Ehlers-Danlos Syndrome
Ehlers-Danlos Syndrome (EDS), particularly the hypermobile type (hEDS), is a well-documented contributor to secondary POTS due to its widespread effects on connective tissue, which plays a crucial role in vascular stability. In individuals with EDS, the structural integrity of blood vessels can be compromised. This results in increased vascular elasticity and poor venous return, especially when standing. When the body struggles to push blood back up toward the heart and brain against gravity, the autonomic nervous system compensates by increasing heart rate to maintain adequate circulation—a hallmark feature of POTS.
Beyond vascular laxity, EDS often coexists with other complications that stress the autonomic nervous system. Joint pain, frequent injuries, gastrointestinal dysmotility, and even mast cell activation are common in the EDS population—all of which can heighten the body’s stress response and place additional demand on autonomic regulation. The cumulative effect of these stressors creates a physiological environment where orthostatic intolerance, tachycardia, and other symptoms of POTS become chronic, not just occasional. This is why clinicians increasingly recognize EDS as a root driver in secondary POTS presentations.
Autoimmune Disorders (including Sjögren’s syndrome, rheumatoid arthritis)
Autoimmune disorders such as Sjögren’s syndrome and rheumatoid arthritis can trigger secondary POTS by initiating a cascade of immune-mediated damage that affects the autonomic nervous system. Inflammation, a hallmark of these conditions, doesn’t confine itself to joints or glands—it can extend to peripheral nerves, including the small fibers responsible for autonomic regulation (a condition called small fiber neuropathy). When these nerves are damaged, the body struggles to maintain homeostasis during posture changes, which may result in the dizziness, tachycardia, and fatigue characteristic of POTS.
Additionally, autoimmune diseases can indirectly disrupt autonomic balance through chronic systemic stress. Take Sjögren’s, for example: severe dryness of mucous membranes can cause significant discomfort and fatigue, demanding compensatory physiological responses. Likewise, in rheumatoid arthritis, joint pain and systemic inflammation often lead to reduced physical activity, deconditioning, and vascular stiffening—all risk factors that can intensify orthostatic intolerance. Immunosuppressive treatments may further complicate the picture, altering vascular tone and hormonal feedback systems. These overlapping factors make autoimmune-related secondary POTS a complex and multifaceted clinical presentation.
Diabetes Mellitus
Diabetes mellitus—particularly when poorly managed over time—can lead to secondary POTS through its damaging effects on the autonomic nervous system, a condition called diabetic autonomic neuropathy. High blood glucose levels can injure small autonomic nerve fibers that regulate key involuntary functions like heart rate, blood pressure, and vascular tone. As these nerves deteriorate, the body’s ability to respond to positional changes (such as standing up) becomes compromised. This often results in symptoms like lightheadedness, rapid heart rate, and fatigue—hallmark features of POTS.
Beyond direct nerve damage, diabetes contributes to systemic inflammation, impaired circulation, and metabolic dysregulation. Insulin resistance and elevated blood sugar levels can alter how blood vessels dilate and constrict, reducing overall hemodynamic stability. Additionally, diabetes-related complications like dehydration, reduced physical activity, and nutritional deficiencies further stress the cardiovascular system. These compounding effects make diabetes a significant and often underrecognized contributor to secondary POTS, especially in patients with long-standing or poorly controlled disease.
Sarcoidosis
Sarcoidosis can lead to secondary POTS primarily through its potential to cause granulomatous inflammation in the autonomic nervous system. While sarcoidosis is best known for affecting the lungs and lymph nodes, it can become systemic, infiltrating neural tissues—a condition known as neurosarcoidosis. When granulomas form in or near autonomic ganglia or nerve pathways, they can disrupt the delicate signaling required to regulate heart rate, blood pressure, and vascular tone. This damage can manifest as autonomic dysfunction, including the hallmark orthostatic intolerance seen in POTS.
Beyond direct nerve involvement, systemic inflammation from sarcoidosis can contribute to widespread fatigue, muscle weakness, and exercise intolerance. These symptoms often result in reduced physical conditioning, which exacerbates orthostatic challenges. Additionally, treatments for sarcoidosis—particularly corticosteroids and immunosuppressants—can alter fluid balance, vascular responsiveness, and stress hormone regulation, all of which further destabilize autonomic control. The combination of neurologic involvement and systemic burden makes sarcoidosis a complex but significant contributor to secondary POTS in select patients.
Amyloidosis
Amyloidosis contributes to secondary POTS primarily by causing infiltrative damage to the autonomic nervous system and cardiovascular structures. This rare condition is characterized by the buildup of abnormal protein deposits—amyloid—within organs and tissues. When these deposits accumulate in autonomic nerves, they can disrupt the communication between the brain and body that regulates involuntary functions like blood pressure and heart rate. As a result, patients may experience pronounced orthostatic intolerance, palpitations, and fatigue—hallmarks of POTS.
In addition to direct nerve involvement, amyloid can affect blood vessels and the heart itself, leading to restrictive cardiomyopathy, low cardiac output, and impaired vascular tone. These complications hinder the body’s ability to adapt to positional changes, compounding the autonomic dysfunction. Moreover, fluid imbalances and reduced blood volume—common in systemic amyloidosis—further exacerbate POTS symptoms. The interplay of nerve impairment, cardiovascular strain, and systemic metabolic impact makes amyloidosis one of the more complex and serious underlying causes of secondary POTS.
Viral Infections (including COVID-19, Epstein-Barr, mononucleosis)
Viral infections—including COVID-19, Epstein-Barr virus (EBV), and mononucleosis—are well-established triggers of secondary POTS due to their potential to disrupt autonomic balance during and after the acute phase. These viruses can provoke a sustained immune response that results in inflammation, immune dysregulation, and even direct nerve damage, particularly targeting the small fibers that support autonomic regulation. In post-viral POTS, the autonomic nervous system may become hypersensitive or inefficient, leading to symptoms like rapid heart rate, fatigue, and brain fog when standing.
Long COVID has brought particular attention to this pathway, with many patients developing persistent autonomic symptoms that mirror or meet POTS diagnostic criteria. Similarly, EBV—the virus behind mono—can lead to prolonged fatigue and cardiovascular instability that lingers beyond the typical illness. The mechanism appears to be a combination of immune overactivation, deconditioning, and potentially direct autonomic nerve involvement. In some cases, molecular mimicry may even cause the immune system to mistakenly attack autonomic nerves, deepening dysfunction. The result is a complex interplay between infection, recovery, and long-term autonomic instability—one that clinicians are still working to fully understand.
Chemotherapy
Chemotherapy can contribute to secondary POTS through its neurotoxic and cardiovascular side effects, especially in treatments that affect small fiber nerves or the autonomic ganglia. Several common chemotherapeutic agents—like vincristine, cisplatin, and taxanes—can induce peripheral neuropathy, which may include the small autonomic fibers responsible for regulating heart rate, blood pressure, and vascular tone. When these nerves are damaged, the body’s compensatory response to standing or stress becomes impaired, resulting in hallmark POTS symptoms like tachycardia, dizziness, and fatigue.
Beyond direct nerve toxicity, chemotherapy often triggers profound deconditioning due to extended periods of fatigue, reduced activity, and muscle atrophy. This physical decline weakens cardiovascular efficiency, making the shift from lying down to standing more taxing on the body. Additionally, chemotherapy-induced anemia, fluid loss, and electrolyte imbalances further stress the autonomic nervous system, pushing susceptible individuals toward POTS-like dysregulation. For cancer survivors, these effects may linger well beyond the end of treatment, emphasizing the need for targeted rehabilitation strategies that support autonomic recovery.
Traumatic Injury
Traumatic injury—particularly involving the head, spine, or thoracic region—can precipitate secondary POTS by directly impairing autonomic nerve pathways or triggering systemic deconditioning. For example, a concussion or traumatic brain injury (TBI) can disrupt central autonomic control centers that regulate heart rate, blood pressure, and vascular tone. Likewise, spinal cord trauma, especially in the cervical or upper thoracic segments, may interrupt the flow of autonomic signals to the heart and blood vessels. These disruptions impair the body’s ability to respond to changes in posture, often leading to the hallmark symptoms of POTS: rapid heartbeat, dizziness, and fatigue upon standing.
In addition to neurological factors, traumatic injuries often lead to reduced mobility and cardiovascular deconditioning, which compound the autonomic dysfunction. Extended bed rest, blood volume shifts, and muscle atrophy weaken the circulatory system’s adaptability. Inflammatory responses and chronic pain—common after injury—can also amplify sympathetic nervous system activity or contribute to dysautonomia. These effects may persist long after the physical injuries appear to heal, making it essential for post-trauma rehabilitation protocols to include autonomic evaluation and support when POTS-like symptoms emerge.
Multiple Sclerosis
Multiple sclerosis (MS) can lead to secondary POTS through its direct impact on the central nervous system, where it causes inflammation and demyelination of nerve fibers—including those involved in autonomic regulation. When MS lesions affect areas like the brainstem or spinal cord that coordinate cardiovascular responses, the body may struggle to maintain proper vascular tone and heart rate when changing positions. This disruption often leads to orthostatic intolerance and the characteristic spike in heart rate seen in POTS. In some cases, MS-related damage may extend to peripheral autonomic fibers as well, compounding dysfunction.
Beyond neurological damage, MS frequently results in fatigue, muscle weakness, heat intolerance, and reduced mobility, all of which contribute to cardiovascular deconditioning. This diminished baseline fitness can heighten POTS symptoms by reducing the body’s capacity to adjust to positional shifts. Additionally, medications used in MS management—such as corticosteroids, anticholinergics, or muscle relaxants—can interfere with blood pressure regulation or hydration status, adding yet another layer of autonomic stress. Together, the neurologic and systemic effects of MS make it a notable, though underrecognized, contributor to secondary POTS in clinical settings.
Lupus
Lupus, particularly systemic lupus erythematosus (SLE), can lead to secondary POTS through its multisystem inflammatory effects and impact on the autonomic nervous system. Chronic inflammation associated with lupus can damage blood vessels and small autonomic fibers, disrupting the body’s ability to regulate blood pressure and heart rate effectively. This is especially true when small fiber neuropathy develops—a known complication of lupus—resulting in orthostatic intolerance and the hallmark tachycardia of POTS. In some cases, autoantibodies produced in lupus may directly target autonomic components, compounding the dysregulation.
Beyond nerve involvement, lupus often causes fatigue, joint pain, and systemic flares that lead to decreased physical activity and cardiovascular deconditioning. These factors make it more difficult for the circulatory system to compensate for postural changes, a central feature of POTS. Steroid use—common in managing lupus flares—can further affect fluid retention, vascular tone, and hormonal feedback, subtly undermining autonomic stability. With its overlapping layers of systemic and neurologic stress, lupus represents a potent driver of secondary POTS, often requiring a multidisciplinary approach to management.
Spinal Disorders
Spinal disorders can lead to secondary POTS when they interfere with the structural integrity or function of the autonomic pathways that travel along or through the spine—especially in the cervical and upper thoracic regions. Conditions like degenerative disc disease, cervical stenosis, or spinal cord compression can place pressure on nerve roots or central autonomic tracts, disrupting the signals that manage blood pressure, heart rate, and vascular tone. Inflammatory spinal conditions such as ankylosing spondylitis may also impair autonomic regulation through immune-mediated nerve damage or postural rigidity that alters venous return.
Even without direct nerve injury, spinal disorders often result in chronic pain, decreased mobility, and physical deconditioning—each of which can stress the autonomic system. Limited movement reduces cardiovascular endurance and muscular support for circulation, which can exaggerate orthostatic intolerance. Pain medications, such as opioids or muscle relaxants, may further dampen autonomic responsiveness or lead to fluid imbalances that worsen POTS symptoms. In this multifactorial context, spinal disorders act as both structural and systemic contributors to secondary POTS, particularly when autonomic signs emerge gradually alongside chronic spinal symptoms.
Celiac Disease
Celiac disease can lead to secondary POTS through immune-mediated damage and systemic nutrient malabsorption that affect both the gastrointestinal and autonomic nervous systems. In individuals with celiac disease, gluten exposure provokes inflammation in the small intestine, damaging the villi that are essential for nutrient absorption. This chronic inflammation and intestinal damage can lead to deficiencies in key nutrients such as B12, iron, magnesium, and electrolytes—all of which are crucial for optimal nerve and cardiovascular function. When the autonomic nerves are weakened or stressed by these deficiencies, regulation of heart rate and blood pressure can become impaired, contributing to POTS-like symptoms.
Additionally, many individuals with celiac disease experience fatigue, weight loss, and deconditioning, especially during active flares or prior to diagnosis. The combination of chronic inflammation, poor nutrient absorption, and reduced physical activity creates a physiological environment that heightens orthostatic intolerance. Some research also suggests that autoimmune cross-reactivity may play a role—where the immune system mistakenly targets components of the autonomic nervous system, similar to what’s observed in other autoimmune-driven causes of POTS. In this way, celiac disease acts through both direct and indirect mechanisms to destabilize autonomic function, making it a notable contributor to secondary POTS in susceptible individuals.
Lyme Disease
Lyme disease can lead to secondary POTS when the Borrelia burgdorferi infection provokes inflammatory or autoimmune responses that affect the autonomic nervous system. While Lyme is best known for causing joint pain and fatigue, in some cases—particularly when diagnosis or treatment is delayed—it can progress to involve the nervous system (neuroborreliosis). This may result in autonomic nerve damage, small fiber neuropathy, or persistent dysregulation of the immune system. These effects can destabilize heart rate and blood pressure regulation, especially during posture changes, triggering the classic symptoms of POTS.
Even beyond direct nerve involvement, many individuals with Lyme experience prolonged fatigue, deconditioning, and hormonal imbalances, especially in post-treatment Lyme disease syndrome (PTLDS). Persistent inflammation, mitochondrial dysfunction, and immune sensitization can continue to strain autonomic regulation long after the infection clears. Some researchers also suggest that molecular mimicry could lead to autoimmune responses that unintentionally target autonomic nerve fibers. Together, these factors create a complex environment where Lyme disease not only challenges overall health but also sets the stage for chronic autonomic instability in the form of POTS.
Guillain-Barré Syndrome
Guillain-Barré Syndrome (GBS) can lead to secondary POTS by causing acute inflammatory demyelinating polyneuropathy, which often includes involvement of the autonomic nervous system. GBS typically begins with a post-infectious immune response that mistakenly attacks peripheral nerves. When autonomic fibers are affected—especially those that regulate cardiovascular function—patients may develop symptoms like orthostatic intolerance, excessive tachycardia, and blood pressure instability. These features closely mirror those of POTS, particularly during the recovery phase of GBS when residual nerve dysfunction lingers.
In some cases, individuals may not fully recover from autonomic involvement after GBS resolves, resulting in chronic dysautonomia. This is especially likely if the variant form of GBS—acute autonomic neuropathy—was present during the acute illness. Additionally, during and after hospitalization, patients often experience deconditioning, volume depletion, and muscle atrophy
Mast Cell Activation Syndrome
Mast Cell Activation Syndrome (MCAS) can lead to secondary POTS by contributing to chronic immune dysregulation and vascular instability. MCAS is characterized by inappropriate or excessive release of mast cell mediators—such as histamine, prostaglandins, and cytokines—which can cause widespread symptoms affecting multiple systems. When these mediators are released, they can dilate blood vessels, lower blood pressure, and increase heart rate in response to triggers like standing, heat, or stress. This hemodynamic instability can overwhelm the autonomic nervous system, leading to the hallmark symptoms of POTS, including tachycardia, lightheadedness, and fatigue upon standing.
Compounding the issue, MCAS often presents with symptoms that overlap significantly with those of POTS—such as gastrointestinal discomfort, brain fog, flushing, and fatigue—making diagnosis and management more complex. Some researchers speculate that chronic mast cell activation may sensitize or damage autonomic nerve fibers through inflammation or oxidative stress. Additionally, those with MCAS frequently limit activity due to unpredictable flare-ups, contributing to cardiovascular deconditioning, which intensifies orthostatic intolerance. The combination of immunologic, neurologic, and hemodynamic stress makes MCAS a compelling and increasingly recognized contributor to secondary POTS.
Pregnancy/Postpartum
Pregnancy and the postpartum period can trigger secondary POTS due to dramatic shifts in cardiovascular, hormonal, and autonomic function. During pregnancy, the body undergoes profound changes to support fetal development, including increased blood volume, altered vascular tone, and heightened cardiac output. While most of these changes are well-regulated, some individuals experience autonomic dysregulation—especially if there’s an underlying predisposition. In late pregnancy, for instance, venous pooling becomes more common due to compression of abdominal vessels, which can challenge blood return to the heart and mimic or exacerbate POTS symptoms.
Postpartum, the body rapidly reverses many of these adaptations, which can overwhelm the autonomic nervous system. Sudden fluid shifts, blood loss during delivery, hormone withdrawal (particularly estrogen and progesterone), and sleep deprivation all contribute to autonomic instability. Moreover, the stress of labor—whether physical, emotional, or both—can unmask previously latent autonomic dysfunction. Breastfeeding and fluctuating hydration demands can further complicate hemodynamic regulation. For some, what begins as transient orthostatic intolerance in the postpartum window evolves into sustained POTS, particularly if compounded by anemia, deconditioning, or underlying autoimmune shifts that sometimes emerge after childbirth.
Heavy Metal Poisoning
Heavy metal poisoning—caused by toxic accumulation of metals like lead, mercury, arsenic, or cadmium—can contribute to secondary POTS by damaging both the peripheral nervous system and vascular endothelium, which are essential to autonomic regulation. These metals disrupt cellular metabolism, induce oxidative stress, and interfere with neurotransmitter function. When autonomic nerves are affected—particularly the small fibers responsible for cardiovascular control—regulatory mechanisms like baroreflex sensitivity and vascular tone can break down. This leads to hallmark POTS symptoms like tachycardia, lightheadedness, and blood pressure instability when upright.
In addition to direct nerve toxicity, heavy metal exposure often causes systemic inflammation, mitochondrial dysfunction, and immune dysregulation, all of which strain the autonomic nervous system. Chronic exposure may also provoke an autoimmune response or lead to secondary conditions such as chronic fatigue syndrome or small fiber neuropathy, which are themselves associated with POTS. Since the symptoms of heavy metal poisoning can mimic or overlap with dysautonomia, it’s crucial for clinicians to consider toxic exposure when evaluating complex or treatment-resistant POTS cases—especially if occupational, environmental, or dietary risk factors are present.
Paraneoplastic Syndromes
Paraneoplastic syndromes can lead to secondary POTS when cancer-associated immune responses begin targeting the autonomic nervous system, a process known as paraneoplastic autonomic neuropathy. These syndromes occur when the immune system—while attacking cancer cells—mistakenly cross-reacts with healthy neural tissues due to molecular mimicry. When this immune attack affects the autonomic nerves, patients may experience severe dysautonomia, including tachycardia, blood pressure instability, and orthostatic intolerance characteristic of POTS. This is most often seen in association with cancers such as small-cell lung carcinoma, thymoma, or ovarian teratoma.
Beyond immune-mediated nerve damage, paraneoplastic syndromes often bring systemic inflammation, weight loss, and muscle wasting, all of which contribute to cardiovascular deconditioning and further impair autonomic compensation. Treatments for the underlying cancer—such as chemotherapy or radiation—can add neurotoxic and metabolic stressors that deepen autonomic dysfunction. In rare cases, paraneoplastic antibodies (like anti-Hu or anti-CRMP5) may be detectable, helping confirm the autoimmune nature of the dysautonomia. Because these cases are rare and complex, POTS symptoms in a paraneoplastic context require a multidisciplinary approach for both diagnosis and treatment.
Vitamin B12 Deficiency
Vitamin B12 deficiency can contribute to secondary POTS by compromising nerve integrity, oxygen transport, and metabolic stability, all of which are critical for autonomic function. B12 is essential for maintaining the myelin sheath that insulates nerves—including those of the autonomic nervous system. When levels are low, demyelination can occur, leading to neuropathy that disrupts the signaling required to regulate heart rate, blood pressure, and vascular tone. The result is impaired baroreflex sensitivity and poor hemodynamic compensation when standing—hallmarks of POTS.
In addition to nerve damage, B12 deficiency can cause macrocytic anemia, reducing the blood’s oxygen-carrying capacity and leading to fatigue, dizziness, and lightheadedness—symptoms that overlap with and exacerbate autonomic dysfunction. The deficiency may also stem from underlying conditions like pernicious anemia, gastrointestinal disorders (such as Crohn’s or celiac disease), or long-term use of acid-suppressing medications—all of which can themselves be associated with broader autonomic challenges. Because B12 is relatively easy to test and replenish, identifying and correcting this deficiency can be a key step in managing secondary POTS and restoring autonomic balance.
Chiari Malformation
Chiari malformation can lead to secondary POTS by disrupting cerebrospinal fluid (CSF) dynamics and compressing regions critical to autonomic regulation, particularly in the brainstem and upper spinal cord. In Chiari malformation type I—the most commonly associated form—a portion of the cerebellum (the tonsils) descends through the foramen magnum into the spinal canal, which can crowd or exert pressure on the medulla and vagus nerve. These structures are essential for baroreflex function and cardiovascular control, and even subtle compression may impair the body’s ability to manage postural changes, resulting in the orthostatic intolerance and tachycardia seen in POTS.
Symptoms from Chiari malformation often overlap with dysautonomia, including headache, dizziness, fatigue, and balance issues, which can obscure recognition of a coexisting autonomic disorder. In some cases, CSF flow disruption may lead to intracranial pressure fluctuations that further dysregulate autonomic tone. Surgical decompression can sometimes improve POTS symptoms, particularly when neuroimaging reveals anatomical compression. Still, not all Chiari cases with POTS benefit from surgery, which is why individualized neuro-autonomic assessment is crucial in these patients. Chiari adds a distinctive neurostructural perspective to the diverse causes of secondary POTS.
Surgery Complications
Surgical complications can lead to secondary POTS by disrupting autonomic stability through nerve injury, systemic stress, or prolonged physical deconditioning. Surgeries involving the spine, chest, abdomen, or brain are especially impactful, as they may inadvertently affect autonomic nerve pathways or interfere with blood volume regulation. For instance, procedures near the vagus nerve or spinal cord can impair the reflexes that control heart rate and vascular tone. Even surgeries unrelated to the nervous system—such as gastrointestinal or orthopedic operations—can create enough physiological stress or fluid imbalance to destabilize the autonomic response to standing.
The postoperative period is also a critical window in which inactivity, blood loss, pain, and medication side effects can converge to trigger or unmask POTS. Opioids, anesthesia, and sedatives may blunt autonomic reflexes, while intravenous fluids, electrolyte shifts, and inflammation alter cardiovascular balance. Recovery often involves weeks of reduced mobility, which leads to cardiovascular deconditioning—a well-known contributor to orthostatic intolerance. For patients with underlying vulnerabilities, such as connective tissue disorders or mild pre-existing dysautonomia, surgery may be the tipping point that transforms a compensated system into one overwhelmed by postural demands, resulting in secondary POTS.
Vaccine Reactions
Vaccine reactions can, in rare cases, lead to secondary POTS by triggering immune-mediated responses that disrupt autonomic function. Most vaccines are safe and do not result in long-term effects, but some individuals—particularly those with underlying vulnerabilities or predispositions—may experience dysautonomia following immunization. This is believed to occur when the immune system, in its effort to build protection, inadvertently becomes overactive or misdirected. Inflammatory responses, molecular mimicry, or post-vaccination immune reprogramming may target small autonomic nerve fibers, leading to symptoms like orthostatic intolerance, rapid heart rate, and fatigue associated with POTS.
These cases are extremely rare and often difficult to distinguish from other post-viral or post-immune syndromes. Some reports have documented POTS-like symptoms following HPV, COVID-19, or influenza vaccinations, though robust data linking vaccines causally to autonomic dysfunction remain limited. In many situations, the reaction may be part of a broader dysautonomic or post-infectious immune shift rather than a direct effect of the vaccine itself. For those affected, early identification and symptom management—including hydration, compression therapy, and autonomic rehabilitation—can aid recovery. As always, the risks of vaccination must be weighed against the often far greater risks of the diseases they prevent, and any suspected adverse event should be discussed with a knowledgeable provider.
Mitochondrial Diseases
Mitochondrial diseases can lead to secondary POTS by impairing the cellular energy production needed for autonomic regulation. These disorders disrupt the function of mitochondria—the “powerhouses” of the cell—resulting in decreased ATP production across various tissues, including nerves, muscles, and vascular structures. When autonomic nerves don’t receive sufficient energy, their ability to maintain vascular tone and coordinate heart rate responses to postural changes weakens, leading to the classic symptoms of POTS: dizziness, tachycardia, and fatigue upon standing.
In addition to nerve involvement, mitochondrial diseases often cause muscle weakness, lactic acidosis, and exercise intolerance, which contribute to cardiovascular deconditioning. These systemic effects reduce the body’s ability to adapt to orthostatic stress, amplifying autonomic dysfunction. Some mitochondrial conditions may also involve multi-organ systems—including the gastrointestinal tract and endocrine system—further stressing autonomic control. Because these diseases are often underdiagnosed and highly variable in presentation, patients may go years without a unifying diagnosis, even as they struggle with overlapping features of dysautonomia and energy metabolism failure.
Chronic Fatigue Syndrome / ME (Myalgic Encephalomyelitis)
Chronic Fatigue Syndrome / Myalgic Encephalomyelitis (CFS/ME) is a complex condition that significantly overlaps with POTS, both in symptoms and suspected mechanisms. Many individuals with CFS/ME experience orthostatic intolerance, tachycardia upon standing, and profound fatigue. Emerging research suggests that both CFS/ME and POTS may involve autonomic nervous system dysfunction, impaired blood flow regulation, and abnormal energy metabolism. Some theorize that viral infections, immune dysregulation, and mitochondrial dysfunction play a role in both conditions, though whether one causes or amplifies the other remains under investigation.
Importantly, CFS/ME often leads to severe activity intolerance and deconditioning, which can exacerbate or mimic POTS-like symptoms. There may also be overlap in underlying drivers such as small fiber neuropathy, mast cell activation, and low blood volume. Because of these parallels, clinicians sometimes struggle to differentiate between the two or determine whether a patient has both. Including CFS/ME in a secondary POTS discussion helps validate the experiences of individuals navigating this blurred diagnostic territory and fosters better integrated care approaches.
Tethered Cord Syndrome
Tethered Cord Syndrome (TCS) can contribute to secondary POTS by exerting continuous tension on the spinal cord, particularly when the filum terminale or spinal cord is abnormally anchored. This tethering can stretch or compress nerves critical to lower autonomic outflow—affecting bowel, bladder, and cardiovascular regulation. When autonomic signals are impaired, blood vessel tone and heart rate adjustments during posture changes may falter, leading to orthostatic intolerance and POTS-like symptoms.
TCS is particularly relevant in individuals with connective tissue disorders such as Ehlers-Danlos Syndrome, where anatomical laxity increases susceptibility. Because TCS symptoms can be vague—ranging from back pain to urinary dysfunction to leg weakness—it’s often overlooked in dysautonomia workups. Advanced imaging and clinical vigilance are crucial. In some cases, surgical release of the tethered cord can improve both neurologic and autonomic symptoms, making it an important structural consideration in complex POTS cases.
Adrenal Disorders
Adrenal Disorders—such as Addison’s disease, adrenal insufficiency, or post-adrenalectomy states—can contribute to secondary POTS by disrupting fluid balance, vascular tone, and the body’s ability to respond to stress. The adrenal glands produce critical hormones like cortisol and aldosterone, which help regulate blood pressure, electrolyte levels, and vascular responsiveness. When adrenal function is compromised, blood volume tends to drop (a condition known as hypovolemia), and vascular tone weakens. Together, these effects impair the autonomic nervous system’s ability to maintain stable circulation when standing.
Patients with adrenal dysfunction often report fatigue, salt cravings, dizziness, and lightheadedness, which overlap significantly with POTS symptoms. During stressful situations or illness, the lack of adequate hormonal support can push the body into a state of autonomic crisis, triggering or worsening orthostatic intolerance. Treatments like corticosteroid replacement can improve some aspects of dysautonomia, though dose timing and sensitivity to fluctuations often require careful management. Adrenal disorders are an often-missed factor in secondary POTS but can be pivotal when identified early.
Postural Structural Syndromes
Postural structural syndromes—including conditions like atlantoaxial instability (AAI), cervicomedullary compression, and craniocervical instability (CCI)—can lead to secondary POTS by compromising mechanical integrity and neural signaling at the junction where the brain connects to the spinal cord. This region houses critical autonomic centers, including the vagus nerve, medulla oblongata, and parts of the sympathetic outflow tract. When ligaments are lax (often due to connective tissue disorders like Ehlers-Danlos Syndrome), even subtle misalignment or instability in this area can compress or irritate these structures, leading to dysautonomia.
Symptoms often fluctuate with posture—aggravated by upright positions, head tilt, or neck movement—and may include dizziness, tachycardia, nausea, headaches, and sensory disturbances. Because these syndromes are mechanically driven, traditional autonomic testing may miss the root cause unless paired with targeted imaging like upright MRI or dynamic flexion-extension views. In some cases, bracing or surgical stabilization can alleviate symptoms if conservative management fails. Including postural structural syndromes in a secondary POTS framework is crucial for recognizing the complex interplay between anatomy and autonomic function—especially in patients who don’t respond to standard dysautonomia treatment.
Medication-Induced POTS
Medication-Induced POTS is an underrecognized but increasingly acknowledged form of secondary dysautonomia. Certain medications—such as vasodilators, antidepressants (especially SNRIs or tricyclics), beta-agonists, stimulants, and withdrawal from beta-blockers—can either unmask latent autonomic instability or directly impair baroreflex function and vascular tone. For example, medications that dilate blood vessels can worsen venous pooling, while others may exaggerate sympathetic nervous system responses, leading to excessive heart rate upon standing.
In susceptible individuals—especially those with pre-existing hypermobility, autoimmune issues, or baseline dysautonomia—even small shifts in neurochemical balance or vascular behavior can push the system past compensation. Additionally, polypharmacy and interactions between drugs can create complex hemodynamic profiles that mirror or intensify POTS. Identifying medication triggers requires a careful clinical history, review of pharmacology, and possibly monitored tapering. Including this category helps patients and providers consider reversible causes that might otherwise be overlooked.
Sleep Disorders
Sleep disorders can contribute to secondary POTS by undermining the body’s ability to restore and regulate autonomic function during rest—particularly through disrupted sleep architecture, oxygenation, and circadian balance. Conditions like obstructive sleep apnea (OSA), insomnia, narcolepsy, and restless leg syndrome impair restorative sleep phases, including slow-wave and REM sleep, which are critical for autonomic nervous system recovery. In OSA, for instance, repeated drops in oxygen levels (hypoxia) and frequent arousals trigger sympathetic surges that dysregulate heart rate variability and blood pressure rhythms over time.
Even in non-apnea sleep disturbances, fragmented or insufficient sleep contributes to baseline fatigue, orthostatic intolerance, and heightened sympathetic tone during the day, all of which mirror or worsen POTS symptoms. Additionally, melatonin disruption and cortisol imbalances—hallmarks of circadian dysregulation—can interfere with vascular reactivity and blood volume regulation. Since many POTS patients report unrefreshing sleep, incorporating formal sleep evaluation into the diagnostic process can unearth important contributors and improve management strategies. Addressing sleep disorders not only enhances daytime energy but also supports long-term autonomic stability, making them a key piece in the POTS puzzle.
