Managing POTS

May 2024 Dr Graham Exelby

Currently under review and peer review to accommodate new findings

Summary:

To summarize the clinical findings we have found in POTS, there are a series of vascular compression syndromes that we have found in all POTS (over 350).  These are described in “Assembling the Pieces in POTS,” and the accompanying documents in the POTS portfolio.  For many, venturing into the DNA mutations that underpin POTS and Long COVID may be required before satisfactory answers can be found- DNA Mutations in POTS and Long COVID  (56)

This article firstly outlines the accepted management protocols, then explores management beyond these basic protocols, based on addressing causes, rather than symptoms of POTS.

Head and neck vascular and mechanical pathology underpins 85% of POTS and drives symptoms, with impaired venous, arterial and lymphatic flow in the head and neck, and consequent vascular flow changes in the brainstem and brain proper. 

While case studies have found changes in head and neck vascular and musculoskeletal function in most POTS, there are many with intra-abdominal compression areas.   Increasingly there is a high incidence of Median Arcuate Ligament Syndrome (MALS), Superior Mesenteric Artery Syndrome (SMA) as well as the Nutcracker and May-Thurner Syndromes presenting as POTS.   This concurs with the increased incidence noted between pre-Covid and post-Covid patient numbers.

Introduction:

The Australian Doctor Therapy Update on POTS from 2022 by Lau, Gallagher and Seeley (1) provides an excellent introduction  to POTS management of the recognized symptoms.

Management that moves past control of basic symptoms revolves around sound histories and family histories.   Any comorbidity needs to be assessed to look for implications in the POTS dysfunction in each patient.   DNA does play a vital role, sometimes easily identified in family history, and may provide explanations for patients where symptoms are resistant to management protocols.  

Identification of symptom patterns, looking for “drivers” will usually expose the “culprits.”  The vast majority of patients have a combination of cervical spine dysfunction/poor posture, thoracic outlet syndrome, and Internal Jugular Vein obstruction (stenosis).     Lymphatics are involved although almost impossible to confirm radiologically, but commonly seen on the chest wall and sometimes in the neck.   The head and neck pathology is complicated by other drivers such as PTSD, and Intra-abdominal vascular compression syndromes.   Successful management requires a broad assessment of each element, and not relying on medication that controls some of the symptoms.

Approaching a POTS patient

The importance of a detailed history, including a sound family history as there is usually a genetic predisposition, and these are critical to understanding the problems facing a POTS patient.   This is well-described by Raj et al (2): “The medical history should focus on possible underlying causes and associated disorders, potential POTS triggers and precipitating events, severity of symptoms, factors that can improve or worsen symptoms, the patient’s ability to exercise and how the symptoms affect the patient’s quality of life.

Part of the assessment should include “scales” that are available, for fatigue, autonomic dysfunction and sensitization. These include the NASA Lean test that confirms POTS, Bell’s Functionality Scale, CSI Inventory (sensitization), MSPQ (dysautonomia), Fatigue Severity Scales and Malmo POTS Score.  It allows the clinician to get an idea of where the dysfunction is coming from.   An example may be a high CSI score and moderate MSPQ might point to a glutamate issue and if not post-COVID, an area where diet change is likely to be very effective in reducing symptoms.

Standing and lying ECGs are of extreme importance, especially if post-COVID or if there is ADHD as a co-morbidity, looking for QTc prolongation, that may affect what medication can be used safely, eg H1/H2 blockade.  A prolonged QRS and QTc interval may reflect myocarditis in COVID, where the virus affects ion channels involved in ventricular repolarization, disruption of the cardiomyocyte integrity and dysfunction in the myocardial conduction system.(50)(51)

The vast majority of POTS patients have multiple “drivers” where the most common is the upper cervical spine with its impact not only on the cervical sympathetic chain, lymphatic and venous obstruction, much worse with hypermobility, and Ehlers-Danlos Syndrome, and where the Thoracic Outlet Syndrome has both mechanical effects from the scalenes on the cervical spine as well as vascular pressure change, where “normal” physiotherapy may increase symptoms.  Neck symptoms may be longstanding even from birth, or rotational trauma in MVAs and other mechanical causes.   Attention to neck stability and posture is vital for this group.

Clinicians should ask about symptoms that suggest possible signs of autonomic dysfunction, such as gastrointestinal or urinary dysfunction, abnormal sweating, acrocyanosis, dry mouth and unexplained fever. Most patients describe headaches, most commonly migraines.  Many of these migraines are actually describing intracranial pressure symptoms.   Add to this the understanding that the first part of a migraine involves “cortical spreading depression” from the locus coeruleus that closes the glymphatic paravascular spaces impacting on glymphatic function.(52)

Patients also frequently report a combination of diarrhoea and constipation. A substantial subset of patients will describe symptoms related to altered gastric motility, with nausea and vomiting that sometimes limit food and water intake. These patients may describe nausea that is worse with upright posture and that responds to treatment that targets the tachycardia.   Symptoms are often present from birth, associated with being a “colicky baby” or night terrors, sleep disorders, and as a teen, may have an “eating disorder.”   The colicky baby, especially if they had eczema, early asthma, usually have underlying cow dairy intolerances.

Some patients describe symptoms of bladder dysfunction with incontinence or urgency. Complaints of paraesthesia and numbness in the limbs may suggest a small fibre neuropathy as autonomic nerves are small fibre type, implicating microglial activation often exaggerated by glutamate dysfunction, low vitamin B12, glucose dysfunction, but also can be tracked to a compression syndrome eg Popliteal Compression, Thoracic Outlet, May-Thurner or Nutcracker Syndrome.

Heat and cold intolerance are commonly reported, suggesting glutamate dysfunction. Most patients complain of subjective cognitive dysfunction (“brain fog”) and pervasive fatigue, and there may be symptoms associated with mast cell dysfunction.  Clinicians should carefully review medications, as some may worsen symptoms, and ask about adequacy of salt and water intake.”(2)

In addition many POTS patients have been traumatized by previous misguided medical management, and the importance of a “listening ear” that validates their symptoms cannot be overstated.   Some of the underlying causes can be easily seen, other require intense investigation.   Many severely incapacitated POTS patients have found when applying for government support, they are regularly rejected, as these agencies as well as insurance companies are simply not aware of the permanency and severity of their symptoms.  This will require a concerted effort from POTS researchers to provide the information, and be sufficiently convincing to force a change in attitude.  This rejection can have a very damaging effect on the patient psyche.

To understand the complexity requires an understanding of the Dysfunctional Immune response, especially in COVID, the function of the vital glial cells and mast cells.  It also requires using clues such as injuries, mould, parasites, infections and “activators” to look at the other involved pathways.   Diet, especially when there are accompanying food intolerances is always important.

The summary of POTS management by Lau, Gallagher and Seeley (1) includes the following:

• “Postural orthostatic tachycardia syndrome (POTS) presents with orthostatic intolerance, frequently associated with multi-system symptoms.

• In the primary care setting, diagnosis can be undertaken via active standing test. A positive test is met with a sustained heart rate rise of 30 beats per minute or greater (or 40 beats per minute or greater in 12-19-year-olds) with the absence of orthostatic hypotension.

• First-line therapy is lifestyle modification, including fluid loading, high salt diet, use of compression wear and a graded exercise program.

• Pharmacotherapy has a limited evidence base but is utilised to improve day-to-day function and reduce symptom burden in those with persistent symptoms despite lifestyle modification.”(1)

Clinical presentation - Lau, Gallagher and Seeley (1)

• “POTS is a complex chronic disorder that occurs as a result of underlying autonomic dysfunction. Those affected can present with a myriad of symptoms based on the degree of dysautonomia and organ systems affected. The condition is typically poorly recognized by healthcare professionals, with frequent misdiagnosis and/or significant diagnostic delay (median around 24 months). POTS has a significant female preponderance (representing 85% of those affected) with onset often in the adolescent years.

• In some individuals, the onset follows a specific trigger, such as infection (mostly viral), trauma, concussion, or times of significant hormonal change (eg, onset of menses, post-partum, menopause). In others, the onset is more insidious, with a gradual increase in symptoms over time.

• Several comorbidities are commonly seen in patients with the condition, including joint hypermobility (hypermobile spectrum disorder or hypermobile Ehlers-Danlos syndrome), migraine, autoimmune conditions, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia.

• The key feature of POTS is orthostatic tachycardia with absence of postural blood pressure reduction. The presenting symptoms of orthostatic intolerance may include dizziness, light-headedness, brain fog, pre-syncope/syncope, palpitations, chest pain or discomfort, headache, nausea, visual disturbance, fatigue and tremulousness. These symptoms typically improve with recumbence.

• It is extremely common for individuals to report a constellation of non-orthostatic symptoms, including sleep or cognitive disturbances, bloating/constipation, thermo¬regulatory disturbance, urinary symptoms and exercise intolerance.

• POTS is a fluctuating condition, often involving ‘flares’ interspersed with periods of relatively well-controlled symptoms. The aetiology is unclear, although several mechanisms have been proposed, including autoimmunity. Although POTS has been categorised into various sub-types (such as hypovolaemic, neuropathic or hyperadrenergic), there is significant crossover, and an individual may experience features of more than one subtype.”

Diagnosis - Lau, Gallagher and Seeley (1)

“Diagnosis is based on symptomatology, in addition with tachycardia observed with standing. It is generally agreed that symptoms should be present for at least three months before POTS can be confirmed.

Additionally, other potential causes or contributors to orthostatic tachycardia must be excluded. These include medications, such as sympathomimetics and anticholinergic agents, and medical conditions, such as anaemia, dehydration, fever, pain, anorexia nervosa, hyperventilation, severe deconditioning, hyperthyroidism and phaeochromocytoma.

In the primary care setting, to determine change in heart rate and blood pressure, a 10-minute active standing test can be performed after the patient has been supine for five minutes. This involves assessing heart rate and blood pressure upon standing, over 10 minutes. A positive standing test is a sustained heart rate rise of 30 beats per minute or greater in adults, or 40 beats per minute or greater in those aged 12-19 years, in the absence of orthostatic hypotension (drop in systolic blood pressure of greater than 20mmHg), within three minutes of standing. An absolute heart rate of 120 beats per minute or greater at any time during the standing test is also diagnostic.

It should be noted that the heart rate criteria have been disputed when clinical suspicion is high, particularly in adolescents. Diurnal variations in heart rate responses to orthostatic stress have been observed in this population and therefore testing is better performed in the morning.

Given the fluctuating nature of the condition, a negative active standing test does not conclusively exclude a POTS diagnosis. For those with suggestive symptoms but who do not meet the heart rate criteria, the Canadian Consensus Statement suggests a diagnosis of postural symptoms without tachycardia (PSWT), acknowledging that that there must be a high index of clinical suspicion and that the criteria for POTS may be met at a future time point.

Management  - Lau, Gallagher and Seeley (1)

“Non-pharmacological" management (1)

In the absence of curative treatment, management of POTS is largely directed at alleviating symptoms, although most interventions have a rather limited evidence base. Initial strategies involve lifestyle modifications to improve and support blood volume. These include fluid loading, high salt diet, use of compression wear and graded recumbent exercise.

Fluid loading can be achieved by recommending consumption of 2-3 litres per day. The majority of this should come from water, although electrolyte drinks are frequently utilised in this population. In the absence of any contradictions, a high salt diet (up to 10g per day) is recommended, achieved by increasing intake of high salt foods and adding salt to meals. Additional salt tablets (600mg) can be used (two tablets, three times per day), although these may worsen gastrointestinal symptoms and/or be poorly tolerated.

Compression garments may assist in supporting blood flow with upright posture, with one study demonstrating improved stroke volume on head up tilt table testing with both full (abdominal and full leg) and abdominal-only compression.

Exercise is helpful but often requires commencement of recumbent activity before more upright activity can be tolerated. In a small ‘before and after’ study, six months of unsupervised home exercise training enhanced quality of life, reduced supine and standing heart rates, and reduced the frequency of syncope. Guidance from an exercise physiologist who is familiar with POTS is often helpful to avoid post-exertional malaise, where symptoms acutely exacerbate within 24 hours of exercise.

Common triggers to avoid include hot, humid environments, hot showers, scenarios that require prolonged standing, and excessive alcohol, tea, coffee or energy drink intake. Online support groups and patient advocacy organisations can provide additional support to this population and their carers. https://www.ausdoc.com.au/therapy-update/postural-orthostatic-tachycardia-syndrome/ for online resources.

Pharmacological (1)

“There are several pharmacological options to support ongoing symptoms that are refractory to lifestyle management alone. Medications used to ameliorate orthostatic tachycardia include ivabradine, a selective funny current (If) inhibitor (the funny current is a mixed sodium–potassium inward channel in the sinoatrial node) or beta blockers (propranolol or metoprolol)."(1)

Ivabradine’s use is limited by cost and potential adverse reactions.  Ivabradine is FDA-approved in the United States for use in patients with symptoms due to stable heart failure and an ejection fraction of 35% or less to reduce their risk of hospital admission for worsening heart failure.   It’s mode of action is to block the channel responsible for the cardiac pacemaker current which regulates heart rate.  

Ivabradine is metabolized by CYP3A4. Concomitant use of verapamil or diltiazem with ivabradine should be avoided. Verapamil and diltiazem are CYP3A4 inhibitors; they increase ivabradine levels and hence the risk of bradycardia. The most common adverse effects include bradycardia, atrial fibrillation, high blood pressure, and visual changes (phosphenes.)  Others include fatigue, pounding in the ears, lightheadedness and headache.  Ivabradine can cause bradycardia, sinus arrest, and heart block.(49)

"Some individuals with hyperadrenergic-type POTS may have high blood pressure along with tachycardia, that improves on recumbence and with heart rate slowing medications. Therefore, beta blockers should be used cautiously, even with apparent initial hypertension, as they carry a risk of hypotension following adequate rate control."(1)

"Fluid and volume retention can be assisted with the addition of fludrocortisone."(1)

"Midodrine is an effective alpha-adrenergic agonist that can also be helpful in supporting upright posture through vasoconstriction and is generally well tolerated. Unfortunately, neither ivabradine nor midodrine are listed on the Pharmaceutical Benefits Scheme for POTS and therefore pose a substantial cost to the users. Specialist POTS cardiologist or physician referral to assist with titration of these medications may be advantageous, especially if the primary care practitioner is unfamiliar with these treatment options."(1)

A small proportion of patients with POTS require intermittent or chronic intravenous fluid therapy alongside pharmacotherapy.”(1)

Multidisciplinary care -  Lau, Gallagher and Seeley(1)

“A significant proportion of patients with POTS have multi-system symptoms despite good heart rate and blood pressure control, as a result of their autonomic dysfunction. Many experience significant impacts on their ability to attend school or work and participate in social activities, often resulting in detrimental mental health effects and financial hardship."(1)

Multidisciplinary management is frequently warranted, potentially including neurology, orthopaedic, gastroenterology, pain physician, rheumatology, immunology, psychiatry and vascular surgery input. Additionally, allied healthcare is often required, including physiotherapy, exercise physiology, dietetics, occupational therapy and psychology involvement.”(1)

Established Lifestyle Measures:

1. Avoid situations that can exacerbate symptoms eg heat, alcohol

2. Liberal intake of salt and water

3. Sleep with head of bed elevated- bed head raised 10 cm

4. Use of compression garments

5. Physical counter manoeuvres

6. Drinking water before getting up in the morning

7. Strategies to avoid upright exercise eg seated rower, recumbent bike, swimming

Raj et al (2), provide a suggested initial approach to a POTS patient.

Non-pharmacological treatments- all started at initial visit

1. Water 3l/day

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

3. Waist-high compression garments

Raj et al continue: 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

2. If beta-blocker contraindicated in high standing heart rate: Ivabradine 5 mg bd

3. If standing heart rate is not too high and blood pressure is low: Midodrine 5 mg tds

Garland et al (5) describe that considerable clinical overlap exists between POTS and vasovagal syncope with patients experiencing similar orthostatic symptoms related to insufficient adaptation to blood volume shifts during upright posture.  They found differences emerge during head up tilt table testing, as in patients with POTS, sympathetic tone increases during upright tilt, there is an early and sustained tachycardia, and patients complain of presyncope without frank syncope. 

In contrast, patients with vasovagal syncope experience delayed symptoms and abrupt drops in BP and HR and are more likely to lose consciousness.   From studies such as these, treatment of POTS includes exercise and medications directed at decreasing sympathetic tone or increasing blood volume.(5)

Established Therapeutics

Table 1: POTS Therapeutics

a. Heart Rate Inhibitors

b. Vasoconstrictors

c. Sympatholytic medication

d. Blood Volume Expanders

e. Others

IVIG is showing promise in the control of small fibre neuropathy with research from Long COVID. (60)

Progression from basic management.

An initial assessment should include rating scales - which might include:

• Central Sensitization Index (CSI) to assess sensitization, the cause of which may be astrocyte/glutamate with microglial/small fibre neuropathy + mast cell activation.(61)

• Malmo POTS Severity Score. (62)

• Modified Somatic Perceptions Questionairre (MSPQ) for autonomic stability.(63)

• Fatigue Severity Scale (FSS) (64)

• Bell's Functionality Scale to assess overall level of function (65)
  

The Dysfunctional 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.   TLR 2 and 4 and mast cells are the first “responders”.

Clough et al (28) 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 and therefore they are widely used to study neuro-inflammation.”

“Microglia are involved in neuroprotective and neurotoxic responses in the CNS in response to SARS-COV 2 infection. The severe cytokine storm in COVID -19 patients is associated with increased serum levels of proinflammatory cytokines and increased BBB permeability due to cytokine-induced damage. Cytokines activate microglia and astrocytes and activate microglia to secrete inflammatory mediators, inducing altered neuroplasticity, and other neuropathologies resulting in neuro-cognitive impairment. SARS-COV2 induces a mitochondrial-dependent intrinsic apoptotic pathway, leading to the activation of caspase-9 followed by initiation of executioner caspases-3/7.”(28) 

Thus, our data suggests that SARS-COV2 induces a significant inflammatory response, increased oxidative stress, inflammasome activation and mitochondrial dysfunction in microglial cells, all of which contribute to COVID associated neuropathology. This study provides important mechanistic insights into SARS-COV2 induced mitochondrial dysfunction which underlies COVID-19 associated neuropathology.”(28)

The emergent theories of astrocyte/glutamate dysfunction, which is TLR2-driven,  can sometimes be seen, given the clear association of this in autism spectrum, ADHD, visual snow, fibromyalgia and migraine.   The astrocytes form the paravascular spaces so important in pressure control in the glymphatic system, and the theories may explain fatigue as one of the major components of POTS and CFS by impaired glymphatic function.   Griffith University continues its research into CFS, and more recently into Low Dose Naltrexone (LDN) it the management of these, and at this point it’s benefits through TLR4 modulation and improved astrocyte/glymphatic functioning.    The work by Hulens (18) and others puts POTS and CFS in the same basic pathology.  

This TLR2/ astrocyte pathway helps differentiate glymphatic dysfunction secondary to the astrocyte dysfunction, against the microglial activation, and neuropathic changes with increased sensitisation. 

The research into astrocyte/glutamate in Gulf War Veterans, autism and other neurodivergent disease (21)(22)(23) demonstrated the potential usefulness of low glutamate diets although when applied to POTS patients with these co-morbidities, while some have significant improvements, the complexity of associated metabolic dysfunction associated with histamine and other dysfunction with the various DNA mutations identified in POTS and Long Covid seldom provides the desired level of metabolic and inflammatory control.  It is simply not one factor involved.

The autonomic instability the process by which the TLR4-cytokine-mast cell-driven microglial activation causes the small fibre neuropathy with subsequent autonomic instability needs to be assessed and controlled, and the autonomic overactivity and inflammation reduced.  The sensitization which appears to be TLR2-astrocyte-mast cell-driven needs also to be addressed, usually with diet modification to start.   While the POTS “activator” are varied, and “drivers” similarly varied, the process remains the same.   Simple factors such as posture, diet and  stress are very important as they contribute to the inflammatory load.

All co-morbidities, which are frequent, needs to be correctly assessed.  The most common as described by Raj et al (2) are Fibromyalgia Syndrome, EDS, migraine, auto-immune disorders (especially Hashimotos Syndrome) and mast cell activation disorder. Raj (2) describes coeliac disease, but in general, clinical findings are that food intolerances as a driver is far more common than coeliac disease.  

Raj et al (2) in 2022, describe the presence of small fibre neuropathy and genetic predisposition.   They also describe comorbidities of:

o   migraine,

o   Ehlers-Danloss Syndrome,

o   CFS,

o   Fibromyalgia,

o   auto-immune diseases,

o   mast cell activation disorder

o   coeliac disease

With EDS in particular, comes intracranial pressure disorders, that can vary from Intracranial hypertension to CSF leaks, and the most common seen in my experience, is intracranial vascular pressure dysfunction, and most commonly clinically, a combination of venous obstruction and glymphatic dysfunction.

Fatigue in POTS may have a variety of potential causes.  These include metabolic dysfunction, mitochondrial dysfunction, small fibre neuropathy with autonomic instability, and glymphatic dysfunction which can have mechanical/hydraulic causes as well as astrocyte/ glymphatic/ paravascular space dysfunction, and combinations of all of these.

Mechanical and Hydraulic Causes underpinning POTS symptoms:

The “mechanical and hydraulic” causes we have found in clinic are described as:

• Thoracic Outlet Syndrome (TOS). Arterial TOS can have direct effects on cerebral circulation, and intracranial vascular hypertension.   Venous TOS is clinically and functionally directly related to JOS and cervical spine dysfunction, generally from poor posture and trauma.  It can also impact on the cervical spine via the scalenes  – Thoracic Outlet Syndrome

• Jugular Outlet Syndrome (JOS) where the Internal Jugular Vein (s) is compressed between the transverse process of the first cervical vertebra and the stylohyoid ligament.  Jugular Outlet Syndrome is intricately linked to the Thoracic Outlet Syndrome and upper cervical pathology.  

• Internal Jugular Vein Stenosis (IJVS) and Internal Jugular Vein Obstruction (IJVO)- (40)(41)(42) collectively with Jugular Outlet Syndrome, both affect venous outflow from the brain,(47) but the jugular dilation of the Internal Jugular Vein potentially affects the vagus, carotid baroreceptors, cervical sympathetic chain and jugular nerve.   These are usually associated with a Thoracic Outlet Syndrome that may need surgery

• Collectively the JOS and IJVS has been referred to as chronic cerebrospinal venous insufficiency (CCSVI) (40). Dynamic scanning of the Subclavian and Internal Jugular veins in a small preliminary study of 15 has shown the Internal Jugular Vein to dilate as the arms are elevated, and when neck flexion is added, obstruction to Internal Jugular Vein flow has been shown, the IJV flow return slow to return.  These results mirror the findings by van Campen, Rowe and Visser (44) in middle cerebral artery flow in CFS.   As this has been accompanied by POTS symptoms, this requires formal studies to confirm the importance of this finding, and to differentiate the relative importance of each facetInternal Jugular Vein Dysfunction- Jugular Outlet Syndrome, Internal Jugular Vein Stenosis and Obstruction.  

• Loss of cervical lordosis/ flexion kyphosis – potentially impacting on Vertebral Artery flow as found by Bulut (45), Vertebral Vein and surrounding lymphatics.  This may be mechanical or from vasoconstriction.   Ehlers-Danlos Syndrome and cervical dysfunction associated with hypermobility can be major factors.   Little recognized, tongue-tie has a place as it has been shown to be associated with upper cervical subluxation and dysfunction.   Chiropractic research has shown C1 misalignment in 1 direction and C2/3 in the opposite direction.  This is then thought to be associated with C2 dysfunction and may cause dysautonomia.(53) Cervical Spine Abnormality, Ehlers-Danlos Syndrome and Vertebral Vascular and Lymphatic Dysfunction.  ·      

• All the above clinically cause lymphatic obstruction as these surround the compressed Internal Jugular and Vertebral Veins.   This impaired lymphatic flow potentially creates “backpressure” in the Glymphatic System which is affected by genetic predisposition, sleep disorder, and most importantly Covid infections. Glymphatic System  ·      

• Clinical studies have shown lymphatic obstruction at the venous angle-junction of the subclavian and internal jugular veins, involving the chest wall and probably the lymphatic and thoracic ducts.   This may have implications in Azygous dysfunction and cardiac preload dysfunction that typifies the POTS-related shortness of breath. ·      

• The combination of these changes is described in Intracranial Hypertension, Intracranial Hypotension, CSF Leaks and Craniovascular Pressure Change ·      

• In the abdomen the primary mechanical /hydraulic drivers involve the Coeliac axis (MALS and SMA), Renal Vein Compression with gonadal vein reflux (Nutcracker Syndrome) with pelvic congestion, and May-Thurner Syndrome involving the iliac veins.  Recent advances in radiology has shown a high incidence of left renal vein compression associated with Superior Mesenteric Artery Syndrome (SMA), providing a potential explanation for intra-abdominal venous (and spinal vein plexus) dysfunction in SMA, previously unable to be explained. The venous congestion potentially involves the Azygous and spinal vein systems.   Intra-abdominal Vascular Compression Syndromes   .        

• With pelvic congestion, renal vein and iliac vein compression, blood flows into the point of least resistance, seen in vertebral and paravertebral venous congestion/dilatation.   Obstruction can be seen frequently in venous engorgement in thighs, often accompanied by lipoedema.  The vertebral venous system has no valves and Scholback (79) describes the potential to cause intracranial pressure change.  To achieve this, there also has to be obstruction in the head and neck. ·      

• The Azygous system of veins, which includes the hemiazygous and accessory hemiazygous veins provide an alternative blood flow from the lower half of the body to the superior vena cava and was recognized by Nicolaides et al as significant in their work on venous outflow abnormalities and MS (54) and explored by Scholbach.(43)   ·      

• Azygous system and vertebral venous congestion looks to be an important potential causes for the preload dysfunction in POTS.   Symptoms can at times only be explained by dysfunctional azygous flow, but again we have no evidence to confirm this as yet except in specific case studies. Cervical Spine Abnormality, Ehlers-Danlos Syndrome and Vertebral Vascular Dysfunction, Intra-Abdominal Vascular Compression Syndromes, Case Studies 

POTS “Activators”, “Drivers” and Co-Morbidities

Table 2: Activators- This list has been compiled largely from clinical observation from this clinic.

• COVID

• Trauma especially to upper cervical spine and coccyx, occasionally other areas, and including clavicular fractures, and shoulder dislocations affecting the Thoracic Outlet

• Other infections, including parasites especially blastocystis.  There are many subspecies of this parasite, and only some are pathogenic.(source- discussion with infectious diseases physician)

• Sustained stress

• PTSD

• Pregnancy

• Surgery

• Sustained use of backpacks, cameras (particularly if an associated occupation)

• Prolonged mould /chemical exposure

• Combinations of these, and virtually anything causing sustained activation of immune response

POTS “Drivers”and Co-Morbidities

Table 3: POTS Drivers. This list has been compiled largely from clinical observation.

• Thoracic outlet syndrome (arterial and venous)

• Jugular outlet syndrome

• Internal Jugular Vein Obstruction

• Loss of normal lordosis, abnormal kyphosis in neck flexion, poor posture, compounded by Craniocervical instability and hEDS.

• MALS, SMA syndrome, Nutcracker Syndrome, May-Thurner Syndrome

• Stress

• PTSD

• Diet

• Backpacks

• Breast weight

• Breast implants

• Poor posture

• Prolonged phone, laptop usage with poor head forward flexed (and rotated) posture

• Weight training

• Occupation/sports

Table 4: Other contributors:

• Anatomical variants eg abnormal cerebral, vertebral vasculature

• Hypermobility in cervical spine (Ehlers-Danloss Syndrome)- Cervical Spine Abnormality, Ehlers-Danlos Syndrome and Vertebral Vascular and Lymphatic Dysfunction

• Chiari malformations

• Low-lying cerebellar anatomy (likely increased vulnerability)

• Larger brainstem (shown so far in CFS and Long Covid) – (likely increased vulnerability) (58)

Table 5: POTS Co-morbidities

• CFS/ME- chronic fatigue syndrome.  Essentially POTS is CFS/ME with autonomic instability.  Tilt tests in CFS in small studies confirms the similar process (2)

• Mast Cell Activation Syndrome

• Fibromyalgia

• Migraine -sensitization (with sustained aura, a patent foramen ovale is not uncommon)

o   Microembolic via PFO (migraine esp aura > 20 mins, vertebrobasilar, hemiplegic types)

• Cerebral hyperintensities on MRI
  

  • Small vessel disease (assess through retinal arteriography)

  • Microemboli through PFO
    

  • Glymphatic obstruction/increased perivascular spaces

  • Covid-related vasculopathy

• Hashimotos Thyroiditis

• ANA +ve titre, often low complement C3- other autoimmune disease

• IBS

• ADHD

• Autism Spectrum Disorder

• Spinal symptoms

• Endometriosis

• Pelvic Congestion

• Sleep disorder/ unexplained anxiety- reflects sympathetic overactivity

• Fatty liver

Fatigue

Fatigue in POTS may have a variety of potential causes.  These include metabolic dysfunction, mitochondrial dysfunction, small fibre neuropathy with autonomic instability, and glymphatic dysfunction which can have mechanical/hydraulic causes as well as astrocyte/ glymphatic/ paravascular space dysfunction, and combinations of all of these.  

Often, the underlying causes are not fully explained until DNA is examined, for example fatigue is a common symptom of PEMT mutations and its associated mitochondrial dysfunction, and is thought to be involved in neurodegenerative disease.(101)  The linking of PEMT with glutamate dysfunction creates a valuable area for future research.

While low glutamate diets may be helpful, but most POTS have metabolic dysfunction that is far more than just glutamate, especially involving histamine and mast cell activation pathways.

Table 6: Potential sources of Chronic Fatigue

• Mitochondrial dysfunction /oxidative stress.

• Reactivation of EBV and similar viruses

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

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

• Neurotransmitter dysfunction -Dopamine/serotonin/glutamate pathways

• Intracranial pressure abnormality with HPA axis dysfunction

• Direct cardiac damage (eg pericarditis, myocarditis, reduced Ejection Fraction)

• Pulmonary damage- embolic, inflammatory, malignancy

• Renal dysfunction through multiple causes including renal vein thrombosis and nephrotic syndrome

• Liver disease, with reduced clearance of fibrin degradation products

• Undiagnosed malignancy that can accompany Natural Killer Cell dysfunction.(57)(58)(59)

• Metabolic pathway abnormality/ DNA mutations /Dietary triggers.  These include PEMT mutations and dysfunction in phosphatidycholine and phosphatidylserine metabolism where there are no biomarkers.

• Other vital DNA mutations associated with dysfunction include APO E4 with its known increased cardiovascular, neurodegenerative and liver dysfunction potential.

• Small fibre neuropathy
  

  • Autonomic instability eg POTS, dysautonomia, orthostatic hypotension

  • Impaired cardiac function

  • Very common (again IL-6 and TNFa)-accompanying exaggerated neuropathy, rheumatoid arthritis, reactive arthritis, PMR strongly suggestive of TLR4 mutations

• Cardiac preload failure (unexplained shortness of breath with postural change)

  • Locus coeruleus

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

    • Sensitization mechanically
      

    • Secondary to Thoracic /Lymphatic duct obstruction

    • Associated with Intra-abdominal vascular dysfunction

Clinical Suggestions for Management. 

While “drivers” are being worked out, major improvements may be possible with some simple suggestions that have been very useful in clinical practice:

• Validation of a patient’s symptoms, and the opportunity to describe their symptoms and concerns with no “gaslighting” or similar to push these to psychological causes is I feel very important. This does not mean that psychological causes are not important though, as most do have anxiety and depression secondary to their condition, and the ones in particular with sleeping disorders and chronic anxiety commonly have a problem with mechanically-driven sympathetic overactivity.

• Often the severity of the sensitization that underpins the microglial activation is so severe, that no physical therapy can be safely commenced. You may need to look at control of the TLR4 activation and/or mast cell activation before starting any formal treatment. If the comorbidities include those where astrocyte/glutamate dysfunction may be a part, a trial of low glutamate diet may be able to reduce the levels of sensitization and cognitive dysfunction. Some are so sensitized that they cannot tolerate the expedients used in normal pharmacy medication and require compounded medication. This is a very difficult area and best left to specialty practitioners if not improved with dietary and postural changes.

• Diet modification can be valuable in those hypersensitized patients to start reducing the sensitization load.  If the comorbidities include those where astrocyte/glutamate dysfunction may be a part, a trial of low glutamate diet plus removal of any food the patient has observed causes symptoms may be able to reduce the levels of sensitization and cognitive dysfunction. Unfortunately this low glutamate diet alone is seldom successful, and I seldom see glutamate as a stand-alone problem.   Dieticians experienced in managing POTS food-drivers, can make a significant improvement with reduction of inflammatory cytokines.  

• Acupuncture is a valuable tool, with its TLR4 modulation (30) and ability to reduce the autonomic instability (31).   Our studies have concentrated on a Japanese style, Kiiko-Matsumoto with its convincing effectiveness, and this is often needed to stabilize symptoms before physical therapy can be employed.   This can be a critical step before physical therapy can be commenced.

• Control physical drivers -good posture most important, especially with phones and laptops and lymphatic therapy combined with physiotherapy, depending on the specific underlying cause in each patient. Most commonly the combination of neck pathology (trauma, EDS, loss of lordosis or flexion kyphosis), with venous thoracic outlet syndrome and venous jugular outlet syndrome “drives” the symptoms. Physiotherapy, lymphatic drainage and osteopathy offer varying levels of response, largely dependent on whether the “drivers” have been fully elucidated, and the skill of the therapists.

• The postures associated with the head pressure and “brain fog” combinations, especially if associated with pulse-synchronous tinnitus and similar symptoms can be important in determining intracranial pressure, or vascular pressure dysfunction. Symptoms worse when lying typically may reflect Intracranial Hypertension, even when radiology cannot confirm this, while pressure standing appears to be intravascular pressure change, most commonly from venous and lymphatic obstruction. Care with possible CSF leaks after trauma and in EDS.

•  MALS is characterized by chronic abdominal symptoms associated with median arcuate ligament compression of the coeliac artery. The selection of patients is difficult in the management of MALS.  A study from Queensland in 2017 provided valuable information on patient selection for surgery.  Ho et al (29) found patients more likely to respond to decompression if the patients had post-exertional pain. Patients who presented with vomiting and unprovoked pain were unlikely to respond to surgery. In contrast with previous studies, postprandial pain was not found to be predictive of outcome. (144)

• They described how surgical management has evolved during the past five decades, but long-term outcomes remain variable, with symptom relief occurring in 65% to 87% of treated patients.   In clinical practice, selection of appropriate patients for surgical treatment remains difficult because both clinical and radiographic features of MALS are nonspecific.

• In management of nonoperatively treated patients, options included dietary alteration, medical therapy (analgesia, laxatives, and antacid therapy). We are currently trialling osteopathy for fascial release to the psoas and crura release for the MALS and Nutcrackers. 

• These intra-abdominal compression syndromes may be associated with increased spinal vein pressure as blood is diverted into this valveless venous plexus, and is commonly associated with pelvic congestion symptoms. Back pressure into the portal venous system causing fatty liver is an area being investigated.

• While physiotherapy remains the mainstay, with the “crowding” at the jugular foramen, osteopathy offers a decompression, and venous sinus and lymphatic drainage techniques, as lymphatic obstruction clinically appears to be a significant factor, so again we are trialling this for the cervical spine as well as obstruction at the stylohyoid and venous angles.

• Paced recovery with exercise physiologist / rehabilitation program is a vital part of recovery, once the “drivers” are removed or controlled. Especially in EDS, this can be very difficult, requiring assistance from physiotherapists skilled in this management. In this group, CSF leaks, “cerebellar crowding,” Chiari malformations, cardiac and other collagen dysfunction may be present requiring specialist attention.

• In this group, CSF leaks, “cerebellar crowding,” Chiari malformations which cause CSF obstruction as they compress the craniocervical junction, cardiac and other collagen dysfunction may be present requiring specialist attention. Stress management

• Restoration of sleep hygiene, as the glymphatic function depends on sleep.

• Mast cell activation control. Again stress and metabolic management are vital. The mast cell activation is a normal part of the immune response, but some patients have significant dysfunction in keeping with genetic mutations, and may require high level management.   If medication is sought, advice from clinicians skilled in mast cell management should be considered.  I believe too much emphasis is being placed on medication-based mast cell suppression rather than tackling the various TLR activations and the causes for this, and the cascade of metabolic changes from “downstream” DNA mutations and often very simple postural and other mechanical changes.  

Visceral Sensitivity and IBS

Karantanos et al (32) described the most important mechanisms in IBS include visceral sensitivity, abnormal gut motility and autonomous nervous system dysfunction. The interactions between these three mechanisms make bowel's function susceptible to many exogenous and endogenous factors like gastrointestinal flora, feeding and psychosocial factors. Recent data indicate that according to the above mechanisms, the influence of genetic factors and polymorphisms of human DNA in the development of IBS is equally important.”

Visceral sensitivity is regulated in many levels, mediated at the level of enteric mucosa and submucosa, the level of spinal cord, the level of thalamus and the level of cerebral cortex.(32)

Coss-Adams and Rao (35) showed there is evidence that interactions within the brain and gut axis (BGA) that involves both, the afferent- ascending and the efferent-descending pathways as well as the somatosensory cortex, insula, amygdala, anterior cingulate cortex and hippocampus are deranged in IBS showing both the activation and inactivation.

The primary afferent neuron terminals of enteric nervous system (ENS) which are localized in submucosal tunica of gastrointestinal tract (Meissner plexus) and between smooth muscle fibres (Auerbach plexus) transmit stimuli to central nervous system (CNS) through sympathetic and parasympathetic autonomic nervous system (SNS and PNS).

Glymphatics and Gut-Brain Axis.

Natale et al (39) describe that a “large body of evidence shows how gastrointestinal pathologies can affect the CNS bypassing or altering blood-brain barrier (BBB) and related pathways, including the glymphatic system. In a novel experimental study - synuclein fibrils injected into the duodenal and pyloric muscularis layer can spread in the brain, first in the dorsal motor nucleus, and then in the locus coeruleus” and then further.

Furthermore, “via the microbiota-gut-brain axis, triggering Receptors Expressed on Myeloid cells (TREM)-positive activated macrophages along with inflammatory mediators may reach the brain through blood, glymphatic system, circumventricular organs, or the vagus nerve. This may foster pro-inflammatory reactions in the brain, bridging inflammatory bowel disease and neurological disorders.”(39) This is thought to occur from the SARS-CoV-2 viral infection.

Inflammation in IBS:

Low grade inflammation has been implicated as one of the underlying mechanisms of IBS. Variations in the circulating pro-inflammatory interleukin-6 (IL-6) levels and IL-6 gene polymorphisms have been demonstrated in IBS. Basasharti et al (37) found levels of pro-inflammatory interleukins 2,6 and 8 have been found to be elevated in IBS, especially in the post-infectious IBS (against non-post-infectious IBS) and reduction of anti-inflammatory IL-10 in both.

Having variable or migratory arthritis may suggest a dietary cause. The trick is to find the culprits here. Everyone is off doing gluten and dairy free diets, but most are wrong. It may be cow milk, as this is the first “toxic” chemical the body is exposed to in life, but after that there are many possible candidates. Research in 1999 by Dr David Freed showed the deadly nightshades, the lectins, to be triggers to a wide range of autoimmune disease. But everyone has different triggers and using the same diet in everyone simply does not work.(38)

Exorphins in IBS:

Exorphins are “exogenous opioid peptides” which include gluten exorphin, and can be isolated from various sources eg dairy, and vegetables eg spinach and soy. Research in areas such as autism and schizophrenia have found that genetic mutations can lead to increased absorption in these groups.

Brain opioid peptide systems are known to play an important role in motivation, emotion, attachment behaviour, and responses to stress and pain, the control of food intake and the “rewarding” effects of alcohol and nicotine.

Molecular biologist Dr Valerio Vittone describes: “Soy-derived exorphins may influence brain function and metabolic processes. Similarly, spinach contains opioid peptides that can interact with opioid receptors, affecting both gastrointestinal and neurological functions. The impact of these exorphins can be quite profound, particularly in individuals with certain metabolic or genetic predispositions as we often observe in our problematic patients.”

“Furthermore, nightshades are also very problematic. the potential presence and impact of opioid peptides in nightshade vegetables, such as tomatoes, potatoes, and peppers, are less well-documented however, may represent an intriguing area for further research. These foods contain alkaloids and other compounds that may interact with metabolism and immune function in genotype-specific ways. From my perspective, The interplay between an individual's genotype and their response to food exorphins is a critical factor.”

“Nutrigenomic approaches, which examine the interaction between diet and genes, are particularly relevant here. Variations in genes related to opioid receptors or metabolic enzymes could significantly alter an individual's response to these dietary peptides.”

When starting diet change, think about foods that you know you, or your patient react to- eg dairy, or bread, or gluten, and remove these. If you have migraine, autism, ADHD, fibromyalgia, a 2 week trial of low glutamate, while continuing to avoid the known reactive foods is worth trialling to gauge any response, followed by a formal consultation with the dietician to progress beyond this diet trial. When the symptoms of mast cell activation are obvious, removing histamine-containing food is usually necessary. Many of the diets available on the internet are simply not validated. Unless competent with dietary modification I recommend using a registered dietician.

There will still be some which are simply not obvious, and these may be answered using DNA profiling with Dr Vittone. This is particularly so when mutations such as PEMT (with its neurodegenerative associations) are present, where there are no biomarkers, only DNA to detect its presence.

Gastroparesis:

When gastroparesis is a dominant symptom, a common problems in MALS or SMA-drivers, gastroenterologist Dr Rebecca Ryan, who has a special interest in these, recommends:

• 6 small meals a day

• Low fat

• Low insoluble fibre

• If severe, may need a liquid or pureed form as gastric emptying is impaired

Mast cell activation can be a major factor, so looking at low histamine may be needed.

Lifestyle and physical treatments for consideration:

So much of the pathology involves physically-controllable learned postural dysfunction. The most common physical “drivers” we have found in POTS involves:

• the upper cervical spine, especially with trauma and hypermobility particularly the Ehlers-Danlos Syndrome.   There are no guidelines for radiologists to assess loss of lordosis or flexion kyphosis, and as the neck in your people is “straighter” assessing pathology in neck shape is very difficult.   Posture is a major factor, and attention to the “enemies”, the phones, computers, backpacks can have very rewarding results.   I point out the increasing weight of backpacks in our children and the lessons learnt in WW2, then forgotten.(27)

• Thoracic Outlet Syndrome-especially seen in people who work above their heads, weight-lifting, waiters etc

• Jugular Outlet Syndrome/ Internal Jugular Obstruction.  By and large, treatment of the cervical dysfunction and Thoracic Outlet control the IJV venous backpressure.  Rarely surgery is needed to the stylohoid, IJV valve or thoracic outlet.

• These are usually found together and management protocols for the “triad” needed

• Intra-abdominal compression pathology has been found far more frequently since Covid, and theories for this include possible collagen dysfunction, although the increased sensitization from microglial may account for some or all of this.

Thoracic Outlet Syndrome is generally poorly managed with few therapists able to understand its complexity.  A Roos test will provide valuable clues to its presence. Generally start with avoidance of lifting above the head, backpacks, carrying heavy weights, restrict the weight of bags to a minimum.   Knowledge of where the nerves, veins and arteries are being jammed are important via dynamic ultrasounds by sonographers who understand its complexity.  Compression is often in a “forward position” so use of computers and driving can be impacted.  Breast weight is a significant factor on TOS (27) and often head and shoulder-forward postures are adopted to reduce its impact, complicating the physical causes.  Computers, especially with neck flexion are major culprits.

EDS and upper cervical neck trauma usually require tertiary level physiotherapy and particular care with if not familiar with their instability. Specialized neck collars can be helpful when symptoms are severe, but soft collars are basically “neck warmers.” I recommend reading Dr Pradeep Chopra excellent summary “Connecting the dots with EDS, POTS, MCAS, GI, Neurological and Physiotherapy in managing pain in EDA.” (48)

Lymphatic obstruction, most commonly at the stylohyoid and the venous angle where the subclavian and IJV meet, while difficult to prove does provide improved symptoms when done by appropriate therapists.  Clinical studies have shown lymphatic obstruction at the venous angle involving the chest wall and probably the lymphatic and thoracic ducts.  Again, primary management we direct to the neck and thoracic outlet, but we are getting good results in trials using lymphatic therapy.

The Nutcracker/ May-Thurner and Pelvic Congestion Syndrome seldom are “sole” drivers, and usually contribute to the head and neck “drivers”. Management is generally with osteopathic treatment before any surgery is contemplated.

Median Arcuate Ligament Syndrome (MALS) and Superior Mesenteric Artery Syndromes (SMA) are increasingly being found. These often have severe symptoms requiring naso-jejunal feeding. The products being used in these feeds is usually dairy or soy-based and may compound the symptoms. As it is the loss of fat pad in the SMA, management is often best at restoring this. Again osteopathic treatment may be considered as a first choice option. Appropriate gastro-enterology referrals are usually required.

The triad- neck/JOS/TOS: Computers, phones and backpacks- the “usual enemies!”

• Prolonged computer and phone use produces head-forward posture

• Forward head posture causes headache, neck pain, TMJ disorders, alterations to length and strength of soft tissue in the neck, and scapula and shoulder dyskinesia

• Poor neck posture, heavy backpacks and breast weight impact on neck and shoulder pathology- POTS can be triggered by sustained use of backpacks.

Cervical Spine Health- a place to start- Courtesy Kjetil Larsen- MSK Neurology

“Good cervical and shoulder posture and lower overall cervical tension (ie. reducing / eliminating neck "clenching") are the two most important factors of prevention for cervical spine health and risk of neck pain.

Posture in general is a heated topic within physical medicine lately, and many claim that it does not matter. Many POTS symptoms are directly related to posture, trauma, EDS, and the neck, especially with loss of lordosis and flexion kyphosis, and when combined with the vascular problems associated with Thoracic Outlet Syndrome and Jugular Outlet Syndrome

Kjetil Larsen quotes: “It is my opinion that cervical posture is a misunderstood topic, but still, one very important topic.

• First and foremost, correcting "forward head posture" is a myth, and pulling your neck back will only make it worse.

• Secondly, contributors to neck pain are often many more than just cervical spine.

• Thirdly, pulling your shoulders back and down is possibly the biggest mistake you can make.

• Finally, exercises will not improve nasty posture. It will, however, improve muscle function and tolerance.

So, what to do?

• Make your neck "long" (or stay tall), but don't pull the head back; pulling back will exacerbate cervical hinging, obstruct the internal jugular veins and also increase strain on the subclavian vasculature and brachial plexus.

• Don't chin tuck. Raise your shoulders slightly, so that the collar bone does not rest on the brachial plexus.

• Don't "clench up", ie. try to maintain good posture with minimal effort. Clenched posture, even if it looks good, tends to make things much worse.

• Finally, strengthen your trapezius, levator scapulae and sternocleidomastoid muscles gently twice per week.

• The postural guidelines, as such, should be applied for the rest of one's life. They are permanent changes, not exercises.”

DNA Mutations in POTS and Long Covid

While the use of DNA is increasingly recognized, its use is limited in traditional medical management.    In patients with complex metabolic dysfunction, this may provide ways to improve management.  

Gene expression in the brain is dramatically regulated by a variety of stimuli. While the role of neural activity has been extensively studied, less is known about the effects of metabolism and nutrition on transcriptional control mechanisms in the brain. In the last twenty years, it has become clear that epigenetics plays a crucial role in modulating central nervous system functions and finally behaviour.(6) 

A polygenic risk score (PRS) estimates the genetic risk of an individual for some disease or trait, calculated by aggregating the effect of many common variants (usually defined as minor allele frequency  1%) in the genome, each of which can have a small effect on a person’s genetic risk.  associated with the condition.  A PRS is the weighted sum of a collection of genetic variants, usually single nucleotide polymorphisms (SNPs) or single base-pair variations from the reference genome.(7)

From the DNA studies by Dr Valerio Vittone,(8), molecular biologist researching the underlying DNA mutations in POTS and Long Covid, there is increasing evidence that multiple mutations in the Toll-Like Receptors (especially “first responders” TLR2 and TLR4) play a large role in the individual immune response, and associated with “downstream” mutations can create a domino effect responsible for the individual problems being caused by Covid.    Mutations in the mast cell membrane and in Dao enzyme and HNMT function are also significant contributors that may be involved in the pathogenesis of Long Covid, and when combined with his other findings, clear paths are emerging to reduce the severity of COVID infections and in the management of Long Covid.  

In POTS and in Long Covid where autonomic instability and pain (in particular fibromyalgia) is significant, it appears likely that it is mutations in the COMT gene that among other important functions, may be one of the most important mutations “downstream” from TLR4. It is thought at present that all POTS patients have one of the COMT mutations.

In COVID there is a well-described hyperinflammatory response.  The spike (S) protein potently induces inflammatory cytokines and chemokines including IL-6, IL-1β, TNFα, CXCL1, CXCL2, and CCL2.  This activation appears to be through the TLR2 pathway. (26)

A single mutation, by itself, may be insufficient to cause the symptoms of Long Covid. However, we have been recognising patterns that allow clinicians to treat POTS (and increasingly, long COVID). As the sensitisation from the microglial activation and small fibre neuropathy is controlled, we can work with management protocols.   More than 400 genes differentially expressed in long covid patients.   There is seldom only 1 mutation involved.   The major mutations Dr Vittone has found are as follows.

• TLR2 and TLR4 mutations: There is increasing DNA evidence that multiple mutations in the Toll-Like Receptors (especially “first responders” TLR2 and TLR4) play a large role in the individual immune response, and associated with “downstream” mutations can create a domino effect responsible for the individual problems being caused by Covid.

• Mast cells- membrane, HNMT, Dao enzyme function.  Activation triggers include

  • TLR activation

  • Oxidative stress (Reactive Oxygen Species)

  • Extracellular mitochondrial components from damaged mitochondria

  • Glutathione depletion (compromised clearance of free radicals)

• COMT (impaired processing of catecholamines, 2 types, fast and slow COMT-  is a critical mutation in POTS.  Clues include a family history breast cancer, autism, ADHD, POTS/dysautonomia, fibromyalgia, Parkinson’s disease).  COMT gene production is itself influenced by methylation. (12)  Usually, methylation shuts down gene production.   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, pain perception,(13) Parkinson’s disease,(14)  and auto-immune disease.  

• Methylation. It is now well recognized that DNA methylation, in concert with other regulators, is a major epigenetic factor influencing gene activities.  DNA methylation involves the transfer of a methyl group onto the C5 position of the cytosine to form 5-methylcytosine.    DNA methylation regulates gene expression.  Methyl groups can be added directly to the DNA molecule and this process can determine the way DNA is transcribed to RNA, a fundamental first step in the process of gene expression by recruiting proteins involved in gene repression or by inhibiting the binding of transcription factor(s) to DNA. 

• The methylation cycle is essential for mental and physical health. It is critical to the metabolism of catecholamines in the synapse via an enzyme (COMT) as well as the synthesis of ‘depression-relevant' compounds such as melatonin, myelin basic protein, carnitine, CoQ10, etc.   Methylation is required to inactivate histamine.

• Methylation mutations  eg MTHFR- the 677 MTHFR mutation typically is associated with increased homocysteine, and affects collagen function via SAMe and other molecules as well as increased thrombotic risk, and plaque formation in different tissues. Elevated plasma levels of homocysteine are a metabolic risk factor for atherosclerotic vascular disease, as shown in numerous clinical studies that linked elevated homocysteine levels to de novo and recurrent cardiovascular events. High levels of homocysteine promote oxidative stress in vascular cells and tissue because of the formation of reactive oxygen species (ROS), which have been strongly implicated in the development of atherosclerosis.  Other significant mutations,eg BHMT, PEMT and CHKA are connected to MTHFR and the folate and methylation cycle so mutations in genes like MTR and MTFHR indirectly affect them too.

• PEMT mutations- Phosphatidylethanolamine N-methyltransferase (PEMT) catalyzes phosphatidylcholine synthesis.   PEMT and similar mutations are involved in vascular complications, neurodegeneration and thrombo-inflammation.   It is thought that PEMT gene polymorphisms are associated with non-alcoholic fatty liver disease (NAFLD).   Fatigue is a common symptom of PEMT mutations and its associated mitochondrial dysfunction, and is thought to be involved in neurodegenerative disease.   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.  At present, only DNA can reveal whether this is present as there are no biomarkers for it.

• TRP mutations- TRPM3 appears critical in NK (Natural Killer) immune cell function, with implications for Ca2+ signalling, cell function,(4) and glymphatic function.     The transient receptor potential melastatin subfamily 3 (TRPM3) is one of the most primitive receptors in the body, activated by a wide variety of agents, from bacteria and viruses to temperature and environmental factors such as perfumes. This diversity made it a logical suspect for a condition like CFS that has so many different triggers in different people. 

  • Prof Sonya Marshall-Gradisnik and the Griffith University Chronic Fatigue team working with TRPM3 function in the research into chronic fatigue at Griffith University  (9)(10)(11)  have linked mutations in this pathway with “glymphatic” function with consequent reduced clearance of waste solutes from the brain with production of fatigue and brain fog and the therapeutic benefit of Low Dose Naltrexone

  • TRPA1 is a key ion channel that detects oxidative stress and a range of endogenous and exogenous chemicals (smoke, solvents, cold air). 

  • TRPM3 activity is impaired in CFS/ME patients suggesting changes in intracellular Ca2+ concentration, which may impact NK cellular functions. This investigation further helps to understand the intracellular-mediated roles in NK cells and confirm the potential role of TRPM3 ion channels in the aetiology and pathomechanism of CFS/ME.(20)(19)

• STAT 3 : This plays an important role in inflammation and tumorigenesis by regulating cell proliferation, differentiation and metabolism.  It is a critical factor in IL-6 regulation.  There are no statistics published as yet on Covid-related malignancy, but its pathways can however be seen through the DNA pathways already uncovered- eg TLR4/ RAGE/STAT3. The direct effect of Covid on natural Killer cells (NK cells) looks also to be critical as this cell’s function is vital in controlling malignancy.

• NFkB (Nuclear factor kappa-light-chain-enhancer of activated B cells)    NFkB is a protein complex that plays a crucial role in regulating the immune response, inflammation, and cell survival. The primary function of NFkB is to control gene expression in response to various signals, such as pro-inflammatory cytokines, bacterial or viral products, stress, and oxidative damage. 

• IL-6 and other Interleukins

• Oxidative stress and mitochondrial mutations eg eNOS, SOD2. NO metabolism- associated with the development of FMS and pain sensitization, and a likely problem in Long Covid. 

• Lipoprotein a (LPa): High levels of LPa, found in 20% of European descent, increases the inflammatory response and thrombotic risk in COVID-19.

• Dysregulation of CCL2 expression has been implicated in the pathogenesis of various health conditions, including Rheumatoid Arthritis, IBS, MCAS, breast cancer, fibromyalgia, chronic fatigue, chronic pain syndromes, POTS, connective tissue disease, Raynaud’s disease, pelvic congestion, ADHD, autism.

• APO E4 - The Apolipoprotein E allele 4 is a major genetic risk factor for Alzheimer's disease, as this lipid carrier is important for maintaining homeostasis necessary for a healthy environment of the brain.  This mutation is seen in around 15 to 20% of the general population, with 2-3% being homozygous with the increased risks that are associated.  This is emerging as a significant mutation in resistant cognitive impairment.

  • APO E is particularly concentrated in astrocytic processes at the pial surface and around the blood vessels.  In addition, the choroid plexus and tanycytes in the wall of the third ventricle also produce Apolipoprotein E. Thus, Apolipoprotein E production is co-localized with CSF production sites and transport pathways suggesting that lipids are transported by the glymphatic system. 

  • The glymphatic system is thought to play a central role in macroscopic distribution of lipids in the brain and that medium to large lipid soluble molecules might require carrier particles in order to be delivered via the CSF. Astrocytes thus play a key role in lipid synthesis and lipid distribution by releasing lipid carrier proteins, such as Apolipoprotein E, and in maintaining the highway for distribution, the glymphatic system.  

  • APO E4 mutation also affects arteries, significantly increasing coronary artery disease risk ,decreased mitochondrial function, decreased insulin sensitivity, increased insulin resistance, fatty liver and progression to cirrhosis (APO E4 contributing to altered VLDL metabolism and increased atherosclerosis).

The mechanical and other activators and drivers do not necessarily cause symptoms in other people.  DNA polymorphisms and sensitisation appears to make the difference, and while this list is incomplete, we are normally able to see the impact of mutations in POTS, Long Covid and comorbidities, eg Hashimoto’s and rheumatoid arthritis.   DNA can provide valuable clues to underlying metabolic dysfunction and may “tip the balance” as we strive to control underlying causes of our patients’ POTS and Co-morbidities.

Summary:

To summarize the management of POTS, there are accepted protocols which have been may control most POTS symptoms but this article then explores management beyond these basic protocols, based on addressing causes, rather than symptoms.

For many, recognition of the mixture of microglial and astrocyte dysfunction, the importance of secondary mast cell activation and then addressing posture, and physical “drivers” that typify POTS, using combinations of physiotherapy, diet and acupuncture, further improvements can be made.  

This article is one of a series in a portfolio on POTS, headed by “Assembling the Pieces in POTS,” and the accompanying documents in the POTS portfolio that detail research in each area.   Research is continuing, especially in the lymphatic obstruction of the lymphatic ducts and thoracic duct, as well as the paravertebral venous plexus and azygous systems.   With Covid, there has appeared to be a significant increase in particular “drivers” especially Median Arcuate Ligament Syndrome with its accompanying gastroparesis, as well as a major increase in ADHD.

We cannot as yet ascertain if these “rare diseases, especially MALS and SMA” signify the microglial -induced small fibre neuropathic central sensitization, or a change in collagen or both.   Improved radiological methods may also be a significant factor.  As we have no way to confirm these at present, so this remains a series of comparative observations.0

References:

1. Lau,D, Gallagher,C, Seeley, M. Postural orthostatic tachycardia syndrome. 2022. AusDoc Therapy Update. https://www.ausdoc.com.au/therapy-update/postural-orthostatic-tachycardia-syndrome/

2. Raj SR, Fedorowski A, Sheldon RS. Diagnosis and management of postural orthostatic tachycardia syndrome. CMAJ. 2022 Mar 14;194(10):E378-E385. doi: 10.1503/cmaj.211373. PMID: 35288409; PMCID: PMC8920526.

3. Blitshteyn S, Whiteson JH, Abramoff B, Azola A, Bartels MN, Bhavaraju-Sanka R, Chung T, Fleming TK, Henning E, Miglis MG, Sampsel S, Silver JK, Tosto J, Verduzco-Gutierrez M, Putrino D. Multi-disciplinary collaborative consensus guidance statement on the assessment and treatment of autonomic dysfunction in patients with post-acute sequelae of SARS-CoV-2 infection (PASC). PM R. 2022 Oct;14(10):1270-1291. doi: 10.1002/pmrj.12894. Epub 2022 Oct 8. PMID: 36169154; PMCID: PMC9538426.

4. Abed, H, Ball, P, Wang, L. Diagnosis and Management of postural orthostatic tachycardia syndrome: A brief review. 2012. J Geriatric Cardiol. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390096/#

5. Garland EM, Raj SR. Differential Diagnosis of Vasovagal Syncope: Postural Orthostatic Tachycardia. Vasovagal Syncope. 2014 Aug 6:179–88. doi: 10.1007/978-3-319-09102-0_14. PMCID: PMC7123721

6. Pizzorusso T, Tognini P. Interplay between Metabolism, Nutrition and Epigenetics in Shaping Brain DNA Methylation, Neural Function and Behavior. Genes (Basel). 2020 Jul 3;11(7):742. doi: 10.3390/genes11070742. PMID: 32635190; PMCID: PMC7397264.

7. Collister,J., Liu, X, Clifton,L. Calculating Polygenic Risk Scores (PRS) in UK Biobank: A Practical Guide for Epidemiologists. 2022. Front. Genet., https://www.frontiersin.org/articles/10.3389/fgene.2022.818574/full#:~:text=A%20polygenic%20risk%20score%20(PRS,genome%2C%20each%20of%20which%20can

8. Vittoni, V. DNA Mutations that Underpin POTS and Long Covid. 2023. https://www.mcmc-research.com/post/dna-mutations-that-underpin-pots-and-long-covid

9. Eaton‑Fitch et al. Impaired TRPM3‑dependent calcium influx and restoration using Naltrexone in natural killer cells of myalgic encephalomyelitis/chronic fatigue syndrome patients Journal of Translational Medicine https://doi.org/10.1186/s12967‑022‑03297‑8

10. Cabanas, H., Muraki, K., Eaton, N. et al. Loss of Transient Receptor Potential Melastatin 3 ion channel function in natural killer cells from Chronic Fatigue Syndrome/Myalgic Encephalomyelitis patients. Mol Med 24, 44 (2018)https://doi.org/10.1186/s10020-018-0046-1

11. Marshall-Gradisnik et al. Examination of Single Nucleotide Polymorphisms (SNPs) in Transient Receptor Potential (TRP) Ion Channels in Chronic Fatigue Syndrome Patients. Immunology and Immunogenetics Insights 2015:7 1–6 doi:10.4137/III.S25147.

12. Kaltoft,M et al. Lipoprotein(a) during COVID-19 hospitalization: Thrombosis,inflammation, and mortality. 2022. Athersclerosis https://doi.org/10.1016/j.atherosclerosis.2022.07.015

13. Sadhasivam S, Chidambaran V, Olbrecht VA, Esslinger HR, Zhang K, Zhang X, Martin LJ. Genetics of pain perception, COMT and postoperative pain management in children. Pharmacogenomics. 2014 Feb;15(3):277-84. doi: 10.2217/pgs.13.248. PMID: 24533707; PMCID: PMC4151110.

14. Zhao, C., Wang, Y., Zhang, B. et al. Genetic variations in catechol-O-methyltransferase gene are associated with levodopa response variability in Chinese patients with Parkinson’s disease. Sci Rep 10, 9521 (2020). https://doi.org/10.1038/s41598-020-65332-2

15. Moore, L, Le, T, Fan, nG. DNA Methylation and its basic Function. Neuropsychopharmacology. 2013. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3521964/

16. Methylation. Wikipedia. https://en.wikipedia.org/wiki/Methylation

17. Moore, L, Le, T, Fan, nG. DNA Methylation and its basic Function. Neuropsychopharmacology. 2013. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3521964/

18. Hulens M, Dankaerts W, Rasschaert R, Bruyninckx F, De Mulder P, Bervoets C. The Link Between Empty Sella Syndrome, Fibromyalgia, and Chronic Fatigue Syndrome: The Role of Increased Cerebrospinal Fluid Pressure. J Pain Res. 2023;16:205-219

19. Li T, Jing J, Sun L, et al. TLR4 and MMP2 polymorphisms and their associations with cardiovascular risk factors in susceptibility to aortic aneurysmal diseases. Biosci Rep. 2019;39(1):BSR20181591. Published 2019 Jan 8. doi:10.1042/BSR20181591

20. Zhong, Q., Zou, Y., Liu, H. et al. Toll-like receptor 4 deficiency ameliorates β2-microglobulin induced age-related cognition decline due to neuroinflammation in mice. Mol Brain 13, 20 (2020). https://doi.org/10.1186/s13041-020-0559-8

21. Zhang,P et al. Enhanced Glial Reaction and Altered Neuronal Nitric Oxide Synthase are Implicated in Attention Deficit Hyperactivity Disorder. Front. Cell Dev. Biol, 2022. https://doi.org/10.3389/fcell.2022.901093

22. Langan, M.T., Kirkland, A.E., Rice, L.C. et al. Low glutamate diet improves working memory and contributes to altering BOLD response and functional connectivity within working memory networks in Gulf War Illness. Sci Rep 12, 18004 (2022). https://doi.org/10.1038/s41598-022-21837-6

23. Brandley,E, Kirkland, A, Baron,M, Baraniuk, J, Holton,K. The Effect of the Low Glutamate Diet on the Reduction of Psychaitric Symptoms in Veterans with Gulf War Illness: A Pilot Randomized-Controlled Trial. Front. Psychiatry. 2022. https://www.frontiersin.org/articles/10.3389/fpsyt.2022.926688/full

24. Romanos J, Benke D, Pietrobon D, Zeilhofer HU, Santello M. Astrocyte dysfunction increases cortical dendritic excitability and promotes cranial pain in familial migraine. Sci Adv. 2020 Jun 5;6(23):eaaz1584. doi: 10.1126/sciadv.aaz1584. PMID: 32548257; PMCID: PMC7274778.

25. Li L, Acioglu C, Heary RF, Elkabes S. Role of astroglial toll-like receptors (TLRs) in central nervous system infections, injury and neurodegenerative diseases. Brain Behav Immun. 2021 doi: 10.1016/j.bbi.2020.10.007.

26. Khan S, Shafiei MS, Longoria C, Schoggins J, Savani RC, Zaki H. SARS-CoV-2 spike protein induces inflammation via TLR2-dependent activation of the NF-κB pathway. bioRxiv [Preprint]. 2021 Mar 17:2021.03.16.435700. doi: 10.1101/2021.03.16.435700. Update in: Elife. 2021 Dec 06;10: PMID: 33758854; PMCID

27. De Silva, M. The Costoclavicular Syndrome: a “new cause.”Annals of Rheumatic Diseases, 1986; 45, 916-920

28. Clough E, Inigo J, Chandra D, Chaves L, Reynolds JL, Aalinkeel R, Schwartz SA, Khmaladze A, Mahajan SD. Mitochondrial Dynamics in SARS-COV2 Spike Protein Treated Human Microglia: Implications for Neuro-COVID. J Neuroimmune Pharmacol. 2021 Dec;16(4):770-784. doi: 10.1007/s11481-021-10015-6. Epub 2021 Oct 2. Erratum in: J Neuroimmune Pharmacol. 2021 Dec 11;: PMID: 34599743; PMCID: PMC8487226.

29. Ho KKF, Walker P, Smithers BM, Foster W, Nathanson L, O'Rourke N, Shaw I, McGahan T. Outcome predictors in median arcuate ligament syndrome. J Vasc Surg. 2017 Jun;65(6):1745-1752. doi: 10.1016/j.jvs.2016.11.040. Epub 2017 Feb 8. PMID: 28189355.

30. Lai PC, Yen CM, Lin MC, Chen YH, Liao HY, Huang YW, Lin YW. Electroacupuncture Attenuates Fibromyalgia Pain via Toll-like Receptor 4 in the Mouse Brain. Life (Basel). 2023 May 11;13(5):1160. doi: 10.3390/life13051160. PMID: 37240805; PMCID: PMC10222451.

31. Liao HY, Lin YW. Electroacupuncture reduces cold stress-induced pain through microglial inactivation and transient receptor potential V1 in mice. Chin Med. 2021 Jun 3;16(1):43. doi: 10.1186/s13020-021-00451-0. PMID: 34082798; PMCID: PMC8173787

32. Karantanos,T., Markoutsaki,T., Gazouli,M., Anagnou, N., Karamanolius,D. Current insights in to the pathophysiology of Irritable Bowel Syndrome Gut Pathog. 2010; 2: 3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2876056

33. Patel, S, Singh A, Misra V, Misra, S, Dwivedi M, Trivedi P. Levels of interleukins 2, 6, 8, and 10 in patients with irritable bowel syndrome. Indian J Pathol Microbiol. 2017 Jul-Sep;60(3):385-389. https://www.ncbi.nlm.nih.gov/pubmed/28937377

34. Liu,l., Liu, B., Chen,S., Wang, M., Liu, Y., Zhang, Y, Yao, S. Visceral and somatic hypersensitivity, autonomic cardiovascular dysfunction and low- grade inflammation in a subset of irritable bowel syndrome patients Journal of Zhejiang University-SCIENCE B (Biomedicine & Biotechnology) 2014 15(10):907-914

35. Coss-Adame, E., Rao, S. Brain and Gut Interactions in Irritable Bowel Syndrome: New Paradigms and New Understandings Curr Gastroenterol Rep. 2014 April ; 16(4): 379. doi:10.1007/s11894-014-0379-z.

36. Margaret M. Leach, Craig Phillips, David Joffe, Charles Fisher, Michael Appleberg, Michael Jones, John E. Kellow, Irritable Bowel Syndrome Patients Exhibit Post-Prandial Autonomic Dysfunction. Gastroenterology. https://www.gastrojournal.org/article/S0016-5085(00)82623-2/pdf

37. Bashashati,M.,Moradi, M., Sarosiek,I.: Interleukin-6 in irritable bowel syndrome: A systematic review and meta-analysis of IL-6 (-G174C) and circulating IL-6 levels. Cytokine. 2017 Nov;99:132-138. doi: 10.1016/j.cyto.2017.08.017. Epub 2017 Sep 5. https://www.ncbi.nlm.nih.gov/pubmed/2888649

38. Freed,D: Do Dietary Lectins Cause Disease: BMJ 1999: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1115436

39. Natale,G et al. Glymphatic System as a Gateway to Connect Neurodegeneration from Periphery to CNS. 2021. Glymphatic System as a Gateway to Connect Neurodegeneration From Periphery to CNS. Front. Neurosci. 15:639140. doi: 10.3389/fnins.2021.6391

40. Nicolaides AN, Morovic S, Menegatti E, Viselner G, Zamboni P. Screening for chronic cerebrospinal venous insufficiency (CCSVI) using ultrasound: recommendations for a protocol. Funct Neurol. 2011 Oct-Dec;26(4):229-48. PMID: 22364944; PMCID: PMC3814564.

41. Ding J, Guan J, Rajah G, Dornbos D III, Li W, Wang Z, Ding Y, Ji X, Meng R. Clinical and neuroimaging correlates among cohorts of cerebral arteriostenosis, venostenosis and arterio-venous stenosis. Aging (Albany NY). 2019 Dec 2;11(23):11073-11083. doi: 10.18632/aging.102511. Epub 2019 Dec 2. PMID: 31790365; PMCID: PMC6932895.

42. Zhou D, Ding J, Asmaro K, Pan L, Ya J, Yang Q, Fan C, Ding Y, Ji X, Meng R. Clinical Characteristics and Neuroimaging Findings in Internal Jugular Venous Outflow Disturbance. Thromb Haemost. 2019 Feb;119(2):308-318. doi: 10.1055/s-0038-1676815. Epub 2019 Jan 3. PMID: 30605919.

43. Scholbach, T.: Diagnosis and treatment of vascular compression syndromes of the abdomen based on the anatomical features of man and gender-specific characteristics after puberty. https://scholbach.de/wp-content/uploads/2017/09/20170917-vascular-compression-syndromes-website.pdf

44. Van Campen, C.; Rowe, P.C.; Visser, F.. C Cerebral blood flow remains reduced after tilt testing in myalgic encephalomyelitis/chronic fatigue syndrome patients. Clinical Neurophysiology Practice. 2021. https://doi.org/10.1016/j.cnp.2021.09.001

45. Bulut,M et al. Decreased Vertebral Artery Hemodynamics in Patients with Loss of Cervical Lordosis. 2016. Med Sci Monit; 22:495-500 https://medscimonit.com/abstract/index/idArt/897500

46. Cole S. Bowdino; Justin Owens; Palma M. Shaw. Anatomy, Abdomen and Pelvis, Renal Veins, 2023. StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK538298/

47. Frydrychowski AF, Winklewski PJ, Guminski W (2012) Influence of Acute Jugular Vein Compression on the Cerebral Blood Flow Velocity, Pial Artery Pulsation and Width of Subarachnoid Space in Humans. PLoS ONE 7(10): e48245.

48. Chopra,P. Connecting the dots with EDS, POTS, MCAS, GI, Neurological and Physiotherapy in managing pain in EDA. Presentation. 2018. https://www.ehlers-danlos.com/wp-content/uploads/2022/12/2018-EDS-Webinar-Chopra.pdf

49. Reed, M, Kerndt,C, Nicolas, D. Ivabradine. StatPearls. 2023. https://www.ncbi.nlm.nih.gov/books/NBK507783/

50. Hung Y, Lin WH, Lin CS, Cheng SM, Tsai TN, Yang SP, Lin WY. The Prognostic Role of QTc Interval in Acute Myocarditis. Acta Cardiol Sin. 2016 Mar;32(2):223-30. doi: 10.6515/acs20150226a. PMID: 27122953; PMCID: PMC4816921.

51. Etheridge SP, Asaki SY. COVID-19 Infection and Corrected QT Interval Prolongation—Collateral Damage From Our Newest Enemy. JAMA Netw Open. 2021;4(4):e217192. doi:10.1001/jamanetworkopen.2021.7192

52. Aaron J. Schain,Agustin Melo-Carrillo, Andrew M. Strassman,Rami Burstein Cortical Spreading Depression Closes Paravascular Space and Impairs Glymphatic Flow: Implications for Migraine Headache. J Neurosci. 2017 Mar 15; 37(11): 2904–2915. doi: 10.1523/JNEUROSCI.3390-16.2017

53. Ebel, T. Your Baby’s Tongue Tie. 2023. https://www.thrivefamchiropractic.com/your-babys-tongue-tie/

54. Zamboni P, Galeotti R. The chronic cerebrospinal venous insufficiency syndrome. Phlebology. 2010 Dec;25(6):269-79. doi: 10.1258/phleb.2010.009083. PMID: 21106999.

55. Ryan, R. https://www.drrebeccaryan.com.au/blank-1

56. Vittone,V, Exelby, G. DNA Mutations that Underpin POTS and Long Covid. 2023. https://www.mcmc-research.com/post/dna-mutations-that-underpin-pots-and-long-covid

57. Malengier-Devlies B, Filtjens J, Ahmadzadeh K, Boeckx B, Vandenhaute J, De Visscher A, Bernaerts E, Mitera T, Jacobs C, Vanderbeke L, Van Mol P, Van Herck Y, Hermans G, Meersseman P, Wilmer A, Gouwy M, Garg AD, Humblet-Baron S, De Smet F, Martinod K, Wauters E, Proost P, Wouters C, Leclercq G, Lambrechts D, Wauters J, Matthys P. Severe COVID-19 patients display hyper-activated NK cells and NK cell-platelet aggregates. Front Immunol. 2022 Oct 5;13:861251. doi: 10.3389/fimmu.2022.861251. PMID: 36275702; PMCID: PMC9581751.

58. Di Vito C, Calcaterra F, Coianiz N, Terzoli S, Voza A, Mikulak J, Della Bella S, Mavilio D. Natural Killer Cells in SARS-CoV-2 Infection: Pathophysiology and Therapeutic Implications. Front Immunol. 2022 Jun 30;13:888248. doi: 10.3389/fimmu.2022.888248. PMID: 35844604; PMCID: PMC9279859.

59. van Eeden C, Khan L, Osman MS, Cohen Tervaert JW. Natural Killer Cell Dysfunction and Its Role in COVID-19. Int J Mol Sci. 2020 Sep 1;21(17):6351. doi: 10.3390/ijms21176351. PMID: 32883007; PMCID: PMC7503862.

60. Dalakas MC. Post-COVID Small Fiber Neuropathy, Implications of Innate Immunity, and Challenges on IVIG Therapy. Neurol Neuroimmunol Neuroinflamm. 2024 May;11(3):e200248. doi: 10.1212/NXI.0000000000200248. Epub 2024 Apr 17. PMID: 38630951.

61. The Central Sensitization Inventory. https://www.emdr-training.net/wp-content/uploads/2019/09/CSI_Inventory_and_Scoring.pdf 19. Malmo POTS Score. https://potsfoundation.org.au/wp-content/uploads/2023/03/Malmo-POTS-Score-vFinal.pdf
    

62. MSPQ. https://www.tac.vic.gov.au/files-to-move/media/upload/dram.pdf

63. Fatigue Severity Scale (FSS). https://www.sralab.org/sites/default/files/2017-06/sleep-Fatigue-Severity-Scale.pdf

64. Bell's Functionality Score. https://fibromyalgiaaustralia.org.au/wp-content/uploads/BellsFunctionalityScore.pdf