Postural orthostatic tachycardia syndrome

Postural orthostatic tachycardia syndrome (POTS, also postural tachycardia syndrome) is a condition of dysautonomia, to be more specific orthostatic intolerance, in which a change from the supine position to an upright position causes an abnormally large increase in heart rate, called tachycardia. Several studies show a decrease in cerebral blood flow with systolic and diastolic cerebral blood flow (CBF) velocity decreased 44% and 60%, respectively. Patients with POTS have problems maintaining homeostasis when changing position, i.e. moving from one chair to another or reaching above their heads. Many patients also experience symptoms when stationary or even while lying down.

Symptoms present in various degrees of severity depending on the patient. POTS can be severely debilitating. Some patients are unable to attend school or work, and especially severe cases can completely incapacitate the patient.

Symptoms
The hallmark symptom of POTS is an increase in heart rate from the supine to upright position of more than 30 beats per minute or to a heart rate greater than 120 beats per minute within 12 minutes of head-up tilt. This tachycardic response is sometimes accompanied by a decrease in blood pressure and a wide variety of symptoms associated with hypotension. Low blood pressure of any kind may promote the following:


 * lightheadedness, sometimes called pre-syncope (pre-fainting) dizziness (but not vertigo, which is also called dizziness)
 * exercise intolerance
 * extreme fatigue
 * syncope (fainting)
 * Excessive thirst (polydipsia)

Chronic or acute hypoperfusion of tissues and organs in the upper parts of the body are thought to cause the following symptoms:


 * cold extremities
 * chest pain and discomfort
 * disorientation
 * tinnitus
 * dyspnea
 * headache
 * muscle weakness
 * tremulousness
 * visual disturbances

Autonomic dysfunction is thought to cause additional gastrointestinal symptoms:
 * abdominal pain or discomfort
 * bloating
 * constipation
 * diarrhea
 * nausea
 * vomiting

Cerebral hypoperfusion, when present, can cause cognitive and emotive difficulties. Symptoms that persist in the supine (recumbent) state are difficult to attribute to "cerebral hypoperfusion"
 * brain fog
 * burnout
 * decreased mental stamina
 * depression
 * difficulty finding the right word
 * impaired concentration
 * sleep disorders

Inappropriate levels of epinephrine and norepinephrine lead to anxiety-like symptoms:
 * chills
 * feelings of fear
 * flushing
 * overheating
 * nervousness
 * over-stimulation

Symptoms of POTS overlap considerably with those of generalized anxiety disorder, and a misdiagnosis of an anxiety disorder is not uncommon.

Associated conditions

 * POTS is often accompanied by vasovagal syncope, also called "neurally mediated hypotension" (NMH) or "neurocardiogenic syncope" (NCS). Vasovagal syncope is a fainting reflex due to a profound drop in blood pressure. Autonomic dysfunction that occurs with these disorders causes blood to inappropriately pool in the limbs away from the heart, lungs, and brain. The combination of misdirected bloodflow and hypotension will invoke syncope. Tachycardia associated with POTS may be a cardiac response to restore cerebral perfusion.
 * POTS may be coexist with chronic fatigue syndrome as one of the CFS symptoms as part of the orthostatic intolerance of this condition. Treating POTS may improve some of the patients CFS symptoms.
 * Some patients with fibromyalgia complain of dysautonomia-related symptoms. Treating these patients for POTS will often improve myofascial and neuropathic pain.
 * Autonomic dysfunction is most likely responsible for irritable bowel syndrome in many patients as well.
 * Patients with Ehlers-Danlos syndrome may also have POTS. Joint hypermobility is a feature of the most common subtype of Ehlers-Danlos.
 * Some POTS patients experience symptoms associated with restless leg syndrome. Treating POTS should also relieve these symptoms.
 * Some findings link this with hypermobility
 * A small percentage of pediatric cases of POTS have been associated with moderate to severe memory loss.

Causes
The causes of POTS are not fully known. Most patients develop symptoms in their teenage years during a period of rapid growth and see gradual improvement into their mid-twenties. Others develop POTS after a viral or bacterial infection such as mononucleosis or pneumonia. Some patients develop symptoms after experiencing some sort of trauma such as a car accident or injury. Women can also develop POTS during or after pregnancy. These patients generally have a poorer prognosis.

In one large test, 12.5% of 152 patients with POTS reported a family history of orthostatic intolerance, suggesting that there is a genetic inheritance associated with POTS.

So far, no one has provided an explanation for POTS that is applicable to all sufferers. However, there are many theories:


 * Alpha-receptor dysfunction may be occurring in some POTS patients. Alpha-1 receptors cause peripheral  vasoconstriction when stimulated. Alpha-1 receptor supersensitivity may be causing dysautonomia in some patients.


 * An autoimmune process has been suggested as a causal mechanism in many POTS patients, supported by the finding of autoantibodies against ganglionic alpha 3 acetylcholine receptors in a percentage of POTS patients. Anecdotally it has been suggested that POTS patients exhibit higher comorbid autoimmune diseases than the general population and frequently report a family history of autoimmunity or migraine.


 * POTS patients frequently exhibit low blood volume or hypovolumia yet some patients appear to have an abnormal renin-aldosterone response to this volume deficit. This may account for the dramatic improvement some patients experience after intravenous saline.


 * Beta-receptor supersensitivity may occur with hyperadrenergic states in some people with POTS.


 * Hyperdopaminergic states may be the underlying problem for some people with orthostatic intolerance. Some patients have been found to have a significant increase in upright dopamine levels. Free plasma norepinephrine also tends to be higher in these patients. Increased peripheral dopamine is associated with increased extraction of salt from plasma by the kidneys.


 * Reduced venous return is one of the main mechanisms that cause POTS symptoms. Venous return can be reduced due to conditions such as hypovolemia (low plasma volume/low blood volume), venous pooling, and denervation. A hyperadrenergic state may result as the body attempts to compensate for these abnormalities.

Anything that can damage the autonomic nervous system can potentially cause POTS. There are hundreds of things that can cause autonomic nerve damage, for example: Additional causes of Autonomic Neuropathy are described on Medscape.
 * physical traumas to autonomic nerves (car accidents, falls, head/spinal injuries during sports)
 * toxic drug and chemical exposures (heavy metal poisoning, organophosphate pesticide poisoning, some chemotherapy drugs, thallium, pyridoxine, etc.)
 * vitamin deficiencies (B12 is the most common vitamin deficiency associated with autonomic neuropathy)
 * infectious or acute diseases, such as HIV, Diphtheria, Chagas Disease, Lyme Disease, and Guillain Barre Syndrome
 * chronic diseases, such as CIDP, Diabetes, Multiple Sclerosis, Sjogren's Syndrome, Lupus, Celiac Disease and other autoimmune diseases.
 * inherited or genetic diseases (Familial Dysautonomia, Hereditary Sensory Autonomic Neuropathy)

Expression of Norepinephrine transporter (NET) protein appears to be reduced in some POTS patients. Cardiac neurotransmission imaging of norepinephrine reuptake measured utilising MIBG has also been found to be abnormal in some POTS patients, suggesting cardiac denervation or NET deficiency.

Levels or activation of endothelial vasodilating molecules such as nitric oxide or hydrogen sulfide may be increased in some POTS patients.

Sympathetic Overactivity is observed in many POTS patients. The sympathetic overactivity can be secondary to a number of factors, some of which may be peripheral denervation, venous pooling, or end-organ dysfunction. Sympathetic underactivity can also occur in some forms of orthostatic intolerance, such as pure autonomic failure.

Recent studies have described a subset of POTS patients that appear to have elevated angiotensin II levels coupled with paradoxically reduced absolute blood volume, signs of increased sympathetic activity and reduced peripheral blood flow. This subset of POTS patients appear to have abnormal catabolism of Angiotensin II that may contribute to reduced blood volume and orthostatic intolerance.

An epigenetic mechanism (hypermethylation of CpG islands in the NET gene promoter region) that results in reduced expression of the noradrenaline (norepinephrine) transporter and consequently a phenotype of impaired neuronal reuptake of norepinephrine has been implicated in both postural orthostatic tachycardia syndrome and panic disorder.

Diagnosis
POTS can be difficult to diagnose. A routine physical examination and standard blood tests will not indicate POTS. A tilt table test is vital to diagnosing POTS, although all symptoms must be considered before a final diagnosis is made. Tests to rule out Addison's Disease, pheochromocytoma, electrolyte imbalance, Lyme Disease, Celiac Disease, and various food allergies are usually performed. A blood test may be performed to verify abnormally high levels of norepinephrine present in some POTS patients.

Between 75 and 80 percent of POTS patients are female and of the menstruating age. Most male patients develop POTS in their early to mid-teens during a growth spurt or following a viral or bacterial infection. Some women also develop POTS symptoms during or after pregnancy.

Prognosis
Many POTS patients will see symptom improvement over the course of several years. Those who develop POTS in their early to mid teens during a period of rapid growth will most likely see complete symptom resolution by their mid twenties. Patients with post-viral POTS will sometimes improve greatly or even see a full symptom resolution. Adults who develop POTS, especially women during or after pregnancy, usually see milder improvement and can be plagued with their condition for life. Rarely, a teenager who develops POTS will gradually worsen over time and have lifelong symptoms. Patients with secondary POTS as a consequence of Ehlers-Danlos Syndrome will also usually struggle with symptoms for life. In some patients the only cure for POTS is time.

Many adult patients report a relapsing/remitting course characterised by periods of partial remission and occasional 'flare-ups' or exacerbations.

Recovered individuals do complain of occasional, non-debilitating recurrence of symptoms associated with autonomic dysfunction including dizzy spells, lightheadedness, flushing, and transient syncope, as well as symptoms of irritable bowel syndrome. These symptoms are consistent with B12 deficiency in absence of anemia, which should always be ruled out directly by checking B12, homocysteine and methylmalonic acid.

Treatment
Most patients will respond to some form of treatment. Lifestyle changes, in particular drinking extra water and avoiding trigger situations such as standing still or getting hot are necessary for all patients. Some patients also benefit from the addition of other treatments, such as certain medications.

Dietary changes

 * Drinking more water improves symptoms for nearly all patients. Most patients are encouraged to drink at least 64 ounces (two liters) of water or other hydrating fluids each day.
 * Alcohol has been shown to drastically exacerbate all types of orthostatic intolerance due to its vasodilation and dehydration properties. In addition to its adverse effects, it interacts unfavorably with many of the medications prescribed for POTS patients.
 * Eating frequent, small meals can reduce gastrointestinal symptoms associated with POTS by requiring the diversion of less blood to the abdomen.
 * Increasing salt intake, by adding salt to food, taking salt tablets, or drinking sports drinks and other electrolyte solutions (most doctors recommend drinking Gatorade or Pedialyte, or Nuun active hydration tablets), is a treatment used for many people with POTS; however, salt is not recommended for all patients. Increasing salt is an effective way to raise blood pressure in many patients with orthostatic hypotension by helping the body retain water and thereby expanding blood volume.  Different physicians recommend different amounts of sodium to their patients.
 * Diets high in carbohydrates have been connected to impaired vasoconstrictive action. Eating foods with lower carbohydrate levels can mildly improve POTS symptoms.
 * Some patients report an improvement in symptoms after switching to a strict gluten-free diet, even if they have tested negative for Celiac Disease.
 * Caffeine helps some POTS patients due to its stimulative effects; however, other patients report a worsening of symptoms with caffeine intake.
 * Tilting of the head of the bed to an angle of roughly 30 degrees can also help reduce symptoms.

Physical therapy and exercise
Exercise is very important for maintaining muscle strength and avoiding deconditioning. Though many POTS patients report difficulty exercising, some form of exercise is essential to controlling symptoms and, eventually, improving the condition. Exercises that improve leg and abdominal strength may aid in improving the muscle pump and, therefore, preventing pooling of blood in the abdomen and lower extremities.

Aerobic exercise performed for 20 minutes a day, three times a week, is sometimes recommended for patients that can tolerate it. Certain modalities of exercise may be more tolerable initially, such as riding a recumbent bicycle or swimming. However, as tolerable, upright exercise may benefit the participant through orthostatic training. All exercise programs for POTS patients should begin with low-intensity exercises for a short duration and progress slowly.

Medications
Patients whose POTS symptoms are due to B12 deficiency need pharmacological doses of B12 for repletion of tissues.

Several classes of drugs often provide symptom control and relief for POTS patients. Treatments must be carefully tested due to medication sensitivity often associated with POTS patients, and each patient will respond to different therapies in different ways.

The first drug of choice for symptomatic relief of POTS is usually fludrocortisone, or Florinef, a mineralcorticoid used to increase sodium retention and thus increase blood volume and blood pressure. An increase in sodium and water intake must coincide with fludrocortisone therapy for effective treatment.

Dietary increases in sodium and sodium supplements are often used.

Beta blockers such as atenolol, metoprolol and propanolol are often prescribed to treat POTS. These medications slow down the excessive heart rate response (tachycardia) that POTS patients experience. They also work by blocking the effects of epinephrine and norepinephrine released by the Autonomic Nervous System. In addition, beta blockers reduce Sympathetic Nervous System activity by blocking Sympathetic impulses. For some patients, Beta blockers increase POTS symptoms (e.g., lowering blood pressure, increasing fatigue, which is why they are often prescribed in conjunction with Midodrine). Beta blockers may be dangerous to individuals with asthma or allergies.

Midodrine (Proamatine), is approved by the U.S. Food and Drug Administration (FDA) to treat orthostatic hypotension, a condition related to POTS. It is a stimulant that causes vasoconstriction and thereby increases blood pressure and allows more blood to return to the upper parts of the body. Use of midodrine is often discontinued due to intolerable side-effects, and it is known to cause supine hypertension (high blood pressure when lying down). Some doctors prefer to start patients on Midodrine without the concomitant use of Beta blockers and then add Beta blockers once the dose of Midodrine has been properly adjusted. This gives the Midodrine time to start raising the patient's blood pressure which often helps avoid the hypotension that is a common side effect of Beta blockers. Obviously lowering the blood pressure of a POTS patient would exacerbate any existing orthostatic hypotension.

Antidepressants, especially selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (Prozac), sertraline (Zoloft), citalopram (Celexa), escitalopram (Lexapro), and paroxetine (Paxil), can be extremely effective in re-regulating the autonomic nervous system and raising blood pressure. Some studies indicate that serotonin-norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine (Effexor) and duloxetine (Cymbalta) are even more effective. Tricyclic antidepressants, tetracyclic antidepressants, and monoamine oxidase inhibitors are also occasionally, but rarely, prescribed. A combination of two antidepressants, usually an SSRI or SNRI with bupropion (Wellbutrin) or mirtazapine (Remeron), is also shown to be very effective.

Medications used to treat attention deficit disorder and attention deficit hyperactivity disorder such as methylphenidate (Ritalin) and Adderall effectively increase norepinehprine and dopamine levels, thereby increasing vasoconstriction and blood pressure. Central Net inhibition can reduce sympathetic outflow through stimulation of A2 adrenoreceptors.

In some cases, when increasing oral fluids and salt intake is not enough, intravenous saline is used to help increase blood volume, as many POTS patients suffer from hypovolemia. Increasing blood volume can decrease POTS symptoms caused or worsened by low blood volume such as tachycardia, low blood pressure, fatigue, and syncope. Infusions can be taken on an as-needed basis in an Emergency Room, or on a regularly scheduled manner at an infusion center or at home with the assistance of a home-care nurse. Many patients report a profound though short-lived improvement in their symptoms from saline infusions.

In the UK, Ivabradine has been used to treat patients with POTS symptoms with good effect. Ivabradine acts by reducing the heart rate in a mechanism different from that of beta blockers and calcium channel blockers, two commonly prescribed antianginal drugs. It is classified as a cardiotonic agent.


 * Anti-anxiety medications, such as alprazolam (Xanax), lorazepam (Ativan), and clonazepam (Klonopin), can be used to combat imbalances of adrenaline usually seen with POTS patients.
 * Angiotensin converting enzyme inhibitors, or ACE inhibitors, are used to increase vascular capacity, cardiac output, and sodium and water excretion.
 * Clonidine can work in patients with reduced sympathetic activity. Clonidine lowers catecholamine(epinephrine and norepinephrine) production. This appears paradoxical, as Clonindine is normally associated with reduced sympathetic drive through a2 adrenoreceptor stimulation.
 * Disopyramide (Norpace) is an antiarrhythmic medication that inhibits the release of epinephrine and norepinephrine.
 * Erythropoietin, used to treat anemia via intravenous infusion, is very effective at increasing blood volume. It is seldom used, however, due to the dangers of increasing the hematocrit, the inconvenience of intravenous infusion, and its prohibitively expensive cost.
 * Pregabalin (Lyrica), an anticonvulsant drug, has been shown to be especially effective in treating neuropathic pain associated with POTS. In fact, Lyrica was the first and, for its first year on the market, the only prescription drug approved by the FDA to treat fibromyalgia. Some POTS patients also report improvement in concentration and energy while on Lyrica.
 * Pseudoephedrine and phenylephrine, over-the-counter decongestants, increase vasoconstriction by promoting the release of norepinephrine.
 * Pyridostigmine (Mestinon), inhibits the breakdown of acetylcholine, promoting autonomic nervous system activity. It is especially effective in patients exhibiting symptoms of excessive sympathetic activity.
 * Theophylline, a drug used to treat respiratory diseases such as COPD and asthma, is occasionally prescribed at low doses for POTS patients. Theophylline increases cardiac output, increases blood pressure, and stimulates epinephrine and norepinephrine production. Due to its very narrow therapeutic index, Theophylline is known to cause a wide variety of side-effects and even toxicity.
 * Women who report a worsening of symptoms during menstruation will often use combined (containing both estrogen and progestin) forms of hormonal contraception to prevent hormonal changes and an aggravation of their condition.
 * IVIG (Intravenous Immunoglobulin) infusions may be helpful for patients whose POTS is caused by autonomic neuropathy associated with Guillain Barre Syndrome, Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), Sjogren's Syndrome or other autoimmune diseases.
 * Dihydroergotamine or DHE may be useful in some patients as a selective venoconstrictor through serotoninic receptor agonism.

Recently it has become a popular belief that medical marijuana may have positive effects on POTS patients. However, there is little evidence supporting its efficacy, and the active constituents of marijuana are often associated with postural hypotension.

There are anecdotal reports of benefit being derived from Horse Chestnut seed extract (Aescin), Rehmannia glutinosa, Licorice root, and Ruscus aculeatus (Butcher Broom) however there is currently no research to support the efficacy of these herbal remedies that is specific to POTS.

External body pressure
Pressure garments can reduce symptoms associated with orthostatic intolerance by constricting blood pressures with external body pressure.

Compression devices, such as abdominal binders and compression stockings, help to reduce the amount of pooling blood. Compression stockings should be at least 30–40 mm Hg and will work best if they are waist-high. Compression stockings should be fitted to achieve the greatest benefit. If the patient finds compression stockings of 30-40 mmHg to be too uncomfortable, consider a lesser compression such as 20-30 mmHg. Many patients see improvement with that level of compression, with full-length/waist-high stockings.

Compressions suits (G-Suits) have also been used with some good results.

Changes in environment
Some patients report that symptoms worsen with changes in barometric pressure (for instance, before a thunderstorm) and changes from outdoors to indoors (it is presumed that barometric pressure is higher inside) and depending on weight of clothes and coverage. These patients may find relief by moving to a new location where barometric pressure is relatively stable, e.g. San Diego.

History
POTS was first named and identified by Schondorf and Low in 1993; however, the syndrome has been described in medical studies dating back to at least 1940. Hypertension associated with POTS has been previously described as the "hyperadrenergic syndrome" by Streeten and as "idiopathic hypovolemia" by Fouad. Hypotension associated with POTS has been previously described as the "neurally mediated hypotension" form of POTS.