has been with Spectral CT scans, where depending on symptoms, from head to pelvis, 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 usually understandable.  Dynamic ultrasound techniques have developed not only to look at postural changes and these are very important for those who cannot tolerate dye, or where CT is not considered ideal, and overcomes the limitations of CT or MRI being done supine.

Figure 2: Brain Spect Scan with Hyperperfusion and hypoperfusion in the brainstem

Source: Mermaid Molecular Scanning


Spect brain scans typically show hyperperfusion throughout the brain, and a large number have brainstem hypoperfusion and these have complemented these CTs and MRIs.    The hypoperfused brainstems are thought to be primarily from nor-adrenalin induced vasospasm.  The hyperperfusion is thought to reflect endotheleiitis that potentially disrupts the blood brain barrier (BBB.)  The primary pathology here looks to be venous backpressure from the obstructed IJV and vertebral venous flow that also can affect CSF flow.   The presence of the brainstem hypoperfusion adds the complexity of vasoconstriction affecting arterial flow.


The brain MRIs are often, but not always, able to confirm the changes of increased intracranial pressure, and the pressure elevation may be minimal.   Brain hyperintensities are commonly labelled as small vessel disease, but these can be excluded by high-level retinal photos, which can also show changes such as venous backpressure, arterial tortuosity, optic disc changes, and we have seen post-Covid amyloid plaque.     


Vascular Compression Syndromes


From research into MS over a decade ago, it was shown that compression of the Internal Jugular Vein can cause venous backpressure into the brain, with increased risks for microemboli but also as the veins dilates the potential arises for both the jugular vein (sympathetic overactivity) and vagus (parasympathetic overactivity) to be affected. These poorly investigated areas are called Jugular Outlet Syndrome, or Venous Eagle, and Internal Jugular Vein Obstruction and Stenosis.  


The Thoracic Outlet Syndrome (TOS) appears to be closely associated with the Internal Jugular Vein Obstruction (IJVO), (and it seems to Thoracic Duct and Right Lymphatic Duct obstruction.)  This obstruction, usually only seen on dynamic ultrasound, causes intracerebral venous backpressure, and complicating this, as the jugular vein dilates within the carotid sheath, it can affect the vagus nerve, the jugular nerve, the carotid artery, and probably the baro (or pressure) receptors in the Carotid arteries, with potential implications in POTS pathogenesis.   The controversial thoracic outlet syndrome is probably one source of persistent elevated “D-Dimer” in various conditions, especially Covid-related disease, as these can often be tracked back to physical activity. The research in 1942 in soldiers with backpacks (costoclavicular syndrome) and the blood clots -Paget-Schroetter Syndrome has been forgotten over the decades since WW2.  


There is also commonly obstruction of the Internal Jugular Vein at the stylohyoid, the vein jamming between the stylohyoid and the transverse process on the first cervical vertebra (C1) Jugular Outlet Syndrome (or Venous Eagle.)  When severe, the vagus and other cranial nerves eg glossopharyngeus can be affected.   In most Jugular Outlet Syndromes, correcting posture especially in the cervical spine can relieve the symptoms.   In all the TOS/JOS/IJV compressions, the mechanical interactions are complex and it is often difficult to differentiate main culprit, but it appears in all, that the cervical spine is usually a major contributor. This is particularly so when migraine is present, with drivers in C0/1/2/3 regions.  The Cortical Spreading Depression that typifies migraine causes temporary glymphatic flow impairment by closing paravascular spaces and opens questions about exactly what is the relationship with migraine to POTS.


Intracranial Pressure Abnormalities and “Hydraulic Dysfunction”


The TOS/ JOS/IJVO/cervical dysfunction combine to impact on lymphatic flow from the head and neck, and this may be reflected in increased backpressure in the CSF.  Intracranial CSF pressures and intracranial venous pressures are coupled by arachnoid granulations, predominantly in the superior sagittal sinus, so there is a unidirectional flow of CSF through these granulations at a pressure gradient of 3-5 mm Hg.  As the intracranial venous pressure rises, the pressure in the subarachoid space rises until it is 3-5 mm higher than the venous sinus and at which point CSF drains across the arachnoid granulations, and this equilibrium the basis connecting the intracranial pressure and venous sinus pressure.( Townsend and Fargen)


Absorption of  CSF is through arachnoid granules and villi of intracranial and spinal venous sinuses CSF-ISF drainage is via meningeal lymphatic vessels and along the cranial nerves into deep cervical lymph nodes.   There are direct connections between lymphatic channels along cranial nerves, vascular structures and cervical lymph nodes (Albayram et al)


Lymphatics provide sympathetic signals affecting lymphatic ducts, cerebral arteries and arterioles.   Vertebral lymph vessels connect to peripheral sensory and sympathetic ganglia and form vertebral circuits connecting to thoracic duct. (Boisserand et al)


Research from Kjetil Larsen confirms how poor posture, injuries, and things like excessive phone and computer use with change in neck shape and the consequent loss impact on arterial, venous and lymphatic flow affects the flow of blood in the brain, but also how this affects the Thoracic Outlet and Jugular Outlet Syndromes.   Arterial TOS complicates symptoms even further as the Subclavian artery compresses, changing flow dynamics in the head and neck.


When you lie down, blood transfers from the brain via Internal Jugular Veins, and when seated/standing through the Vertebral Veins.   Symptoms of intracranial HT tend to be worse lying, and when seated/standing symptoms could reflect CSF leaks that can occur after trauma or in the Ehlers-Danlos Syndrome group.   Most standing symptoms however in clinic appear to be from vascular pressure change as blood is unable to move as the weight of the head pulls down on the neck, jamming veins and lymphatics at the craniocervical junction with the likelihood of sympathetic-driven (from the lymphatic compression) vasoconstriction, providing a valuable clue to brainstem hypoperfusion so typical of CFS.  


Again lymphatic compression is hard to prove, as it is still only a clinical finding, but I believe a major component of the very typical head or eye pressure, and especially in the production of hyperintensities in the brain. Given the slowness of lymphatic flow, obstruction alone could not account for the symptoms.   Lymphatic drainage techniques do provide significant improvements in symptoms.


A typical ICH has pressure (or eye) pressure lying, often with pulse-synchronous tinnitus and visual aberrations.  Venous backflow tends to be worse standing, reflecting the importance of vertebral venous obstruction.   Another variation is when severe seated, then settling walking when you might look at pelvic congestion.


Coat Hanger Pain


Coat hanger pain from top of neck onto shoulders is fairly typical in POTS (and a major part of Fibromyalgia).   This is hypoperfusion with muscle depolarization and mitochondrial dysfunction (mitochondria provide the energy source for cellular functioning.)  In PEM if prolonged, the metabolism changes to one based on amino acids.  


Intra-abdominal Compression Syndromes


Intra-abdominal compression areas, especially the Median Arcuate Ligament Syndrome, Nutcracker Syndrome and May-Thurner syndromes sometimes can be the primary drivers, or simply contribute to the overall picture.   Latest Spectral CT findings show that renal vein compression can push blood into the spinal and azygous veins as blood has to go somewhere, and while many get the pelvic congestion problem.  


Blood entering the epidural plexus from the left side, via the collaterals of the left renal vein, fill the plexus which may become engorged. Its pressure rises so that the blood is diverted more or less, depending on the actual pressure, up and down the spine and heads to exits with a pressure less than in the left renal vein.


Spinal plexus/blood flow is valveless.   Veins at the level of the intervertebral discs communicate with veins that enter the spinal canal.  In the case of Nutcracker phenomenon the hemiazygos vein and the ascending lumbar vein are subject to considerably increasing pressure. The blood flow changes its direction into the intervertebral veins, so that eventually renal vein blood is injected into the spinal canal.


Scholbach describes that while blood may leave the spinal canal via intervertebral veins on the right side of the spine, if the pressure is high enough the cerebrospinal fluid is shifted towards the skull and causes a slight but perceptible rise of the pressure inside the skull.  This he reports causing dizziness, headache, and exacerbating the Chronic Cerebrospinal Venous Insufficiency.


In clinical studies, the thoracic outlet compression also appears to obstruct the Thoracic and Right Lymphatic ducts at the base of the neck (venous angle).  The flow on from this appears to be changes to the function in the Azygous venous system in the chest and abdomen.  


Preload Dysfunction and the Azygous/Thoracic Duct Dysfunction


Our hypothesis concerns a dysfunctional azygous venous system in the chest and abdomen especially in areas where scoliosis is present, especially T7-8 areas where the azygous crosses sides.  At T4 the azygous and thoracic duct is in close proximity to the aortic arch baroreceptors which may trigger sympathetic activity, and we believe to be the underlying cause of the “T4 Syndrome.”    Increased venous pressure is likely to be involved in people with renal vein compression at L2, another area where Hemiazygos dysfunction may be very relevant.  


Cardiac Preload Dysfunction is a characteristic of POTS shortness of breath.   Most patients have a low cardiac stroke volume, increased sympathetic nervous system tone, partial peripheral sympathetic denervation with relative central hypovolaemia and low blood volume.(Raj)  Potential sources may be sympathetic activity (Locus Coeruleus), parasympathetic (vagal/ brainstem) activity, but increasingly it looks to be a dysfunctional Azygous Venous system/ Thoracic Duct sympathetic activation associated with mechanical obstruction. 


The Azygous connects the superior and inferior vena carvae (SVC and IVC), and provides collaterals for major pathway obstruction.  The IVC (formed by junction of the left and right common iliac veins) also joins with the Azygous vein and paravertebral plexus. The SVC drains into the right atrium of the heart via a valveless orifice.   The IVC enters the right atrium inferior to the entrance of the SVC.


The hemi-azygos and accessory hemi-azygos veins cross the midline at T9 and T8, respectively, posterior to the aorta, thoracic duct, and oesophagus.    At T7-8, the diaphragm attaches to the internal costal margins of T7-12 and thus can add strain to the region in conjunction with the spinal curve changes  and tension on the arcuate ligament and thus aorta hiatus.  The azygous vein enters the thorax through the aortic hiatus in the diaphragm just to the right of the cisterna chyli, and arches over right main bronchus at T5-6 and enters SVC at T4.  


 “Trigger areas” in POTS /dysautonomia are common at the T7-8 region.   Case studies have demonstrated tachycardia with rotational stress in this area.  In another case study, surgical clipping of the Azygous produced a rapid onset of POTS. Usually associated with scoliosis in this region, it asks the question if this area has a greater susceptibility to venous congestion and activation of the sympathetics that accompany the Azygous system.  The thoracic outlet syndrome is a logical starting point.  Treating lymphatics in these areas does improve symptoms.   So which is the main culprit?  


Current research is targeting improving management of the dysfunctional azygous/intra-abdominal lymphatic flow, using research from Perrin on lymphatic management.   While we still have a way to go to “prove” these findings, altered treatments are producing improved outcomes.   This requires an integration of current therapies.  These new findings allow us to look at the TOS and neck and other mechanical causes in different ways, and with this improving managements. 

Drivers to Look For


  • Arterial Thoracic Outlet Syndrome- compression of the subclavian artery affecting blood flow in arterial thoracic outlet syndrome, which can cause intracranial hypertension- these can be nasty, and must be checked at least yearly as arterial damage can occur.  These often need a vascular opinion.   Vascular opinions in venous compression are usually useless as these need dynamic assessments while surgeons rely on supine MRAs

  • Jugular Outlet Syndrome, where obstruction at the stylohyoid under the jaw increases venous obstruction and venous backflow into the brain (seen as hyperperfusion in brain Spect scans.) Vagus and other cranial nerves can be affected

  • Internal Jugular Vein Stenosis/Obstruction (IJVS). Dilatation of the internal jugular vein and potential impact on the jugular and vagus nerves, called early studies suggest this may be caused by Thoracic Outlet Syndrome, particularly the arterial version, linked with neck posture changes. We have not seen more than a couple of faulty valves previously described in MS research.

  • Lymphatic Obstruction around the veins in the head and neck with consequent backpressure into the glymphatic system of the brain, with brain fog with “pressure,” potentially affecting the HPA axis and many of the co-morbidities we have been finding. The vascular backpressure itself can cause Intracranial Hypertension.

  • The scalene muscles that form part of the thoracic outlet anatomy pulls at C2/3 (attached to C3 to C6) and can destabilize even further an unstable or rotated upper cervical spine (very important when migraine is present as C2/3 dysfunction is usually the main “driver.”

  • Poor posture and loss of lordosis and flexion kyphosis in the neck is usually a major driver

  • Hypermobility/EDS major compounding factors (also links to mast cells)

  • “Cardiac pre-load dysfunction” is probably caused by dysfunction of the thoracic duct/azygous system from mechanical and nor-adrenalin-induced vasospasm, and /or involvement of the sympathetic chain and “locus coeruleus.” The characteristic shortness of breath can be from either or both noradrenaline and or acetylcholine (sympathetic and/or parasympathetic).

  • It appears likely that the “baroreceptors” or pressure receptors which are predominantly in the ascending aorta/aortic arch and carotid sheath are involved in the “signalling” that when activated cause “Takotsubo-like” responses.

  • Once you activate the baroreceptors there can be oscillations of sympathetic and parasympathetic function-something commonly seen in POTS, and this has been demonstrated in the neck, from the dilated carotid sheath from an IJV obstruction thought to trigger the carotid baroreceptors.

  • Increasingly we are seeing intra-abdominal vascular problems in POTS as the radiology improves. If you put increased venous pressure into the vertebral veins this valveless system can affect intracranial pressure. These intra-abdominal compression areas include the Median Arcuate Ligament Syndrome (MALS), Superior Mesenteric Artery Syndrome (SMA), Nutcracker Syndrome and May-Thurner Syndrome. These can often be successfully managed with musculoskeletal treatments involving the psoas muscles and lymphatic drainage. Control of the venous compression areas of the Nutcracker and May-Thurner and pelvic congestion can provide major improvements in symptoms.

  • Pending a new database search since the new radiology has become available, but is does seem likely that you need a number of things before POTS is overt

    • Cervical dysfunction

    • Head/neck vascular dysfunction

    • Intra-abdominal vascular dysfunction (especially Nutcracker and May-Thurner)


Tackling POTS:

To tackle POTS successfully requires taking a broad look at it, not focussing on medication to control the cardiac symptoms, unfortunately the most common approach.  LDN can be very effective in CFS, especially resistant Long Covid fatigue- looks to modulate TLR4 and likely TLR2, and improves Natural Killer Cell and glymphatic function. 


Mast cell activation is a critical component and initial symptoms of this, or autonomic instability reflecting in sleep disorder, feeding problems, nightmares, anxiety and others, may be seen in infancy.  Close attention to co-morbidities is crucial to get a picture of other autonomic and inflammatory processes that are occurring.


The success in POTS (FMS and CFS) relies heavily on detailed history, to work out from family history where possible the likely DNA predisposition, what have been the precipitating events, to what was the “final” straw) (or in some just 1 problem- trauma, Covid etc), then all drivers need to be sorted before an effective rehabilitation program can be commenced.


Dr Valerio Vittone’s decoding of the DNA has offered an invaluable insight into the underlying genetic mutations that underpin these conditions.   With these comes a variety of metabolic changes that are often very difficult to work out without DNA (especially resistant fatigue and cognitive impairment.)  

Vital main DNA mutations underpinning POTS, Long COVID include TLR4 (first responder in the immune response), various mast cell (dysfunctional mast cell response), COMT (impaired catecholamine, oestrogen and pain pathways to name a few), TRP (natural killer cell and impaired glymphatic function), CCL2  ( a major player in post COVID neonatal neurological damage,) STAT3 (reactive and rheumatoid arthritis,) and PEMT (especially in the thromboinflammatory damage) - discussed more fully in DNA Mutations that Underpin POTS and Long Covid”.


Find a HRV provider, or have your own which gives real-time results.    Easiest is from some of the pathology provided Holter monitors- obtain the full report and you’ll find it on page 2- these check every 5 minutes   Apple watches have limited capability (QML and Laverty are pathology companies providing the HRV service)


Table 1: Traditional initial management (Raj)

  1. Non-pharmacological treatments- all started at initial visit

    1. Water 3l/day

    2. Salt 5ml/day (2 tsp/day)

    3. Waist-high compression garments

  2. Pharmacological treatments that can be started on initial visit if symptoms are severe.

    1. Standing heart rate very high: propranolol 10 to 20mg up to 4 times a day (heart rate inhibitor)

    2. If beta-blocker contraindicated in high standing heart rate: Ivabradine 5 mg bd (sinus node inhibitor)

    3. If standing heart rate is not too high and blood pressure is low: Midodrine 5 mg tds (vasoconstrictor to reduce venous pooling by improving venous tone)


Table 2: Potential sources of Chronic Fatigue

  • Hypoperfusion with mitochondrial dysfunction /oxidative stress (CFS and coathanger pain with progressive muscle depolarization)-prolonged and metabolism changes to amino acid (post-exertional malaise)

  • 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


    • Reactivation of EBV and other viruses

    • Cardiac damage- pericarditis, myocarditis, reduced EF%

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


Table 3: Potential Sources of Brain Fog

  • Impaired Glymphatic flow –especially with associated “pressure”

  • C0/1 dysfunction (? From JOS)

  • Internal Jugular Vein Obstruction at stylohyoid or venous angle

  • Brainstem hypoperfusion

  • Cerebral artery hypoperfusion (? Endotheleiitis from venous congestion)

  • Can be inflammatory or microembolic (Covid). Amyloid at present not measurable

  • APO E4, Lpa, PEMT, other neurodegenerative mutations

  • Variability in brain fog

  • intra-cranial pressure change

  • often improves with diet change, sometimes H1/H2 blockade, TLR4 blockade, LDN.


Management protocol:

  1. Validation of a patient’s symptoms

  2. To work out the drivers for all problems, and try to eliminate these where possible.  This requires close attention to diet, to posture, computer, phone and backpack use, to even choice of exercise, and avoidance of mould and other things that can destabilize the immune response.

  3. To control autonomic instability and inflammation (IL-6 and TNF).    Diet, sustained stress , poor posture and mould in particular can be pro-inflammatory

  4. Often the severity of the sensitization that underpins the microglial activation is so severe, that no physical therapy can be safely commenced

  5. Diet modification can be valuable in those hypersensitized patients to start reducing the sensitization load

  6. To maintain a close watch on comorbidities and work out how these interact with the POTS

  7. Management may start with fluid loading, and increased salt intake

  8. Compression garments may be required to control the blood pooling

  9. Toll Receptors 2 and 4 (or TLR2 and TLR4) are threat receptors that are the "first responders, " found on surfaces of mast or immune cells.  In infections especially Covid, as the spike protein gets into cells, threat receptors TLR3 which are inside cells come into play.  The immune response is usually called a "cytokine storm" from the threat receptors and mast cells.    The cytokines IL6 and TNFα cause "microglial sensitisation" (nerve cells throughout brain and spine) and small fibre neuropathy responsible for autonomic instability, neuropathy eg loss of smell.    As these are responsible for the sensitization from the activated microglia, these may need medication to reduce the mast cell response as well as working on the various mechanical

  10. TLR 2 is associated with astrocyte and glutamate dysfunction, which can have neurological, and other symptoms especially fatigue through impaired glymphatic function.   A short trial of low glutamate diet then assessing other influences eg histamine can be invaluable.   Dietician assistance may be required

  11. Control physical drivers - good posture most important, especially with phones and laptops and lymphatic therapy combined with neck physio. Deciding whether to tackle a TOS or neck first can sometimes be challenging. 

  12. Control the Thoracic Outlet Syndrome.   Arterial TOS needs to be managed carefully and reviewed regularly to reduce the risk of arterial damage.   Deciding whether to tackle a TOS or neck first can sometimes be challenging. When there is Jugular Outlet Syndrome where the jugulars are jammed by the stylohyoid (s), surgery has been the traditional treatment, removing the stylohyoids, but we believe that posture improvement may correct this as well demonstrated by rehabilitation specialist in Norway Kjetil Larsen, who sees the triad of neck, TOS and JOS all part of one problem

  13. Poor posture and loss of cervical lordosis can affect arterial, venous and lymphatic flow, and managing this is paramount.  

  14. This may require “depressurization” at the jugular foramen using an osteopathic treatment

  15. The intra-abdominal compression areas- MALS, SMS and Nutcrackers may respond to treatments from osteopaths skilled in psoas management and lymphatic drainage

  16. Paced recovery with exercise physiologist / rehabilitation program

  17. Kiiko acupuncture to control autonomic instability 

  18. H1/H2 blockade may be helpful especially post-Covid – Famotidine modulates TLR3 activation from spike protein inside cells

  19. Mitochondrial “support” eg NMN may be helpful complementing diet



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