Autonomic Dysfunction, POTS & Dysautonomia
You do not think about your heart rate. You do not decide to dilate your pupils when you enter a dark room.
Autonomic Dysfunction, POTS & Dysautonomia
The Invisible Operating System
You do not think about your heart rate. You do not decide to dilate your pupils when you enter a dark room. You do not consciously redirect blood from your digestive tract to your muscles when a car swerves toward you. The autonomic nervous system handles all of it — thousands of regulatory adjustments per minute, all below conscious awareness.
When this system breaks down, the consequences are bewildering. The heart races upon standing. Blood pressure swings wildly. Digestion halts. Body temperature regulation fails. Exercise becomes impossible. Patients look young and healthy. Their labs come back “normal.” And they are told, again and again, that nothing is wrong — perhaps they are anxious, deconditioned, or seeking attention.
Dysautonomia — dysfunction of the autonomic nervous system — is one of the most underdiagnosed categories in medicine. Postural orthostatic tachycardia syndrome (POTS) alone affects an estimated 1-3 million Americans. Since 2020, that number has grown substantially as post-COVID autonomic dysfunction has emerged as one of the most common long COVID presentations.
Autonomic Nervous System: The Three Branches
Sympathetic nervous system — the accelerator. Originates from the thoracolumbar spinal cord (T1-L2). Increases heart rate, blood pressure, respiratory rate, and alertness. Diverts blood to muscles. Dilates pupils. Inhibits digestion. Releases epinephrine and norepinephrine. This is the fight-or-flight response — designed for brief, intense activation.
Parasympathetic nervous system — the brake. Originates from the brainstem (cranial nerves III, VII, IX, X) and the sacral spinal cord (S2-S4). The vagus nerve (cranial nerve X) is the primary parasympathetic conduit. Decreases heart rate, promotes digestion, stimulates secretion, supports tissue repair. This is the rest-and-digest system.
Enteric nervous system — the “second brain.” Over 100 million neurons embedded in the walls of the gastrointestinal tract. Operates semi-independently but communicates bidirectionally with the CNS, primarily through the vagus nerve. Controls peristalsis, secretion, local blood flow, and immune responses in the gut.
Health is the dynamic balance between these branches — the sympathetic system mobilizing resources when needed, the parasympathetic system restoring them when the threat has passed, and the enteric system managing the complex work of digestion and gut immunity regardless. Dysautonomia is the loss of this balance.
POTS: When Standing Becomes a Challenge
Postural orthostatic tachycardia syndrome is defined by an excessive increase in heart rate upon standing — a rise of 30 beats per minute or more (40 bpm or more in adolescents aged 12-19) within 10 minutes of standing, or a heart rate exceeding 120 bpm upon standing — in the absence of orthostatic hypotension (a significant drop in blood pressure). The standing heart rate criterion was established by the tilt table test, which remains the gold standard for diagnosis.
POTS is not a disease. It is a syndrome — a clinical pattern with multiple underlying mechanisms. Identifying the subtype is essential for targeted treatment.
Neuropathic POTS
The most common subtype. Partial autonomic neuropathy — specifically, small fiber neuropathy (SFN) — damages the sympathetic nerves that control vasoconstriction in the lower extremities. When the patient stands, blood pools in the legs and abdomen because the damaged nerves cannot appropriately constrict the peripheral blood vessels. Compensatory tachycardia occurs as the heart tries to maintain cardiac output despite reduced venous return.
Small fiber neuropathy can be confirmed with a punch skin biopsy (typically from the distal leg and proximal thigh), which quantifies epidermal nerve fiber density. Reduced density confirms SFN. Quantitative sudomotor axon reflex testing (QSART) evaluates sudomotor (sweat gland) autonomic function — another small fiber-mediated pathway.
Causes of SFN in POTS: autoimmune (the most common), diabetes/prediabetes, Sjogren’s syndrome, celiac disease, sarcoidosis, amyloidosis, vitamin B12 deficiency, and post-viral.
Hyperadrenergic POTS
Characterized by excessive sympathetic activation — elevated standing norepinephrine levels (above 600 pg/mL), significant blood pressure increases upon standing (often paradoxical hypertension), tremor, anxiety, and palpitations. The heart races not because of blood pooling but because of a catecholamine surge.
Some hyperadrenergic POTS patients have a norepinephrine transporter (NET) deficiency — the transporter that clears norepinephrine from the synaptic cleft is impaired, leading to exaggerated sympathetic signaling. A subset has mast cell activation syndrome (MCAS), where mast cell mediators (histamine, prostaglandins) drive sympathetic activation.
Hypovolemic POTS
Reduced blood volume — sometimes by 15-20% — means there is simply not enough fluid in the system to maintain adequate venous return upon standing. This can occur from excessive urinary sodium wasting (due to impaired renin-angiotensin-aldosterone signaling), chronic dehydration, or reduced red blood cell mass.
Raj and colleagues at Vanderbilt have characterized the hypovolemic component extensively. Many POTS patients have plasma volume and/or red blood cell mass below normal — a finding that explains why IV fluids often produce dramatic symptomatic improvement.
The Associated Conditions
POTS rarely travels alone. The clustering of associated conditions provides diagnostic and therapeutic clues.
EDS/Hypermobility (Hakim 2017)
Ehlers-Danlos syndrome (EDS) — particularly the hypermobile type (hEDS) — is strongly associated with POTS. Hakim et al. (2017) described the link: lax connective tissue in blood vessel walls leads to excessive venous distensibility (veins stretch too much), promoting blood pooling. Additionally, EDS patients often have cervical spine instability affecting brainstem autonomic centers, and many have co-occurring MCAS.
The Beighton score screens for joint hypermobility (score of 5 or higher out of 9 suggests generalized hypermobility). The 2017 International EDS Consortium criteria require hypermobility plus specific systemic features.
MCAS — The Terrible Triad
Mast cell activation syndrome involves inappropriate mast cell degranulation — releasing histamine, tryptase, prostaglandins, leukotrienes, and cytokines in response to a wide range of triggers (foods, chemicals, temperature, stress, hormonal changes). Symptoms: flushing, hives, GI disturbance, tachycardia, hypotension, anaphylactoid reactions, brain fog, and pain.
The EDS-POTS-MCAS triad is so common it has become a clinical entity in itself. The proposed connection: defective connective tissue (EDS) leads to autonomic dysregulation (POTS) and creates an environment where mast cells — embedded in connective tissue throughout the body — become hyperreactive (MCAS). Each condition amplifies the others.
Autoimmune POTS (Vernino)
Steven Vernino at UT Southwestern has led research into autoimmune autonomic neuropathy. Ganglionic acetylcholine receptor (gAChR) antibodies — which attack the nicotinic receptors in the autonomic ganglia — cause autoimmune autonomic ganglionopathy (AAG). Partial forms present as POTS. These antibodies are found in approximately 10-15% of POTS patients and are associated with more severe dysautonomia.
Other autoimmune antibodies found in POTS patients: anti-adrenergic receptor antibodies (alpha-1, beta-1, beta-2), anti-muscarinic receptor antibodies, and anti-AT1R (angiotensin II type 1 receptor) antibodies. The CellTrend panel tests for these antibodies and is used in research settings, though clinical application is still evolving.
Post-Viral POTS
POTS following viral infection has been documented for decades, but COVID-19 dramatically expanded the population. Post-COVID POTS may result from autoimmune mechanisms (molecular mimicry between viral proteins and autonomic receptors), direct viral neuropathy, endothelial dysfunction, or persistent viral reservoir driving immune activation.
EBV reactivation is another common post-viral trigger. The pattern is characteristic: previously healthy individual develops a viral illness, recovers from the acute infection, and weeks to months later develops orthostatic intolerance, fatigue, and cognitive dysfunction.
Diagnosis
Tilt table test — the gold standard. The patient lies flat for a rest period, then the table is tilted to 60-70 degrees (simulating standing) for up to 45 minutes. Heart rate, blood pressure, and symptoms are continuously monitored. A heart rate increase of 30+ bpm (40+ in adolescents) without significant blood pressure drop confirms POTS.
Active stand test — a simpler in-office alternative. Supine blood pressure and heart rate are recorded after 5 minutes of rest. The patient stands and vitals are recorded at 1, 3, 5, and 10 minutes. Useful for screening but less standardized than tilt testing.
QSART (Quantitative Sudomotor Axon Reflex Test) — evaluates small fiber autonomic function by measuring sweat output in response to acetylcholine iontophoresis at four sites. Reduced output suggests sympathetic sudomotor neuropathy.
Thermoregulatory sweat test — a more comprehensive sweat assessment. The patient is coated with an indicator powder that changes color when wet. In a heated chamber, the pattern of sweating reveals the distribution of sympathetic sudomotor dysfunction.
Catecholamine levels — supine and standing plasma norepinephrine. Standing norepinephrine above 600 pg/mL suggests hyperadrenergic POTS. Fractionated catecholamines (epinephrine, norepinephrine, dopamine) and their metabolites can be measured in 24-hour urine.
Skin biopsy for SFN — 3mm punch biopsies from the distal leg and proximal thigh, stained for PGP 9.5 (a pan-neuronal marker). Reduced epidermal nerve fiber density confirms small fiber neuropathy.
Additional testing: Autoimmune panel (ANA, ESR, complement, SSA/SSB for Sjogren’s, tTG for celiac, ganglionic AChR antibodies), EBV panel, blood volume measurement (Daxor BVA-100 or iodinated albumin technique), iron studies (ferritin, TIBC, transferrin saturation — low RBC mass may be iron-related), thyroid panel, cortisol.
Non-Pharmacological Management
These interventions are first-line and non-negotiable. Many patients can achieve significant improvement without medication.
Salt and Fluid Loading
The hypovolemic component requires aggressive volume expansion. Sodium intake: 10-12 grams per day (this is 4-5 times the standard dietary recommendation — it is therapeutic, not nutritional). Fluid intake: 2-3 liters per day, including electrolyte-containing fluids.
Electrolyte supplementation: LMNT (1000 mg sodium, 200 mg potassium, 60 mg magnesium per packet), Liquid IV, or homemade (1/4 teaspoon salt + lemon juice in water). The sodium is the critical component — it expands plasma volume, improves venous return, and raises blood pressure.
Note: salt loading is appropriate for POTS but contraindicated in hypertension, heart failure, and kidney disease. Context matters.
Compression
Compression garments prevent venous pooling. Waist-high compression stockings (30-40 mmHg) are more effective than knee-high. Abdominal binders (providing 20-40 mmHg of compression over the splanchnic vasculature) are sometimes better tolerated and address the significant volume of blood that pools in the abdominal venous plexus.
Counter-Maneuvers
Physical maneuvers that improve venous return: crossing legs while standing, clenching fists, tensing leg muscles, squatting (the most effective — immediately increases venous return), toe raises. These are rescue techniques for symptomatic moments.
Reconditioning: The Modified Dallas Protocol
Exercise intolerance is a hallmark of POTS — the orthostatic stress of upright exercise triggers symptoms, leading to deconditioning, which worsens POTS, which further reduces exercise tolerance. A vicious cycle.
Benjamin Levine at UT Southwestern (and separately, the Children’s Hospital of Philadelphia — CHOP — protocol for adolescents) developed a structured reconditioning program that breaks this cycle:
Month 1: Exclusively recumbent exercise — recumbent bike, rowing machine, swimming. These positions eliminate orthostatic stress while providing cardiovascular conditioning. Start with 15-20 minutes at 75-80% of maximum heart rate, 3-4 days per week.
Month 2: Gradually introduce semi-upright exercise. Continue recumbent base but add short periods of upright cycling.
Month 3: Introduce upright exercise (walking, elliptical). Short duration initially (10-15 minutes), gradually extending.
Months 4-6: Progress to full upright exercise with strength training. The goal is 30-45 minutes of aerobic exercise, 5-6 days per week, plus 2 days of resistance training.
The key principle: start recumbent, progress slowly, never push into severe symptom exacerbation. Three months of consistent recumbent exercise before attempting full upright activity. Studies show significant improvement in stroke volume, blood volume, heart rate response, and quality of life with this approach.
Pharmacological Management
When non-pharmacological measures are insufficient:
Fludrocortisone — a mineralocorticoid that increases sodium and water retention, expanding blood volume. Starting dose: 0.1 mg daily. Monitor blood pressure and potassium (fludrocortisone can cause hypokalemia). Best for hypovolemic POTS.
Midodrine — an alpha-1 agonist that constricts peripheral blood vessels, reducing venous pooling. Dose: 2.5-10 mg three times daily (avoid evening dosing — can cause supine hypertension). Best for neuropathic POTS with blood pooling.
Beta-blockers (low-dose) — propranolol 10-20 mg three to four times daily is the most commonly used. Paradoxically, low-dose beta-blockade can improve POTS symptoms by reducing the inappropriate tachycardia without causing the hypotension that higher doses would produce. Ivabradine (Corlanor) — a selective If channel blocker that reduces heart rate without affecting blood pressure or contractility — is increasingly used in POTS at doses of 2.5-7.5 mg twice daily. It is better tolerated than propranolol in many patients.
Pyridostigmine — an acetylcholinesterase inhibitor that enhances cholinergic (parasympathetic) signaling at the autonomic ganglia. Dose: 30-60 mg three times daily. Modestly increases venous return and vagal tone without significant blood pressure effects. Particularly useful in patients who cannot tolerate vasoconstrictors.
Droxidopa (Northera) — a norepinephrine precursor, FDA-approved for neurogenic orthostatic hypotension. Used off-label in POTS. Dose: 100-600 mg three times daily. Particularly useful in neuropathic POTS with documented norepinephrine deficiency.
DDAVP (desmopressin) — a synthetic vasopressin analog that promotes water retention by the kidneys. Used acutely (0.1-0.2 mg orally at bedtime or before exertion) for volume expansion. Monitor sodium closely — hyponatremia risk.
The Functional Medicine Approach
Conventional POTS management stops at the medications listed above. The functional approach asks: why is the autonomic nervous system broken?
IV Fluids Acutely
Normal saline (0.9% NaCl) or lactated Ringer’s infusion — 1-2 liters — can provide immediate symptomatic relief in hypovolemic POTS. Some patients receive weekly or biweekly IV fluids as a bridge while root causes are being addressed. An implanted port may be considered for patients requiring chronic IV access (controversial and last resort due to infection risk).
Iron Optimization
Low ferritin (even with “normal” hemoglobin) reduces red blood cell mass, contributing to the hypovolemic component. Target ferritin above 50-70 ng/mL. Iron bisglycinate (25-36 mg every other day, on empty stomach with vitamin C) is the best-tolerated oral form. IV iron (Venofer, Injectafer) for patients who do not tolerate oral iron or have very low levels.
Thyroid Optimization
Both overt and subclinical hypothyroidism impair autonomic function. Free T3 is the active hormone at the tissue level — low free T3 (even with “normal” TSH) contributes to reduced cardiac output and impaired autonomic tone. Hashimoto’s thyroiditis should be managed aggressively (gluten elimination, selenium 200 mcg daily, optimized vitamin D).
Adrenal Support
HPA axis dysregulation — common in chronic illness and chronic stress — produces cortisol patterns (blunted awakening response, flattened diurnal curve) that worsen orthostatic tolerance. DHEA is often depleted. Adaptogenic herbs (ashwagandha 600 mg daily, rhodiola 200-400 mg daily) support HPA axis resilience. Physiological-dose hydrocortisone (5-15 mg daily in divided doses) is used by some practitioners in documented cortisol deficiency.
MCAS Treatment
If MCAS is part of the triad: H1 blocker (cetirizine 10 mg twice daily or fexofenadine 180 mg twice daily) + H2 blocker (famotidine 20 mg twice daily) + mast cell stabilizer (cromolyn sodium 200 mg four times daily before meals, or quercetin 500 mg three times daily) + low-histamine diet. Ketotifen (1-2 mg at bedtime) has both antihistamine and mast cell-stabilizing properties. DAO enzyme (diamine oxidase) supplementation before meals helps with histamine-rich foods.
Autoimmune Workup and Treatment
If autoimmune POTS is suspected: ganglionic AChR antibodies, CellTrend panel, comprehensive autoimmune panel. Treatment for autoimmune autonomic neuropathy: IVIG (intravenous immunoglobulin — 2 g/kg divided over 2-5 days, repeated monthly), plasmapheresis, rituximab in refractory cases. These are specialist-directed therapies but can be transformative when the autoimmune component is identified.
Small Fiber Neuropathy Treatment
Regenerating damaged small fibers: alpha-lipoic acid (600 mg daily — Ziegler et al. multiple RCTs in diabetic neuropathy), acetyl-L-carnitine (1 g twice daily — supports nerve repair), methylcobalamin (5000 mcg daily — B12 is essential for nerve myelination), benfotiamine (300 mg daily — lipid-soluble B1 for nerve protection), and low-dose naltrexone (LDN, 1.5-4.5 mg at bedtime — modulates neuroinflammation and has been reported to improve SFN symptoms in case series).
Vagal Toning
The parasympathetic side of the equation is often neglected. Vagal toning practices — gargling, humming, cold water face immersion, coherence breathing (5.5 breaths per minute), HRV biofeedback — directly strengthen the vagal brake that POTS patients have lost.
The EDS-POTS-MCAS Triad: The Connected Approach
When all three conditions coexist — and they frequently do — they must be treated as a system, not as three separate problems.
The connective tissue is the terrain. EDS creates the structural vulnerability: hypermobile joints that subluxate, lax blood vessels that pool blood, a gut wall that is more permeable, mast cells embedded in structurally abnormal tissue that degranulates more readily.
Treating POTS without addressing MCAS means the mast cell mediators continue driving tachycardia, flushing, and GI dysfunction. Treating MCAS without managing EDS means the structural instability continues triggering mast cell activation through mechanical stress. Treating either without supporting the autonomic nervous system means the regulatory system cannot maintain the improvements.
The integrated approach:
- Stabilize: Salt, fluids, compression, counter-maneuvers, MCAS medications
- Identify drivers: Autoimmune, post-viral, SFN, blood volume, iron, thyroid
- Rehabilitate: Modified Dallas protocol, vagal toning, HRV biofeedback
- Support structure: Physical therapy for joint stabilization (not flexibility — these patients are already too flexible), proprioceptive training, bracing as needed
- Calm the mast cells: Diet, antihistamines, mast cell stabilizers, trigger avoidance
- Address the immune system: LDN, IVIG if autoimmune, antiviral treatment if post-viral
The Clinical Truth
POTS patients are some of the most medically gaslit patients in healthcare. They are young, they look healthy, and their standard labs are normal. They are told they are anxious, deconditioned, or attention-seeking. The average POTS patient sees 7 physicians over 4 years before receiving a diagnosis.
The autonomic nervous system is invisible to routine clinical evaluation. A standard physical exam does not include orthostatic vital signs at 10 minutes. A standard blood panel does not include catecholamines or blood volume. A standard neurology referral does not include skin biopsy for SFN. The tools to diagnose dysautonomia exist — they are simply not part of the default workup.
Functional medicine brings something essential to these patients: the willingness to ask why. Why is the autonomic system failing? What triggered it? What is sustaining it? Is there an autoimmune process? A post-viral process? A connective tissue disorder? Mast cell dysfunction? Nutritional deficiency? Chronic infection?
The autonomic nervous system does not break for no reason. There is always a reason. And when you find it and address it, the system can heal — not always completely, but often substantially.
What would change in your life if your body could trust itself to stand?