Breaking Through in POTS and Long Covid

Revised April 2025. Dr Graham Exelby

We have moved away from the traditional model of treating POTS, CFS, Long COVID, and Fibromyalgia symptomatically. Instead, we now target the underlying causes—addressing the actual disruptions in the body’s physiology, immune signalling, and circulation that drive these syndromes. This shift has provided breakthrough insights into what we now believe are the “access points” to treatment for many patients.

Emerging research from Griffith University (CFS) and Georgetown University (Gulf War Syndrome), along with our clinical data, shows these conditions share a core pathophysiology: brainstem hypoxia. Whether triggered by viruses, trauma, mould exposure, stress, or immune activation, this hypoxia impairs autonomic function and alters neurovascular control. Our work has focused on identifying why this happens and how it can be reversed.

Investigations documented in our POTS papers detail how brainstem hypoxia, autonomic dysfunction, and intracranial pressure dysregulation often stem from mechanical and vascular obstructions. These include:

• Thoracic Outlet Syndrome (TOS)

• Internal Jugular Vein (IJV) compression,

• Cervical Vertebral Vein obstruction,

• Median Arcuate Ligament Syndrome (MALS),

• Superior Mesenteric Artery (SMA) and Nutcracker Syndromes, and

• Pelvic Congestion and May-Thurner Syndromes.

• Cervical spine trauma / Ehlers Danlos Syndrome, heat forward posture

These structural issues impair venous and lymphatic flow, contributing to intracranial hypertension and sensitization.

Using advanced metabolic profiling (e.g., amino acid assays) and brain SPECT imaging, we’ve developed a more accurate picture of these conditions. Our framework is outlined in Beyond the Symptoms: Targeting Underlying Mechanisms in POTS, which details the metabolic, inflammatory, and vascular patterns driving patient symptoms.

Recent reanalysis of genetic data (in collaboration with Dr Valerio Vittone) revealed a common immune-inflammatory signature: DAMP-mediated activation of the RAGE and TLR4 receptors, driving NF-κB and CCL2 signalling in a damaging feedback loop. This cascade underpins persistent inflammation and central sensitization in many patients.

We now recognize mast cell activation as a key amplifier of this process, particularly in impairing lymphatic function. Addressing mast cell activity, improving lymphatic flow, and modulating RAGE/TLR signalling have enhanced our treatment protocols significantly.

Crucially, research into COVID-19 has validated this model. SARS-CoV-2 activates the same threat receptors, triggering mast cells and leading to the cytokine storm. This provides a clear mechanistic bridge between POTS, Long COVID, Fibromyalgia, and immune dysregulation.

POTS Scanning Breakthroughs

Figure 1: 3D Reconstruction of Head and Neck Vasculature

Courtesy Dr Zane Sherif. Mermaid Beach Radiology

In July 2023, we implemented a world-first Spectral CT scan combining arteriography and venography in a single imaging session. When paired with brain SPECT and MRI, this approach has revealed the likely mechanical causes of symptoms like brain fog and pressure headaches—especially identifying IJV compression at C1 and venous outflow obstruction at the base of the neck (typically from TOS).

We also screen for abdominal and pelvic venous compression syndromes (Nutcracker, MALS, SMA, May-Thurner), which reroute blood into the valveless vertebral venous plexus. This vertebral rerouting is a driver of head pressure in POTS patients, and we believe, in combination with anomalies in the Azygous venous system are a significant component of the preload dysfunction that typifies the shortness of breath in POTS.

Because these CT (and MRI) scans are done supine, we usually follow up with dynamic Doppler ultrasound—a key tool developed by sonographers Rylee White and Dani Avey (Australian Ultrasound Specialists, Miami). Their technique can reveal postural vertebral venous abnormalities, which correspond with positional symptom changes as well as in the other compression areas.

Additionally, we have begun mapping lymphatic flow disruptions, especially in the neck, which often accompany venous compression. This step has been crucial in cases of chronic swelling especially of the head and neck, lipoedema, and poor detoxification.

Other important tools include:

• Dynamic cervical X-rays (neutral, flexion, extension) to assess loss of lordosis, flexion kyphosis, and structural abnormalities like incomplete C1 and listhesis.

• MRI venography of the brain, particularly in post-COVID patients with head pressure or pulsatile tinnitus. These require specialist neuroradiological interpretation to differentiate true stenosis from anatomical variation, such as arachnoid granulations or congenital sinus anomalies.

Conclusion

This evolving work represents a leap forward in understanding POTS, CFS, Long COVID, and related syndromes. What were once considered separate “mystery illnesses” are now being unified by a coherent model involving brainstem hypoxia, mechanical vascular compression, immune-metabolic dysregulation, and lymphatic stagnation. Our clinic is committed to delivering individualized care based on these insights, and we are optimistic that this integrated approach offers real hope for lasting improvement. We understand the long journey many patients have endured—and while the answers haven’t come easily, they are now coming into focus.