Dysautonomia in Clinical Practice

Dr Graham Exelby May 2025

Introduction

Dysautonomia refers to a range of conditions caused by dysfunction in the autonomic nervous system (ANS). This includes Postural Orthostatic Tachycardia Syndrome (POTS), Long COVID, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and fibromyalgia.

Patients often present with multisystem symptoms—palpitations, fatigue, lightheadedness, gastrointestinal disturbance, thermoregulatory issues, and brain fog—that defy traditional diagnostic categories. This document outlines a clinically relevant, simplified view of dysautonomia as a disorder driven by chronic inflammation, energy failure, and brainstem–autonomic plexus dysfunction.

The Core Mechanism: Immune and Metabolic Overload

Emerging research shows that chronic low-grade inflammation can overstimulate the nervous system. A key player is TLR4, a receptor activated by infections, stress, toxins, and even certain foods. Once activated, it triggers a cascade of immune signals—including NF-κB, CCL2 (MCP-1), and RAGE—which amplify inflammation and increase sensitivity in the brain’s control centres. This process is referred to as neuroimmune sensitization.

In parallel, patients often show signs of mitochondrial dysfunction, particularly involving enzymes like pyruvate dehydrogenase (PDH). This leads to impaired cellular energy production and a buildup of lactate—explaining the fatigue, exertional intolerance, and chronic pain seen in dysautonomia.

Brainstem Hypoxia and Plexus Dysfunction

The brainstem—specifically the medulla oblongata and the rostral ventrolateral medulla (RVLM)—serves as the central command centre for autonomic regulation. Within this hub, the nucleus tractus solitarius (NTS) integrates baroreceptor and visceral afferent signals and communicates with the dorsal motor nucleus of the vagus and sympathetic premotor neurons in the RVLM. These nuclei regulate descending output to both the cardiac and coeliac plexuses via sympathetic fibres originating from the intermediolateral columns of the spinal cord (T1–T12), and parasympathetic fibres via the vagus nerve.

The cardiac plexus receives sympathetic input from T1–T4 via the cervical and stellate ganglia and parasympathetic fibres from the vagus nerve. It modulates heart rate, contractility, and coronary tone.

The coeliac plexus, in contrast, integrates sympathetic fibres from T5–T12 via the greater, lesser, and least splanchnic nerves, along with parasympathetic vagal and phrenic inputs. It governs splanchnic perfusion, gastrointestinal motility, adrenal output, and reno-mesenteric tone.

Brainstem hypoperfusion or inflammation impairs vagal efferent tone and promotes sympathetic excess, leading to a dual plexus phenotype. Cardiac plexus dysfunction manifests as inappropriate sinus tachycardia, baroreflex failure, and preload reduction.

Simultaneously, coeliac plexus dysfunction produces excessive splanchnic pooling, orthostatic intolerance, and gastrointestinal dysmotility. These outcomes are compounded by feedback loops involving glial priming, mast cell activation, and peripheral neuropeptide release (e.g., Substance P, CGRP, VIP), which sustain excitatory signalling in both plexuses.

Importantly, the sympathetic chain exhibits anatomical continuity from cervical to thoracic to abdominal levels, allowing pathological signals—such as from vertebral or fascial compression—to propagate bidirectionally across these nodes. Consequently, localized mechanical insult (e.g., T8 vertebral rotation or thoracic outlet obstruction) may produce system-wide dysautonomic effects via convergence on the central-autonomic axis.

The brainstem is the control hub for autonomic function. In dysautonomia, poor blood and lymphatic drainage—often due to structural problems like thoracic outlet syndrome, jugular vein compression, or spinal misalignment—can cause hypoxia in these brain regions. Hypoxic stress worsens mitochondrial function and promotes a state of immune overactivation.

This affects two critical autonomic relay stations:

• The cardiac plexus, leading to inappropriate heart rate changes and poor preload.

• The coeliac plexus, which controls gut, adrenal, and kidney function—resulting in nausea, bloating, hypotension, and fatigue.

  
  

The Role of Mast Cells and Glial Cells

Mast cells (immune cells involved in allergic responses) and glial cells (immune cells in the brain) work together to amplify signals of danger. Once activated, they create a feed-forward loop that sustains inflammation and makes patients hypersensitive to exertion, noise, temperature, and even food. This is often mistaken for anxiety or somatization.

Toll-like receptor (TLR) activation

Toll-like receptor 4 (TLR4) operates as a critical gatekeeper of innate immune surveillance, responsive to both exogenous pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS) and endogenous damage-associated molecular patterns (DAMPs) including HMGB1, S100A8/A9, and fibrinogen breakdown products.

1.     Microglia: The Brain's Innate Immune Sentinels

Microglia are the resident macrophages of the central nervous system and serve as the brain’s primary innate immune sensors. Under physiological conditions, they maintain synaptic homeostasis, prune neural circuits, and monitor the extracellular environment. However, in the setting of TLR4 or RAGE activation, microglia rapidly transition into a pro-inflammatory phenotype, releasing cytokines (e.g. TNF-α, IL-1β), chemokines (notably CCL2), and reactive oxygen species.

NF-κB is the central transcriptional driver of this activation. Critically, this microglial reactivity can be prolonged and region-specific—particularly affecting the nucleus tractus solitarius (NTS), locus coeruleus, and hypothalamus, which are integral to autonomic control.  Sustained microglial activation contributes to baroreceptor dysfunction, sympathetic overactivity, and central sensitization seen in POTS and ME/CFS. In some patients, chronic microglial priming creates a state of "neuroimmune memory", amplifying responses to otherwise innocuous stimuli and promoting autonomic instability.

2.     Astrocytes: Metabolic Modulators and Inflammatory Amplifiers

Astrocytes are glial cells with extensive metabolic and structural roles, forming part of the blood–brain barrier and modulating neuronal excitability, ion balance, and neurotransmitter clearance. In neuroinflammatory conditions, they act as key amplifiers of immune signalling. Activated by IL-1β, HMGB1, and CCL2, astrocytes upregulate RAGE and TLR4, becoming active participants in the NF-κB signalling cascade.

Their activation results in production of IL-6, glutamate, and S100B, all of which worsen neuronal excitotoxicity and glial crosstalk.

• Glutamate release occurs via vesicular mechanisms involving Synaptotagmins 4/7/11 and Gq-coupled receptors (e.g., P2Y1R), influencing synaptic plasticity through extrasynaptic NMDA receptors. (de Ceglia et al. 2023 (1)) (Cuellar-Santoyo et al.2023 (2))

• IL-6 secretion is upregulated by inflammatory signals (IL-1β, TNF-α)    (Codeluppi et al. 2014 (3)) or TLR4 activation. (Krasovska & Doering.  2018 (4)

• S100B production modulates astrocyte morphology/migration via Src-PI3K pathways, and amplifies nitric oxide release in glia, with autoregulatory feedback controlling its expression. (Brozzi et al.  2009 (5) (Hernández-Ortega et al. 2024. (6)) (Petrova et al 2000(7))

Importantly, astrocytes respond to hypoxia and mitochondrial dysfunction, further linking them to the metabolic phenotype seen in Long COVID and chronic dysautonomia. In POTS, dysregulated astrocytes may impair neurovascular coupling and blood–brain barrier integrity, contributing to symptoms such as brain fog, orthostatic headaches, and central fatigue.

3.     Mast Cells: Peripheral Sensors with Central Impact

Mast cells are best known for their role in allergic responses, but they also play a central role in sterile inflammation and neuroimmune crosstalk. Located strategically around blood vessels, nerve endings, and autonomic ganglia, mast cells are activated not only by IgE, but also by DAMPs, cytokines, CRH, and neuropeptides.

Once activated, they degranulate, releasing histamine, tryptase, prostaglandins, leukotrienes, and importantly, TNF-α and IL-6, which directly stimulate microglial and astrocytic activation. Mast cells also express TLR4 and RAGE, allowing them to be directly activated by LPS, HMGB1, and oxidative stress.

This places them as first responders in the periphery and CNS, contributing to vascular permeability, postural tachycardia, brainstem neuroinflammation, and central pain amplification. In many patients with POTS and ME/CFS, mast cell overactivity (even without classic MCAS) manifests as flushing, hives, GI dysmotility, and labile blood pressure—linking immune dysregulation with autonomic instability.

4.     NF-κB: The Master Switch of Inflammation

Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a pivotal transcription factor acting as the master regulator of the innate immune response. It is rapidly activated in response to diverse cellular stressors—including pathogen-associated molecular patterns (PAMPs) via Toll-like receptors, damage-associated molecular patterns (DAMPs) via RAGE, as well as cytokines like TNF-α and IL-1β, hypoxia, and oxidative stress.

Once activated, NF-κB translocates to the nucleus where it induces transcription of hundreds of pro-inflammatory genes including CCL2, IL-6, TNF-α, COX-2, and iNOS, (all if which have been noted in DNA studies in POTS and Long-COVID by Vittone and Exelby.2023 (9) to have DNA mutations present.)  This effectively sustains a chronic inflammatory loop.

In dysautonomia and related post-viral syndromes, NF-κB activation drives neuroinflammation, endothelial dysfunction, mitochondrial stress, and autonomic dysregulation. Notably, it primes glial cells, sensitizes baroreflex circuits, and promotes perivascular immune cell recruitment.

Chronic or inappropriate NF-κB signalling contributes to a feed-forward loop in which sterile inflammation becomes self-sustaining—independent of ongoing infection—and underlies the persistent symptoms seen in POTS and Long COVID.

Therapeutic approaches targeting NF-κB directly are under investigation, but upstream modulation via TLR4/RAGE blockade, N-acetylcysteine, low-dose naltrexone, or nicotinamide derivatives offers more practical clinical potential.

5.     RAGE: A Perpetuator of Sterile Inflammation and Neuroimmune Crosstalk

The Receptor for Advanced Glycation End Products (RAGE) is an underrecognized but critically important pattern recognition receptor (PRR) involved in sustaining sterile inflammation—that is, inflammation not caused by pathogens but by endogenous stress signals.

RAGE binds a range of ligands including HMGB1, S100 proteins, amyloid fibrils, oxidized lipids, and advanced glycation end products (AGEs)—many of which are elevated in tissue hypoxia, oxidative stress, or metabolic dysfunction. Once activated, RAGE initiates intracellular signalling cascades that culminate in NF-κB activation, amplifying production of CCL2, IL-6, and other inflammatory mediators.

In dysautonomia, RAGE is particularly relevant to vascular inflammation, endothelial barrier dysfunction, microglial activation, and central sensitization. Its expression is heightened in the brainstem and peripheral nerves under conditions of chronic hypoxia or mitochondrial impairment—both key features in POTS and post-COVID syndromes.

RAGE also localizes to cerebral endothelial cells, vagal afferents, and the coeliac and cardiac plexuses, placing it anatomically and mechanistically at the centre of autonomic disruption.

Importantly, RAGE activation is not self-limiting; it amplifies its own ligands through oxidative feedback, establishing a pathological positive feedback loop. This makes it a critical target in conditions driven by unresolved immune activation, with famotidine, nicotinamide, and TLR4-RAGE inhibitors offering potential avenues for intervention.

6.     CCL2 (MCP-1) and Its Role in Dysautonomia

Chemokines are small signalling molecules, part of the broader cytokine family, that play a crucial role in directing the movement of cells, particularly leukocytes, to areas of inflammation or other biological needs. They act by binding to specific receptors on the surface of cells, triggering signals that lead to cell migration and chemotaxis (movement in response to a chemical stimulus).  

CCL2, also known as monocyte chemoattractant protein-1 (MCP-1), is a key chemokine that orchestrates immune cell trafficking, particularly the recruitment of monocytes, memory T cells, and dendritic cells to sites of tissue inflammation.  

Although largely unfamiliar to most clinicians, CCL2 plays a pivotal role in neuroimmune dysregulation, particularly in conditions such as POTS, Long COVID, and ME/CFS where chronic low-grade inflammation persists without overt infection.

CCL2 expression is tightly regulated but becomes markedly upregulated in response to a broad range of innate immune stimuli—most notably through TLR4, RAGE (receptor for advanced glycation end products), IL-1β, TNF-α, and oxidative stress-induced NF-κB activation.

Once engaged, CCL2 establishes a feed-forward loop of inflammation and tissue infiltration, particularly in the central nervous system and autonomic ganglia, where it has been shown to activate microglia, enhance sympathetic tone, and sustain mast cell–T cell–glial crosstalk.

In dysautonomia, especially POTS, elevated CCL2 levels may reflect a persistent "sterile inflammation" phenotype, linking metabolic dysfunction, endothelial injury, and neuroimmune activation. Its overexpression also correlates with impaired baroreceptor sensitivity and brainstem gliosis in experimental models.

Importantly, CCL2 signalling is attenuated by agents such as famotidine (via modulation of histamine and IL-6), N-acetylcysteine, and upstream blockade of TLR4/RAGE pathways, offering emerging therapeutic relevance.

Genetic variations in the CCL2 gene are associated with an increased risk of developing a wide number of  diseases by activating signalling pathways, including JAK/STAT and NF-κB which can influence cell behaviour, survival, and gene expression across different cell types and tissues.

CCL2 has been identified as a mediator that can be released by activated mast cells, and elevated levels of CCL2 have been found in the serum of patients with Mast cell activation syndrome (MCAS).  CCL2 is a potent activator of mast cells, which are implicated in many POTS patients.  Mast cell degranulation releases histamine and other mediators, exacerbating vasodilation and vascular permeability, tachycardia and orthostatic symptoms.

Dysregulation of CCL2 expression has been implicated in the pathogenesis of various health conditions, including Rheumatoid Arthritis (10), IBS (11), fibromyalgia (12), chronic fatigue (13), chronic pain syndromes (14), POTS, connective tissue disease (15), ADHD (16), autism (17)(18). 

POTS Connection:

CCL2 has been found to be elevated in the serum of patients with POTS, as well as in autonomic dysfunction, suggesting a role for CCL2 in the autonomic dysfunction associated with this condition.  

• Chronic CCL2-mediated inflammation may contribute to sensitize adrenergic receptors, leading to sympathetic overactivity.  This manifests as exaggerated tachycardia and other autonomic symptoms upon standing.

• CCL2 has also been associated with vascular dysregulation and endothelial dysfunction (19) and is thought may contribute to the disruption of the blood-brain barrier (20)

• Elevated CCL2 levels are thought to perpetuate local inflammation and fibroblast activity, leading to collagen and fascia remodelling that impairs lymphatic drainage and contributes to persistent compression. (21)

• CCL2 expression is hypothesized to be associated with other vascular compression syndromes (e.g., May-Thurner, Nutcracker).    CCL2 promotes the recruitment of inflammatory cells, which is critical in local inflammation in compressed areas.

• There is an emerging link involving CCL2 dysregulation and hypoxia-driven lysine dysregulation seen when clinic amino acid results are integrated into these pathways.   Modelling suggests that low lysine is not simply a secondary metabolic marker, but a contributing factor to connective tissue pathology when coupled with chronic CCL2-driven immune activation.  Lysine levels are frequently improved with addition of liposomal nicotinamide riboside.

• Elevated CCL2 can disrupt the function of the paraventricular nucleus (NTS) and hypothalamic paraventricular nucleus (PVN,) critical brainstem regions involved in autonomic regulation.  The PVN projects to the brainstem, particularly to areas involved in autonomic regulation like the rostral ventrolateral medulla (RVLM) and nucleus tractus solitarius (NTS). This projection allows the PVN to influence cardiovascular and respiratory function, and it is also involved in the brain's response to immune challenges. 

• CCL2 and its receptor CCR2 are expressed in central autonomic control centres like the PVN and rostral ventrolateral medulla.(30)   This can result in altered sympathetic outflow to cardiovascular organs, changes in blood pressure regulation and disruption of respiratory control.(22)(23)

• Migraine with aura: CCL2 has been implicated in the inflammation and pain associated with migraine including with aura (which has an association with dysfunction of the Locus Coeruleus and Glymphatic closure,) and implies an association with brainstem hypoxia.

Fibromyalgia Connection

Fibromyalgia (FM) is characterized by widespread musculoskeletal pain, fatigue, and cognitive disturbances. Emerging evidence suggests that CCL2 contributes to FM pathogenesis.  (García-Domínguez 2025.(24))(Zhao et al. 2019 (25))

• Elevated levels: Patients with FM exhibit increased plasma concentrations of CCL2, correlating with symptom severity.

• Mast cell interaction: CCL2 acts as a chemoattractant for mast cells, which are found in increased numbers in FM patients. Activated mast cells release substances that sensitize nociceptors and contribute to pain. 

• Neuroinflammation: CCL2-mediated activation of glial cells in the central nervous system leads to a pro-inflammatory environment, promoting central sensitization and chronic pain.

• Duloxetine, arguably the most effective therapy to control fibromyalgia pain may work in FMS and overlapping dysautonomia not just via serotonin–norepinephrine reuptake inhibition, but also through downregulation of CCL2, which is central to central sensitisation, mast cell–glial crosstalk, and immune-driven fatigue and pain.

CCL2 and Chronic Pain

CCL2 has been implicated in the pathogenesis of chronic pain, and elevated levels of CCL2 have been found in the serum and cerebrospinal fluid of patients with chronic pain conditions.  CCL2 is upregulated in response to peripheral inflammation and nerve injury. It binds to its receptor CCR2 on various cells, including neurons and glial cells, leading to:

• Recruitment of immune cells: CCL2 attracts monocytes/macrophages to sites of injury, contributing to sustained inflammation. 

• Neuronal sensitization: CCL2 enhances excitatory synaptic transmission in the spinal cord by increasing NMDA receptor activity, particularly through the ERK-GluN2B signalling pathway. 

• Glial activation: CCL2 stimulates astrocytes and microglia, leading to the release of pro-inflammatory cytokines and further amplification of pain signals

Other areas where CCL2 dysregulation is implicated:

• Breast cancer: CCL2 has been implicated in the growth and spread of breast cancer cells, and high levels of CCL2 have been associated with a poor prognosis.(26)

• Connective tissue disease: CCL2 has been implicated in the pathogenesis of connective tissue diseases, including systemic sclerosis and rheumatoid arthritis.  

• Chronic fatigue: Elevated levels of CCL2 have been found in the serum of patients with chronic fatigue syndrome (CFS), suggesting a role for CCL2 in the pathogenesis of this condition.(27) It seems likely this reflects CCL2 activation from hypoxia.

• Hypertension: CCL2 has been found to be elevated in the serum of patients with hypertension, and has been implicated in the pathogenesis of hypertension.

• Raynaud’s: CCL2 has been implicated in the pathogenesis of Raynaud's phenomenon, a condition characterized by constriction of the blood vessels in the fingers and toes in response to cold or stress.

• IBS: There is some evidence that CCL2 may be involved in the inflammation and pain associated with irritable bowel syndrome (IBS). Elevated levels of CCL2 have been found in the intestinal mucosa of patients with IBS.

To visually represent the intricate interplay between TLR4 signalling, RAGE activation, CCL2 expression, and the subsequent neuroimmune sensitisation involving glial and mast cell interactions, the following schematic diagrams encapsulate these pathways:

Figure 1. TLR4 and RAGE Signalling Integration: This diagram illustrates the convergence of TLR4 and RAGE pathways upon stimulation by ligands such as LPS and HMGB1, leading to downstream activation of NF-κB and MAPK pathways.

Figure 2. Glial-Mast Cell Interactions in Neuroinflammation: This figure depicts the bidirectional communication between mast cells, microglia, and astrocytes, highlighting the mediators involved in neuroinflammatory processes.

Source: Carthy, Elliott & Ellender, Tommas. (2021). Histamine, Neuroinflammation and Neurodevelopment: A Review. Frontiers in Neuroscience (28)

Figure 3. TLR4 Signalling Pathway Overview: This schematic provides a comprehensive overview of the TLR4 signalling cascade, including both MyD88-dependent and TRIF-dependent pathways, culminating in the production of pro-inflammatory cytokines.

Source: Mantovani S, Oliviero B, Varchetta S, Renieri A, Mondelli MU.(2023)TLRs: Innate Immune Sentries against SARS-CoV-2 Infection. Int J Mol Sci.(29)

Figure 4. CCL2/CCR2 Axis in Inflammation: This diagram focuses on the role of the CCL2/CCR2 axis in mediating inflammatory responses, particularly in the context of TLR4 activation and its implications in neuroinflammation.

Source: Zhang et al.(2022) Role of the CCL2-CCR2 axis in cardiovascular disease: Pathogenesis and clinical implications. (30)

These visual representations can serve as valuable tools to elucidate the complex mechanisms underpinning TLR4-mediated neuroimmune sensitisation and its relevance to conditions such as POTS and Long COVID.

Summary: TLR4–RAGE–CCL2 Axis in Neuroimmune Sensitization

From Priming to Perpetuation: Microglial Activation and Glial–Mast Cell Looping

Once TLR4 priming is established, the central nervous system becomes increasingly susceptible to persistent neuroinflammation. Microglia, the brain’s resident immune sentinels, undergo a shift from a surveillance  to a reactive phenotype, driven by repeated TLR4–RAGE stimulation and metabolic stress. In this state, microglia exhibit heightened expression of NF-κB, NLRP3 inflammasome components, and pro-inflammatory cytokines including IL-1β, TNF-α, and CCL2—all of which reinforce further TLR4 engagement. Critically, microglial activation does not occur in isolation.

Astrocytes—particularly A1-reactive phenotypes—respond to these inflammatory cues by releasing excess glutamate, downregulating glutamate transporters (e.g., GLT-1/EAAT2), and reducing GABAergic tone. This creates a state of excitotoxic amplification, especially vulnerable in the brainstem, hypothalamus, and limbic networks governing autonomic and endocrine regulation.

Mast cells, strategically located along perivascular and dural surfaces as well as within the median eminence and hypothalamus, respond in parallel. Via CRH, IL-33, and substance P, they contribute to microglial recruitment and amplify central sensitisation.

The loop becomes self-sustaining: mast cell mediators (histamine, tryptase, leukotrienes) activate microglia, while microglial-derived CCL2, IL-1β, and ROS further stimulate mast cell degranulation. This glial–mast cell feedback circuit is reinforced under conditions of metabolic insufficiency, hypoxia, or impaired GABA/aspartate cycling—all common in POTS, ME/CFS, and Long COVID.

Ultimately, this establishes a maladaptive central sensitisation complex, no longer dependent on peripheral triggers. Instead, immune memory, metabolic dysfunction, and neuroglial cross-talk drive a persistent hypersensitive state, destabilising baroreflexes, autonomic tone, and systemic homeostasis.

Key Components:

1. TLR4 Activation:

   • Engaged by PAMPs (e.g., LPS) and DAMPs (e.g., HMGB1, S100A8/A9).

   • Utilizes co-receptors MD-2 and CD14 for ligand recognition.

   • Initiates MyD88-dependent and TRIF-dependent signalling pathways.

2. RAGE Engagement:

   • Activated by advanced glycation end-products (AGEs) and DAMPs like HMGB1.

   • Amplifies inflammatory signalling cascades synergistically with TLR4.

3. Downstream Signalling:

   • Activation of NF-κB and MAPK pathways leading to transcription of pro-inflammatory cytokines.

   • Induction of CCL2 (MCP-1) expression, promoting monocyte recruitment.

4. Neuroimmune Sensitization:

   • CCL2-mediated recruitment of immune cells to the CNS.

   • Microglial and astrocyte activation perpetuating neuroinflammation.

   • Mast cell degranulation contributing to blood-brain barrier permeability and further immune cell infiltration.

Diagnostic Clues

• Symptoms worsen with standing, eating, or exertion

• Fatigue not relieved by rest

• Palpitations or presyncope with normal heart structure

• Flushing, hives, or food intolerances

• Poor tolerance of medications or supplements

• Strong symptom fluctuation with infection, stress, or weather changes

Investigations may include:

• (Tilt table) or NASA Lean test (to confirm orthostatic intolerance)

• Plasma and urinary amino acid profiling (e.g., low GABA, lysine, aspartate)

• Brain MRI (ideally with venography if post-COVID for dysfunctional dural sinuses, aberrant arachnoid granulations or white matter changes, especially if head pressure increases when erect, and more so if there is pulsatile tinnitus)

• D-dimer and inflammatory markers in post-viral cases

Management Principles

Treatments should address three levels:

1. Immune Modulation

   • Low-dose naltrexone (LDN) to calm immune signalling

   • Famotidine (not just as a stomach acid reducer, but also to reduce inflammation)

   • Ketotifen or cromolyn for mast cell stabilization

2. Mitochondrial Support

   • Nicotinamide riboside to support NAD+ metabolism

   • Alpha-lipoic acid and N-acetylcysteine (NAC) for redox balance

   • Amino acid supplementation tailored to metabolic profiles

3. Structural and Postural Therapy

   • Assessment for thoracic outlet syndrome, vertebral strain (especially at T8), and jugular vein obstruction

   • Physiotherapy focused on posture, lymphatic flow, and diaphragmatic mechanics

Medication for Consideration in Management

1. Low dose naltrexone (LDN) modulates the TLR4/ NF-κB pathway primarily by antagonizing TLR4, thereby suppressing pro-inflammatory signalling. LDN modulates the TLR4/ NF-κB pathway primarily by antagonizing TLR4, thereby suppressing pro-inflammatory signalling.  It binds to TLR4’s co-receptor MD2, inhibiting downstream NF-κB activation and reducing cytokines like TNF-α, IL-6, and IL-1β.  It binds to TLR4’s co-receptor MD2, inhibiting downstream NF-κB activation and reducing cytokines like TNF-α, IL-6, and IL-1β.   While LDN does not directly block NF-κB or MAPK pathways, it attenuates NF-κB activity indirectly via SIRT1 upregulation, enhancing anti-inflammatory effects.   This dual action curbs chronic inflammation and restores immune balance in autoimmune and metabolic disorders.(Zhang et al. 2020 (31))(Cant et al 2017 (32))(Wang et al. 2016 (33))(Choubey et al. 2020 (34))

2. Famotidine histamine H2R inhibition + CCL2 modulation via IL-6 suppression- activates the vagus nerve inflammatory reflex, leading to attenuation of cytokine storm in a mouse model of severe inflammation. This effect is mediated via the α7 nicotinic acetylcholine receptor (α7nAChR) pathway, resulting in reduced levels of pro-inflammatory cytokines such as TNF and IL-6.  It’s role in Long COVID transcends its classical H2-receptor effects, acting instead on key nodes of immune dysregulation, including RAGE/NF-κB, CCL2, and the mast cell–microglial–astrocytic axis. Through modulation of these pathways, famotidine interrupts the chronic feedforward loop sustaining post-viral inflammation and neuroimmune sensitization.

3. Nicotinamide Riboside- NAD+/SIRT1 enhancement and epigenetic reprogramming

4. Cromolyn- mast cell stabilizer By targeting the mast cell initiators of the RAGE/NF-κB/CCL2 axis, cromolyn may disrupt the core microglial–mast cell–astrocyte feedforward loop driving persistent neuroinflammation

5. H1 -blockers eg fexofenadine, cetirizine and ketotifen:

   1. Fexofenadine is a peripheral anti-histamine, especially in histaminergic symptom clusters. It lacks mast cell stabilization and does not cross the BBB, limiting utility in neuroinflammatory Long COVID

   2. Cetirizine offers slightly better immune modulation, with minimal central effects, and may be useful in mixed cases with both immune and allergic phenotypes

   3. Ketotifen stands out as the only H1 blocker with central anti-neuroinflammatory effects, particularly through mast cell stabilization and inhibition of CCL2, IL-6, VEGF, and glial activation. It is the most likely of currently available medication to modulate RAGE/NF-κB feedforward loops affecting microglia–astrocyte–mast cell crosstalk in Long COVID, though sedation is a limiting factor.

6. N-acetylcysteine (NAC) NAC supports glutathione synthesis, reduces oxidative stress, inhibits NF-κB-driven inflammation, and modulates glutamate excitotoxicity—making it a valuable adjunct in dysautonomia, particularly when redox imbalance, mitochondrial dysfunction, or central sensitization is present. It may also reduce fibrin-amyloid aggregates and support endothelial repair in Long COVID and POTS. However, high doses can act as pro-oxidants, and NAC may trigger symptoms in sulfur-sensitive or mast cell–reactive individuals. It should be introduced cautiously and may require co-administration with B vitamins, ALA, or taurine to optimize efficacy and tolerability, and monitored by clinicians proficient in its use.

Why This Matters

These conditions are frequently misdiagnosed as psychiatric or "functional". Recognizing dysautonomia as a real, immune-metabolic condition empowers GPs to validate patient experience and initiate targeted management. This also opens the door for referrals to cardiology, immunology, physiotherapy, or neurology for further intervention.

Take-Home Summary

• Dysautonomia is a systemic condition involving immune activation, mitochondrial dysfunction, and autonomic circuit disruption.

• Symptoms are not psychological but reflect a complex feed-forward loop involving inflammation and energy metabolism.

• Practical interventions exist and can be life-changing when applied early.

This integrated model offers a practical framework for identifying and managing dysautonomia in the general practice setting—transforming a frustrating diagnostic challenge into a targeted, mechanism-based approach to care.

Conclusion

Dysautonomia—including POTS, ME/CFS, fibromyalgia, and Long COVID—represents a convergence of immune, metabolic, vascular, and anatomical dysfunctions, rather than an idiopathic or psychogenic disorder. This paper proposes a unifying model wherein sustained TLR4–RAGE–CCL2 activation drives neuroimmune sensitization, mitochondrial collapse (notably PDH inhibition and redox stress), and glial–mast cell–neuropeptide feedback loops, all within the anatomical vulnerability of the brainstem and its downstream autonomic plexuses.

At the heart of this model lies brainstem hypoxia—amplified by venous congestion, structural compression, and impaired glymphatic clearance—which creates a permissive environment for mitochondrial failure, glial activation, and excitatory dominance. The resultant dysregulation affects both the cardiac and coeliac plexuses, producing preload failure, splanchnic pooling, and systemic autonomic instability.

Importantly, this framework explains why patients develop multisystem symptoms following diverse triggers—viral infections, trauma, mould exposure, or vertebral strain—and why these symptoms often persist or relapse. Rather than representing separate diseases, these syndromes can be viewed as phenotypic variants along a shared immunometabolic continuum, shaped by individual genetic polymorphisms, environmental exposures, and anatomical predispositions.

Clinically, this model calls for:

• Targeted therapies that modulate TLR4–RAGE–NF-κB–CCL2 signalling (e.g., LDN, famotidine, ketotifen, nicotinamide).

• Mitochondrial rescue strategies (e.g., PDH support, NAD+ repletion, amino acid correction).

• Structural interventions to restore venous-lymphatic drainage and brainstem perfusion.

• Diagnostic paradigms that incorporate metabolomic, genomic, and vascular imaging markers—moving beyond symptom-based labels toward mechanistic stratification.

By aligning molecular immunology, metabolic stress, and anatomical dysfunction within a single framework, this model offers a coherent explanation for the heterogeneity and persistence of dysautonomia. It opens the path toward precision diagnostics and mechanism-based therapeutics that can restore autonomic stability, rather than merely suppress symptoms.

These brainstem structures do not function in isolation but are dynamically linked to peripheral autonomic plexuses via descending sympathetic chains and vagal efferents. Notably, sympathetic continuity between the cervical, thoracic, and abdominal ganglia enables dysfunction—whether immunologic, hypoxic, or mechanical—to propagate bidirectionally, reinforcing dysautonomia at multiple anatomical nodes.

In many cases, subclinical vertebral rotation (e.g., at T8), thoracic outlet impingement, or pelvic venous congestion may impair central venous return, promoting brainstem hypoxia and autonomic destabilization.

This creates a functional continuum—brainstem inflammation drives plexus dysfunction, which in turn feeds back via sympathetic afferents to amplify brainstem neuroinflammation.

References:

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