Dysautonomia  – Causes, Symptoms, Diagnosis, Treatment

Autoimmune dysautonomia encompasses severe sympathetic and parasympathetic failure with relative preservation of motor and sensory function disorders of peripheral autonomic synapses, ganglionic neurons, autonomic nerve fibers, and central autonomic pathways mediated by neural-specific IgG or effector T cells. These disorders may be idiopathic or paraneoplastic, subacute or insidious in onset, and may present as a limited disorder or generalized pandysautonomia. Pandysautonomia is usually subacute in onset and severe and includes impaired pupillary light reflex, anhidrosis, orthostatic hypotension, cardiac arrhythmias, gastrointestinal dysmotility, sicca manifestations, and bladder dysfunction.

Dysautonomia refers to an abnormality of function of the autonomic nervous system. There are two divisions of the autonomic nervous system: the sympathetic and the parasympathetic. Although the latter occasionally may be involved, abnormal function of the sympathetic division produces the most striking symptoms of dysautonomic syndromes. The term orthostatic hypotension is often used as a synonym for dysautonomia. It is the most dramatic of the symptoms and is the one that most often brings the patient to the physician, but it is not an adequate description of the full dysautonomic syndrome.

Types of Dysautonomia

There are at least 15 different types of dysautonomia.

The most common is neurocardiogenic syncope and postural orthostatic tachycardia syndrome (POTS).

Neurocardiogenic syncope

Neurocardiogenic syncope (NCS) is the most common dysautonomia. It affects tens of millions of people worldwide. The main symptom is fainting, also called syncope. This can occur on occasion only, or it may be frequent enough to disrupt a person’s daily life.

Gravity naturally pulls the blood downward, but a healthy ANS adjusts the heartbeat and muscle tightness to prevent blood pooling in the legs and feet, and to ensure blood flow to the brain. NCS involves a failure in the mechanisms that control this. Temporary loss of blood circulation in the brain causes fainting.

Most treatments aim to reduce symptoms. For people who faint only occasionally, avoiding certain triggers can help.

Triggers include:

  • dehydration
  • stress
  • alcohol consumption
  • very warm environments
  • tight clothing

Medication such as beta-blockers and pacemakers may be used to treat persistent or severe cases of NCS.

Postural orthostatic tachycardia syndrome

Postural orthostatic tachycardia syndrome (POTS) affects between 1 and 3 million people in the United States (U.S.). Around 80 percent of them are female. It often affects people with an autoimmune condition.

Symptoms can include:

  • lightheadedness and fainting
  • tachycardia, or abnormally fast heart rate
  • chest pains
  • shortness of breath
  • stomach upset
  • shaking
  • becoming easily exhausted by exercise
  • over-sensitivity to temperatures

POTS is normally a secondary dysautonomia. Researchers have found high levels of auto-immune markers in people with the condition, and patients with POTS are also more likely than the general population to have an autoimmune disorder, such as multiple sclerosis (MS), as well.

Apart from auto-immune factors, conditions that have been linked to POTS or POTS-like symptoms include:

  • some genetic disorders or abnormalities
  • diabetes
  • Ehlers-Danlos Syndrome, a collagen protein disorder that can lead to joint hypermobility and “stretchy” veins
  • infections such as Epstein-Barr virus, Lyme disease, extra-pulmonary Mycoplasma pneumonia, and hepatitis C
  • toxicity from alcoholism, chemotherapy, and heavy metal poisoning
  • trauma, pregnancy, or surgery

Research into the causes of POTS is ongoing. Some scientists believe it might be due to a genetic mutation, while others think it is an autoimmune disorder.

Multiple system atrophy

Multiple system atrophy (MSA) is less common than POTS and NCS.

MSA is estimated to affect between 2 and 5 people in every 100,000. It is often mistaken for Parkinson’s disease because the early symptoms are similar.

In the brains of people with MSA, certain regions slowly break down, in particular the cerebellum, basal ganglia, and brain stem. This leads to motor difficulties, speech issues, balance problems, poor blood pressure, and problems with bladder control.

MSA is not hereditary or contagious, and it is not related to MS. Researchers know little else about what may cause MSA. As a result, there is no cure and no treatment. This is because of its slow progression. Treatment can, however, manage specific symptoms through lifestyle changes and medications.

Autonomic dysreflexia

Autonomic dysreflexia (AD) most often affects people with injuries to the spinal cord. AD normally involves irritation of the region below the level of a patient’s injury. This could be an infection or constipation. As a result, it is classed as secondary dysautonomia.

A range of conditions and injuries can bring on AD. These include, but are not limited to, urinary tract infections (UTI) and skeletal fractures.

The damaged spine prevents pain messages from reaching the brain. The ANS reacts inappropriately, producing severe spikes in blood pressure.

Symptoms include:

  • headache
  • red face
  • blotchy skin
  • blocked nose
  • a slow pulse
  • nausea
  • goosebumps and clammy skin near the site of the injury

Most treatments aim to relieve the initial injury or irritation. This prevents further attacks of AD.

Baroreflex failure

The baroreflex mechanism is one way in which the body maintains healthy blood pressure.

Baroreceptors are stretch receptors situated in important blood vessels. They detect stretching in the artery walls and send messages to the brainstem.

If these messages fail, blood pressure can be too low when resting, or it can rise dangerously during times of stress or activity.

Other symptoms include headaches, excessive sweating, and an abnormal heart rate that does not respond to medication.

Treatment for baroreflex failure involves medications to control heart rate and blood pressure, and interventions to improve stress management.

Diabetic autonomic neuropathy

Diabetic autonomic neuropathy affects an estimated 20 percent of people with diabetes, which equates to around 69 million people worldwide. The condition affects the nerves that control the heart, regulate blood pressure, and control blood glucose levels.

Symptoms can include the following:

  • resting tachycardia, or a fast resting heart rate
  • orthostatic hypotension, or low blood pressure when standing
  • constipation
  • breathing problems
  • gastroparesis, or food not correctly passing through the stomach
  • erectile dysfunction
  • sudomotor dysfunction, or irregularities with sweating
  • impaired neurovascular function
  • “brittle diabetes,” usually type I, characterized by frequent episodes of hyperglycemia and hypoglycemia

Treatment for diabetic autonomic neuropathy focuses on the careful management of diabetes. In some cases, medications such as antioxidants and aldose reductase inhibitors can reduce symptoms.

Familial dysautonomia

Familial dysautonomia (FD) is a very rare type of dysautonomia. It only affects an estimated 350 people, almost entirely of Ashkenazi Jewish descent with roots in Eastern Europe.

Symptoms normally appear in infancy or childhood and include:

  • feeding difficulties
  • slow growth
  • inability to produce tears
  • frequent lung infections
  • difficulty maintaining the right temperature
  • prolonged breath-holding
  • delayed development, including walking and speech
  • bed-wetting
  • poor balance
  • kidney and heart problems

The condition often leads to a syndrome called an autonomic crisis. This involves rapid fluctuations in blood pressure and heart rate, dramatic personality changes, and complete digestive shutdown.

  • Neurocardiogenic syncope (NCS) – NCS is the most common form of dysautonomia. It can cause fainting spells that happen once or twice in your lifetime or multiple times every day. NCS is also called situational syncope or vasovagal syncope.
  • Familial dysautonomia (FD) – People inherit this type of dysautonomia from their genetic relatives. It can cause decreased pain sensitivity, lack of eye tears, and trouble regulating body temperature. FD is more likely to affect Jewish people (Ashkenazi Jewish heritage) of Eastern European heritage.
  • Multiple system atrophy (MSA) – A life-threatening form of dysautonomia, multiple system atrophy develops in people over 40 years old. It can lead to heart rate issues, low blood pressure, erectile dysfunction, and loss of bladder control.
  • Pure autonomic failure –  People with this form of dysautonomia experience a fall in blood pressure upon standing and have symptoms including dizziness, fainting, visual problems, chest pain, and tiredness. Symptoms are sometimes relieved by lying down or sitting.

Causes of Dysautonomia

A myriad of the factors can cause autonomic dysfunction, and more than one can concur even in the same patient. The most common factors known to cause autonomic dysfunction include the following:

  • Degenerative neurologic diseases, such as Parkinson’s disease, multiple-system atrophy, pure autonomic failure presenting or suffering from Orthostatic Hypotension (OH), fixed heart rate responses, etc.
  • An immune-mediated attack, either idiopathic or paraneoplastic, can be a source of focal or generalized autonomic dysfunction, as in Guillain-Barre syndrome, or autoimmune autonomic ganglionopathy
  • Metabolic and toxic damage, as in diabetes mellitus, amyloidosis, and Fabry disease
  • Genetic disorders, like dopamine-beta-hydroxylase deficiency and familial dysautonomia
  • Abnormal reflex responses in carotid sinus hypersensitivity, vasovagal syncope, and other neuro-meditated syncopes; and probably in Postural Tachycardia Syndrome (PoTS)
  • Abnormal sweating responses, as in generalized or focal hyperhidrosis, related to an excessive activation
  • Traumatic or tumoral spinal cord injuries at different levels and presenting with the so-called autonomic dysreflexia
  • Pharmacologic effects of several drugs that interfere with normal autonomic function and provoke symptoms include alpha- and beta-blocker-triggered OH

Dysautonomia may be due to inherited or degenerative neurologic diseases (primary dysautonomia) or it may occur due to injury of the autonomic nervous system from an acquired disorder (secondary dysautonomia).[1][12] The most common causes of dysautonomia include

  • Alcoholism
  • Amyloidosis
  • Autoimmune disease, such as Sjögren’s syndrome or systemic lupus erythematosus (lupus), and autoimmune autonomic ganglionopathy
  • Craniocervical instability
  • Diabetes
  • Eaton-Lambert syndrome
  • Ehlers-Danlos syndrome[rx]
  • Guillain-Barré syndrome[rx]
  • HIV and AIDS[rx]
  • Long COVID[rx]
  • Multiple sclerosis[rx]
  • Paraneoplastic syndrome[rx]
  • Spinal cord injury[rx]
  • Synucleinopathy, a group of neurodegenerative diseases including dementia with Lewy bodies, multiple system atrophy, and Parkinson’s disease[6]
  • Surgery or injury involving the nerves[rx]
  • Toxicity (vincristine)

In the sympathetic nervous system (SNS), predominant dysautonomia is common along with fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, and interstitial cystitis, raising the possibility that such dysautonomia could be their common clustering underlying pathogenesis.[rx]

In addition to sometimes being a symptom of dysautonomia, anxiety can sometimes physically manifest symptoms resembling autonomic dysfunction. A thorough investigation ruling out physiological causes is crucial, but in cases where relevant tests are performed and no causes are found or symptoms do not match any known disorders, a primary anxiety disorder is possible, but should not be presumed.[rx] For such patients, the anxiety sensitivity index may have better predictivity for anxiety disorders, while the Beck anxiety inventory may misleadingly suggest anxiety for patients with dysautonomia.[rx]

Symptoms of Dysautonomia

Symptoms can be hard to predict. These effects can come and go and normally vary in how severe they are. A particular physical activity can trigger more severe symptoms. This may cause people with dysautonomia to avoid overexertion.

Common symptoms include:

  • an inability to stay upright
  • dizziness, vertigo, and fainting
  • fast, slow, or irregular heartbeat
  • chest pain
  • low blood pressure
  • problems with the gastrointestinal system
  • nausea
  • disturbances in the visual field
  • weakness
  • breathing difficulties
  • mood swings
  • anxiety
  • fatigue and intolerance to exercise
  • migraines
  • tremors
  • disrupted sleep pattern
  • frequent urination
  • Temperature Regulation Problems
  • concentration and memory problems
  • poor appetite
  • overactive senses, especially when exposed to noise and light

The symptoms of dysautonomia, which are numerous and vary widely for each individual, are due to inefficient or unbalanced efferent signals sent via both systems.  The primary symptoms in individuals with dysautonomia include

  • Anhydrosis
  • Anxiety
  • Blurry or double vision
  • Bowel incontinence
  • Brain fog
  • Constipation
  • Dizziness
  • Difficulty swallowing
  • Exercise intolerance
  • Insomnia
  • Low blood pressure
  • Orthostatic hypotension
  • Syncope
  • Tachycardia[rx]
  • Tunnel vision[rx]
  • Urinary incontinence or urinary retention[rx]
  • Vertigo[rx]
  • Weakness[r]

Diagnosis of Dysautonomia

Valsalva maneuver – The diagnosis of dysautonomia depends on the overall function of three autonomic functions – cardiovagal, adrenergic, and sudomotor. A diagnosis should, at a bare minimum, include measurements of blood pressure and heart rate while lying flat, and after at least 3 minutes of standing. The best way to achieve a diagnosis includes a range of testing, notably an autonomic reflex screen, tilt table test, and testing of the sudomotor response (QSART or thermoregulatory sweat test).[rx]

Additional tests and examinations to determine a diagnosis of dysautonomia include

  • Ambulatory blood pressure and EKG monitoring
  • Cold pressor test[rx]
  • Deep breathing[rx]
  • Hyperventilation test[rx]
  • Nerve biopsy for small fiber neuropathy[rx]
  • Quantitative sudomotor axon reflex test (QSART)[rx]
  • Testing for orthostatic intolerance[rx]
  • Thermoregulatory sweat test[rx]
  • Tilt table test[rx]
  • Valsalva maneuver[rx]
  • Evaluation for acute (intermittent) porphyria.[rx]
  • Evaluation of cerebrospinal fluid by lumbar puncture[rx]

Vegetative-vascular dystonia

Particularly in the Russian literature,[rx] a subtype of dysautonomia which particularly affects the vascular system has been called vegetative-vascular dystonia. The term “vegetative” reflects an older name for the autonomic nervous system: the vegetative nervous system.

Reference Values

Test ID Reporting name Methodology Reference value
ARBI ACh Receptor (Muscle) Binding Ab Radioimmunoassay (RIA) < or =0.02 nmol/L
GANG AChR Ganglionic Neuronal Ab, S RIA < or =0.02 nmol/L
ANN1S Anti-Neuronal Nuclear Ab, Type 1 Indirect Immunofluorescence (IFA) <1:240
DPPIS DPPX Ab IFA, S IFA Negative
GD65S GAD65 Ab Assay, S RIA < or =0.02 nmol/L

Reference values apply to all ages.

VGKC Neuronal (V-G) K+ Channel Ab, S RIA < or =0.02 nmol/L
CCN N-Type Calcium Channel Ab RIA < or =0.03 nmol/L
CCPQ P/Q-Type Calcium Channel Ab RIA < or =0.02 nmol/L
STR Situational (Striated Muscle) Ab, S ELISA <1:120

Reflex Information:

Test ID Reporting name Methodology Reference value
ARMO ACh Receptor (Muscle) Modulating Ab Live-cell assay (LCA) <20% loss

(reported as __% loss of AChR)

AMPCS AMPA-R Ab CBA, S Cell-binding assay (CBA) Negative
AMPIS AMPA-R Ab IF Titer Assay, S IFA <1:120
AMPHS Amphiphysin Ab, S IFA <1:240
AMIBS Amphiphysin Immunoblot, S Immunoblot (IB) Negative
AN1BS ANNA-1 Immunoblot, S IB Negative
AN2BS ANNA-2 Immunoblot, S IB Negative
CS2CS CASPR2-IgG CBA, S CBA Negative
CRMWS CRMP-5-IgG Western Blot, S Western blot (WB) Negative
CRMS CRMP-5-IgG, S IFA <1:240
DPPCS DPPX Ab CBA, S CBA Negative
DPPTS DPPX Ab IFA Titer, S IFA <1:120
GABCS GABA-B-R Ab CBA, S CBA Negative
GABIS GABA-B-R Ab IF Titer Assay, S IFA <1:120
LG1CS LGI1-IgG CBA, S CBA Negative
NMDCS NMDA-R Ab CBA, S CBA Negative
NMDIS NMDA-R Ab IF Titer Assay, S IFA <1:120
WBN Paraneoplastic Autoantibody WBlot, S WB Negative
PCTBS PCA-Tr Immunoblot, S IB Negative
PCABP Purkinje Cell Cytoplasmic Ab Type 1 IFA <1:240
PCAB2 Purkinje Cell Cytoplasmic Ab Type 2 IFA <1:240
PCATR Purkinje Cell Cytoplasmic Ab Type Tr IFA <1:240

Neuron-restricted patterns of IgG staining that do not fulfill criteria for ANNA-1, ANNA-2, CRMP-5-IgG, PCA-1, PCA-2, or PCA-Tr may be reported as “unclassified anti-neuronal IgG.” Complex patterns that include non-neuronal elements may be reported as “uninterpretable.

Treatment of Dysautonomia

  • H2– receptor antagonist – The treatment of dysautonomia can be difficult; since it is made up of many different symptoms, a combination of drug therapies is often required to manage individual symptomatic complaints. Therefore, if autoimmune neuropathy is the case, then treatment with immunomodulatory therapies is done, or if diabetes mellitus is the cause, control of blood glucose is important.[rx] Treatment can include proton-pump inhibitors and H2 receptor antagonists used for digestive symptoms such as acid reflux.[rx]
  • Monophosphate type-5 phosphodiesterase inhibitor – For the treatment of genitourinary autonomic neuropathy, medications may include sildenafil (a guanine monophosphate type-5 phosphodiesterase inhibitor). For the treatment of hyperhidrosis, anticholinergic agents such as trihexyphenidyl or scopolamine can be used, also an intracutaneous injection of botulinum toxin type A can be used for management in some cases.[rx]
  • Balloon angioplasty – a procedure referred to as transvascular autonomic modulation, is specifically not approved for the treatment of autonomic dysfunction.[rx]
  • Fludrocortisone – a synthetic mineralocorticoid aldosterone analog, increases salt retention and plasma volume. Adverse hypertension, hypokalemia, and headaches may be present.
  • The alpha-1-adrenergic agonist midodrine – causes systemic vasoconstriction leading to an increase in venous return that may be effective in hypotensive phenotypes. Limitations include frequent dosing, urinary retention, and supine hypertension.
  • Clonidine and alpha-methyldopa – are central-acting alpha-2 agonist sympatholytics that may be beneficial in hyperadrenergic subtypes with hypertension as a predominant symptom. May cause adverse sedation, cognitive clouding, and fatigue.
  • Beta-blockers (propranolol, metoprolol) – may reduce upright tachycardia without significant hemodynamic changes. However, worsening fatigue is a concern.
  • Pyridostigmine is an acetylcholinesterase inhibitor – that increases acetylcholine levels in the autonomic ganglia. In turn, this may reduce tachycardia with minimal hemodynamic effects; however worsening cramps, vomiting, and urinary symptoms often limit continued use.

Generally, medications exacerbating specific symptoms such as tachycardia (sympathomimetics including amphetamines, selective serotonin and/or norepinephrine reuptake inhibitors, droxidopa) or worsening orthostatic intolerance (diuretics, calcium channel blockers, nitrates, opiates, tricyclic antidepressants) should be avoided; in specific cases, it may be beneficial in accordance with the patient’s history and presentation.

Complication

Sympathetic innervation is also important in sexual performance. There is a series of events in the sexual experience that all have some dependence on a normally functioning sympathetic nervous system.

  • Arousal – Visual stimuli, fantasy, and other cortical events, integrated with thalamic and hypothalamic impulses, all appear to be important to sexual interest (libido) and arousal. The integrated outflow of these higher neurologic centers seems to involve the sympathetic system, since many drugs that inhibit aspects of CNS sympathetic function diminish the libido; and in the experimental study, a CNS sympathetic stimulator, yohimbine, appears to be aphrodisiac in rats.
  • Tumescence The actual engorgement of genital structures with blood is mediated by sympathetic outflow both from central nervous system centers and through spinal reflexes. In men, this is potency—penile erection. In women, tumescence is manifested as clitoral erection and labial engorgement.
  • Recruitment – Secretions from the testes, seminal vesicles, and prostate are mobilized by the smooth muscle motor-propulsive activity of ductile structures, all of which are richly innervated and respond to sympathetic stimuli. The lubrication process involving secretions from glandular structures of the labia and vagina probably represents the analogous event in women.
  • EjaculationThis is a reflex event mediated in the sacral division of the spinal cord by a parasympathetic loop and is rarely if ever inhibited in dysautonomia or by drugs. Normal anterograde ejaculation, however, depends on adequate closure of the bladder sphincter. This is, as noted, a sympathetic motor function and will be impaired in some dysautonomic syndromes, particularly in diabetes, and by certain drugs.
    The consequence of the failure of sympathetic stimulation to cause closure of the bladder sphincter during the parasympathetic reflex event of ejaculation is retrograde ejaculation. Even though the ejaculatory sensation is present, the failure to emit seminal fluid is a bothersome symptom. It can be sufficiently disquieting to the patient to compromise prescription compliance severely.
    The event in women corresponding to ejaculation is not known. The muscular contractions of the vagina and uterus that occur at the time of climax may be mediated by the parasympathetic reflex system, but this has not been demonstrated.
  • Climax – The autonomic events associated with the culmination of sexual stimulation have the characteristics of a generalized discharge of the sympathetic nervous system. Blood pressure rises, heart rate rises, piloerection occurs, etc. Some drugs that inhibit sympathetic outflow have been described by individual patients, both men and women, as delaying or diminishing the sensation of climax. These reports are apocryphal and have not been studied in a systematic or controlled manner.

What can I do to better live with dysautonomia?

To help manage your dysautonomia symptoms:

  • Do not smoke or drink alcoholic beverages.
  • Eat a healthy diet.
  • Drink a lot of water. Carry water with you at all times.
  • Add extra salt to your diet. Keep salty snacks with you.
  • Get plenty of sleep.
  • Maintain a healthy weight.
  • Keep your blood sugar within normal limits if you have diabetes.
  • Listen to what your body is telling you it needs. For example, take breaks from work or school if your body is telling you it needs rest.
  • If you feel dizzy, sit down, lie down, and/or raise your feet.
  • Stand up slowly.
  • Wear compression stockings and support garments to increase/maintain blood pressure
  • Avoid sitting or standing for long periods of time.
  • Avoid heat. Take lukewarm or cool baths and showers.
  • Talk with your healthcare provider before taking any over-the-counter medicine or supplement.
  • Ask your healthcare provider if you can drink caffeinated beverages or eat foods with artificial sweeteners. Caffeine should be avoided if you have a raised heart rate. Artificial sweeteners can cause migraines in some people.

References

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