top of page

Extracellular Matrix Toxicity and Post-Exertional Malaise

  • Writer: Graham Exelby
    Graham Exelby
  • Jun 13
  • 3 min read

-The Role of Fascial-Lymphatic Obstruction and Brainstem Hypoxia in Long COVID and POTS


Dr Graham Exelby June 2025


Abstract: 

Emerging clinical observations suggest that post-exertional malaise (PEM) in Long COVID and POTS is not solely the result of intracellular energy failure, but may be sustained by the accumulation of neuroinflammatory and hypoxic metabolites within the extracellular matrix (ECM). This toxic burden appears exacerbated by lymphatic and glymphatic drainage failure.


Fascial decompression and targeted lymphatic therapy—including Vodder-style manual lymphatic drainage (MLD)—have been shown to resolve PEM and head pressure in real-time. This paper integrates anatomical, metabolic, and immunological insights to propose a unifying mechanism linking impaired interstitial drainage, ECM toxicity, brainstem hypoperfusion, and sustained neuroimmune sensitization.


1. Introduction: 

Post-exertional malaise is a defining feature of ME/CFS, Long COVID, and POTS, characterized by a disproportionate symptom flare following minimal exertion. Traditional models emphasize mitochondrial dysfunction and impaired energy metabolism. However, novel lymphatic therapies now suggest that PEM can be reversed by mechanical fascial decompression, pointing to the ECM and lymphatic system as active pathophysiological players.


2. Clinical Observation: 

Michelle Hill, lymphatic therapist and researcher, using Vodder manual therapy reports that in patients with PEM and head pressure, opening the cervical, axillary, and parasternal lymphatics in supine position, followed by seated decompression at T8, results in:

  • Immediate reduction in interscapular and suprascapular oedema

  • Resolution of head pressure

  • Significant reduction in PEM symptoms


These outcomes appear linked to the mechanical release of thoracic duct and spinal lymphatic bottlenecks, restoration of glymphatic outflow, and decompression of the cranial venous system. The seated T8 decompression may also influence splanchnic congestion, indirectly improving cerebrospinal and lymphatic drainage.


3. Molecular Hypothesis: ECM Toxicity and Glymphatic Failure 

Hypoxia in Long COVID and POTS (due to impaired vertebrobasilar flow, IJV obstruction, TOS, or MALS) leads to accumulation of:

  • Lactate, succinate (metabolic byproducts)

  • HMGB1, S100A8/9 (DAMPs)

  • Glutamate, ATP, purines (excitotoxins)

  • Advanced glycation endproducts (AGEs)


These ligands activate RAGE, TLR4, P2X7, and mast cell receptors in perivascular and interfascial spaces. Without adequate glymphatic or lymphatic clearance, these molecules perpetuate neuroinflammation, excitotoxicity, and autonomic dysregulation. The net clinical result is PEM, head pressure, and sympathetic overdrive.


4. Anatomical-Mechanical Convergence Points:

Several mechanical choke points appear to modulate interstitial congestion and symptom expression:

  • T8 rotation: Possibly a postural adaptation to splanchnic venous pooling (e.g., from MALS), which increases thoracic duct impedance.

  • C1 fascial tension: The myodural bridge may restrict CSF egress from the 4th ventricle. C1 decompression often restores vagal tone and glymphatic pulse waves.

  • Low-lying cerebellar tonsils: These can cause intermittent crowding at the foramen magnum, obstructing venous and lymphatic drainage when upright.


Each of these sites represents a physical barrier to interstitial clearance. Their release may allow resolution of the ECM-mediated inflammatory loop underpinning PEM.


5. Therapeutic Implications:

  • Manual lymphatic drainage (MLD), specifically targeting the thoracic inlet, cervical fascia, and T8 transition zone, appears capable of rapidly relieving PEM. This should be integrated into early-stage therapy protocols for POTS and Long COVID.

  • Fascial release techniques at C1 and the diaphragmatic crura may restore brainstem glymphatic outflow and normalize vagal parasympathetic tone.

  • Adjunctive therapies:

    • Antioxidants (N-acetylcysteine, alpha-lipoic acid) to buffer ROS from retained metabolites;

    • Mast cell stabilizers (e.g., cromolyn, H1/H2 blockers) to dampen perivascular reactivity;

    • Positional therapy: 45° head-up positioning to facilitate cranial lymphatic egress.

  • Targetted metabolic therapy under investigation, may enhance lymphatic endothelial function and ECM repair.

  • Telmisartan, as a dual ARB and PPAR-γ agonist, reduces RAGE expression and modulates HIF-1α, improving perfusion and interstitial homeostasis.


6. Conclusion: 

PEM, traditionally viewed as a post-viral metabolic collapse, may instead reflect a failure of ECM detoxification and interstitial clearance. Glymphatic stagnation, fascial tension, and thoracic duct congestion trap immunotoxic ligands in vulnerable CNS regions, perpetuating RAGE-driven neuroinflammation. Manual lymphatic therapy offers immediate reversal of these symptoms in responsive patients, highlighting a mechanical-immunological axis central to recovery.


This perspective invites a shift in clinical strategy: from biochemical support alone to multimodal protocols integrating MLD, fascial release, positional therapy, and targeted immune modulation. Future studies should prioritize dynamic imaging of ECM fluid dynamics and controlled trials of lymphatic-based interventions in POTS and Long COVID.

 

 
 
 

Recent Posts

See All

Comentarios


bottom of page