The autonomic nervous system (ANS) is a subcomponent of the peripheral nervous system (PNS) that regulates involuntary physiologic processes, including blood pressure, heart rate, respiration, digestion, and sexual arousal. It comprises sympathetic, parasympathetic, and enteric nervous systems, which are three anatomically distinct divisions. The sympathetic nervous system (SNS), as well as the parasympathetic nervous system (PNS), contain afferent fibers that provide sensory input and efferent fibers that provide motor output to the central nervous system (CNS). The SNS and PNS motor pathways incorporate a two-neuron series: a pre-ganglionic neuron with a cell body in the CNS and a post-ganglionic neuron with a cell body in the periphery that innervates target tissues. The enteric nervous system (ENS) is a large, web-like structure capable of functioning independently of the remainder of the nervous system. It is chiefly responsible for regulating digestive processes and contains over a hundred million neurons of over fifteen morphologies, greater than the sum of all other peripheral ganglia.
The autonomic nervous system (ANS) includes all regions implicated in controlling “autonomic,” unconscious, and involuntary functions in total body homeostasis. In general, the full range of physiologic functions are ultimately necessary for human survival and allow us to interact with the external environment in a wide range of conditions. Together with the slow-acting, long-lasting effects of the endocrine system, the ANS exerts its fast-acting, short-lived effects on the following functions (among others):
- Perfusion of the whole body through regulation of heart rate and blood pressure
- Homoeothermic role through sweating control and shivering,
- Processing of nutrients through control and coordination of different parts of the gut and glands,
- Urinary motility, and
- Pupil movement, focusing, and lacrimation.
Table 1. Autonomic nervous system functions
|Organ||Sympathetic activation||Parasympathetic activation|
Relax (far vision)
Dilation (dilator muscle)
Constrict (near vision)
Constriction (sphincter muscle)
Rate (sinus node)
Decreased or none
|Gastrointestinal tract||Decrease motility||Increase motility|
|Kidney||Antidiuresis (decreased output)||None|
|Clitoris, labia minora||None||Swelling/ Erection|
Constriction, volume mobilization
Glycolysis, glucose mobilization
Dysfunction of one or more subdivisions of the ANS, when accompanying other diseases, is linked to a worse prognosis of the latter. In some circumstances or when severe, dysfunction of ANS itself results in symptoms and disability, which may, in turn, prompt treatment.
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A myriad of the factors can cause autonomic dysfunction, and more than one can concur even in the same patient. Due to the expansive nature of the autonomic nervous system, it can be affected by a wide range of conditions. The most common factors known to cause autonomic dysfunction include the following:
- Amyloidosis, Fabry disease, hereditary sensory autonomic neuropathy, porphyrias
- Genetic disorders like familial dysautonomia and dopamine-beta-hydroxylase deficiency
- Autoimmune: Guillain-Barre, Autoimmune autonomic ganglionopathy, Lambert-Eaton myasthenic syndrome, rheumatoid arthritis, Sjogren, systemic lupus erythematosus
- 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, are related to excessive activation.
- Metabolic/ Nutritional: Diabetes mellitus, vitamin B12 deficiency
- Degenerative neurologic diseases: Parkinson disease, multiple system atrophy/Shy-Drager syndrome, pure autonomic failure presenting or suffering from orthostatic hypotension, fixed heart rate responses
- Infections: Botulism, Chagas disease, human immunodeficiency virus (HIV), leprosy, Lyme disease, tetanus
- Neoplasia: Brain tumors, paraneoplastic syndromes
- Pharmacologic effects of several drugs that interfere with normal autonomic function and provoke symptoms include alpha- and beta-blocker-triggered orthostatic hypotension
- Toxin/drug-induced: Alcohol, amiodarone, chemotherapy
- Traumatic or tumoral spinal cord injuries at different levels and presenting with the so-called autonomic dysreflexia
- Uremic neuropathy/chronic liver diseases
Medications That Exacerbate Orthostatic Hypotension
- Diuretics: furosemide, torsemide, thiazide
- Nitric oxide-mediated vasodilators: nitroglycerine, hydralazine, sildenafil
- Adrenergic antagonists:
- Alpha-1-adrenergic blockers: alfuzosin, terazosin
- Beta-adrenergic blockers: propranolol
- Alpha -2-adrenergic agonists: tizanidine, clonidine
- Renin-angiotensin system inhibitors: lisinopril, valsartan
- Dopamine antagonists:
- Phenothiazines: chlorpromazine
- Atypical antipsychotics: olanzapine, risperidone, quetiapine
- Calcium channel blockers: verapamil, diltiazem
- Selective serotonin receptor reuptake inhibitors: paroxetine
- Antidepressants: trazodone, amitriptyline
Autonomic dysfunction, taken as a whole, is not infrequent. The most common autonomic dysfunction occurs in the cardiovascular control sphere and consists of an abnormal vasovagal response that leads to syncope. Other common manifestations are related to postural tachycardia syndrome (POTS) or changes seen with Parkinson disease and other parkinsonisms. Compared to other areas of autonomic control, urinary incontinence, as observed in multiple sclerosis and other nervous system disorders, is unspecific but not rare. Some symptoms of autonomic disturbance, such as the facial vasomotor and ocular symptoms in trigeminal autonomic headaches, are of secondary significance but help in diagnosis.
Orthostatic hypotension occurs in patients with neurodegenerative disorders such as Parkinson disease, multiple system atrophy, pure autonomic failure, and in individuals with ganglionopathies that affect autonomic nerves and peripheral neuropathy. The prevalence of orthostatic hypotension is proportional to age, and it is more common in institutionalized than community-dwelling elderly. POTS is more prevalent in women. Syncope is highly prevalent in the general population, and the majority of syncope is due to reflex syncope. The frequency of reflex syncope is higher during adolescence and in individuals over 55 years. Carotid sinus hypersensitivity, defecation, and cough syncope occur almost exclusively in the elderly population.
Pathophysiology in ANS depends upon the affected area. Both anatomically related, as well as isolated regions, can be affected. In the cardiovascular system, three pathophysiological syndromes are typically associated with chronic dysfunction of the ANS. These are Postural orthostatic tachycardia syndrome (POTS), orthostatic hypotension with supine hypertension, and reflex cardiovascular syndromes. Hyperhidrosis and hypohidrosis are the main features of temperature control. Fixed mydriasis and myosis, also known as Adie's pupil and Horner syndrome in the eye, are also seen.
Autonomic dysfunction may result from any disease that affects the peripheral or central components of ANS. Primary autonomic dysfunction involves primary (idiopathic) degeneration of autonomic postganglionic fibers without other neurologic abnormalities. Orthostatic hypotension is associated with autonomic dysfunction and motor and cerebellar abnormalities in diseases involving a central degenerative process, as described in the Shy–Drager syndrome. A central degenerative disease process involving preganglionic neuronal degeneration, presenting with orthostatic hypotension and typical parkinsonian symptoms, has been described.
Orthostatic hypotension is defined as a sustained reduction of systolic blood pressure of at least 20 mmHg or diastolic blood pressure of 10 mmHg within three minutes of standing or head-up tilt to at least 60 degrees on the tilt table. The magnitude of fall in blood pressure depends on baseline blood pressure. In patients with supine hypertension, a reduction of 30 mmHg in systolic blood pressure may be an appropriate criterion for orthostatic hypotension. Immediately upon standing, gravitationally mediated redistribution of the blood volume and pooling of 300 to 800 ml of blood in lower limbs and splanchnic venous capacitance system occurs, which leads to a reduction of venous return and cardiac filling pressure. During standing, contraction of skeletal muscles of the lower body prevents excessive pooling and increases venous return to the heart. Orthostatic hypotension is caused by an excessive fall of cardiac output or by inadequate or defective vasoconstrictor mechanisms.
Neurally mediated (reflex) syncope includes vasovagal, carotid sinus, situational (cough, swallowing, micturition) syncope. It refers to a diverse group of conditions in which there is a relatively sudden change in ANS activity leading to a drop in blood pressure, heart rate, and cerebral perfusion. Neurally mediated syncope is best understood as a reflex with afferent, central, and efferent pathways, and the use of 'neurocardiogenic syncope' should be abandoned because the origin of the reflex is rarely in the heart.
Postural tachycardia syndrome (POTS) is defined as a sustained heart rate increment of 30 beats per minute within 10 minutes of standing or head-up tilt in the absence of orthostatic hypotension. For individuals of ages 12 to 19 years, the requirement is at least 40 beats per minute. POTS may be accompanied by symptoms of autonomic overactivity and cerebral hypoperfusion that are relieved by recumbency. The pathophysiology and etiology of POTS are unknown but are likely heterogeneous. POTS is associated with recent viral illness, chronic fatigue syndrome, deconditioning, and limited or restricted autonomic neuropathy.
Diabetic neuropathy is a kind of nerve pathology that may occur for those with diabetes mellitus. Hyperglycemia interferes with a nerve's ability to send signals and weakens the walls of the vasa nervorum blood vessels that supply nerves with nutrients and oxygen. Diabetic neuropathy can affect the nerves of the ANS, especially general visceral afferent (GVA) fibers, resulting in gastroparesis and decreased blood pressure regulation. GVA fibers affected by diabetic neuropathy reduce the response of their corresponding general visceral efferent (GVE).
Parkinson disease is a progressive neurodegenerative disease characterized by bradykinesia and hypokinesia combined with rest tremor and rigidity. Constipation, dysphagia, sialorrhea, rhinorrhea, urinary difficulties, and sexual dysfunction are the common nonmotor problems related to autonomic dysfunction in Parkinson disease. These signs and symptoms are also present in multiple system atrophy (MSA), making it hard to distinguish between the two disorders. However, the autonomic symptoms in MSA are generally more severe than in Parkinson disease. As the disease progresses, MSA tends to be less responsive to levodopa and is often associated with pyramidal and cerebellar findings.
History and Physical
A detailed account of symptoms in each area should guide us to list possible diseases with autonomic dysfunction. Emphasis should be placed on obtaining a good history and comprehensive examination of cardiovascular, urinary, neurological, and sudomotor manifestations. A key feature of autonomic dysfunction, either orthostatic syncope or presyncope, should guide us to suspicion of cardiovascular autonomic dysfunction. In this scenario, the usual orthostatic symptoms consist of lightheadedness, visual blurring or tunnel vision, neckache (coat-hanger pain), nausea, palpitations, tremulousness, weakness, and dizziness. Other symptoms include exercise intolerance, fatigue, shortness of breath, chest pain, anxiety, hyperventilation, acral coldness or pain, concentration difficulty, and headaches. The alternating sweating intensity in different areas of the body, typically a length-dependent distal hypohidrosis with sparing of palms and soles, can raise suspicion for a sudomotor autonomic lesion. Urgency and incontinence tend to relate to a neurogenic bladder more than retention.
Bedside evaluation of the ANS consists primarily of observing cardiovascular reflexes, casual sweating patterns, and pupillary changes. Bedside tests such as orthostatic blood pressure measurement and heart rate (while supine and after three minutes standing) are the most commonly used tests. When the bedside tests are not informative, but suspicion of an abnormal cardiovascular autonomic function is high, tilt table tests with natural cardiovascular stimuli such as Valsalva maneuver, hyperventilation, or cold pressor, are needed.
Sympathetic skin responses can add objective information, and a thermoregulatory sweat test might be a good option if the symptoms of altered sweating predominate.
Vesical ultrasonography and urodynamic studies help diagnose and choose the best pharmacologic approach for urinary dysfunction in autonomic dysfunction.
Other tests are not as useful in changing the management but may play a role in supporting an explanation for the patient's symptoms or as adjunctive for syndromic diagnosis. Blocking eyedrop tests and pupillometry for pupillary abnormalities are examples of such tests.
Some tests do help in management. For example, positive testing for autoantibodies, antibodies against alfa-3-acetylcholine receptors helps support immunosuppressive therapy.
Indications of Tilt Table Test:
- High suspicion of orthostatic hypotension despite an initial negative evaluation (for example, Parkinson disease).
- Patients who have a significant motor impairment that precludes them from having standing vital signs obtained.
- Monitor the span of an autonomic disorder and its response to therapy.
Responses to Head-Up Tilt-Table testing:
Heart rate increases by 10 to 15 beats per minute
Diastolic blood pressure increases by 10 mm Hg or more
Immediate and continuing drop in systolic and diastolic blood pressure
No compensatory increase in heart rate
Symptomatic, sudden drop in blood pressure
Occurs after 10 minutes or more of testing
Systolic blood pressure decreases by 20 mm Hg or more
Diastolic blood pressure decreases by 10 mm Hg or more
|Postural orthostatic tachycardia syndrome||
Heart rate increases by at least 30 beats per minute
Persistent tachycardia of more than 120 beats per minute
Treatment / Management
Treatment, when indicated, can be organized into three levels. Treatment strategies are aimed at etiology, physiopathology, and symptoms.
- Symptom management is the most frequently used and must first address the most bothersome symptoms while keeping the whole picture in mind. Physical measures like exercise, tailored physiotherapy, pressure stockings can help in some cardiovascular autonomic dysfunctions. Sunglasses can be used for mydriatic pupils. Also, a wide range of non-pharmacologic and pharmacologic measures are beneficial, as described below.
- The pathophysiologic aspect can be addressed in the case of immune-mediated disorders. Immunotherapy, such as steroids and other immune suppressor drugs, intravenous immunoglobulins, and plasma exchange, is employed in immune-mediated disorders management strategies.
- Finally, etiology must always be addressed. It is essential to treat certain situations, such as the malignancy found in paraneoplastic and autoimmune autonomic neuropathy. However, it is imperative to taper or withdraw the drugs interfering with the ANS in drug-induced, symptomatic autonomic failure in some other situations.
Management of Orthostatic Hypotension
Non Pharmacological Measures
- Discontinue exacerbating medications.
- Use of compression stockings and abdominal binders.
- Increase salt and water intake: Drinking 500 mL of water upon awakening and reaching 1.5 to 3 L per day is a reasonable target. Salt tablets or high sodium-containing foods also may be beneficial. While the optimal dose varies with the patients, a typical target dose of 6 to 10 g/day of sodium or a target urinary sodium level of 150 to 200 mEq is used.
- Modify lifestyle and daily activities: Slow changing of postures, for example, from supine to sitting and standing to increase the orthostatic tolerance. Avoiding Valsalva-like maneuvers and limiting walking in hot and humid weather, minimize hot showers and saunas as exposure to warm temperatures can cause skin vasodilation and worsen orthostatic hypotension.
- Engaging in an exercise program in a sitting or recumbent position is better tolerated than standing.
Pharmacological intervention is needed if the above measures are insufficient in preventing symptoms and complications of orthostatic hypotension. The two medications approved by US Food and Drug Administration (FDA) to treat symptomatic neurogenic orthostatic hypotension are:
- The alpha-adrenergic agonist, midodrine, and
- The norepinephrine precursor, droxidopa
A synthetic mineralocorticoid, Fludrocortisone, is widely used to treat orthostatic hypotension, is not specifically approved by the FDA for treating neurogenic orthostatic hypotension, and can lead to sustained hypertension in the supine position and other adverse effects. Fludrocortisone can augment intravascular volume and provide symptom relief.
Patients not responding to nonpharmacological measures such as volume augmentation, supine norepinephrine levels must be checked. If the supine norepinephrine level is <220 pg/mL, either midodrine or droxidopa is used, and for other patients, another sympathomimetic, atomoxetine (norepinephrine transporter (NET) inhibitor), can be used as initial pharmacotherapy.
Adjunctive or Alternative Therapeutic Options
- Nonsteroidal anti-inflammatory drugs
- Experimental agents: yohimbine, desmopressin, dihydroergotamine, metoclopramide, norepinephrine infusion (data regarding these agents is limited)
Management of autonomic dysfunction in Parkinson disease:
- Constipation: therapies like Polyethylene glycol, probiotics, and lubiprostone have been studied and found to be more effective than placebo.
- Sialorrhea(drooling): for patients with mild symptoms, the initial step would be to use hard candy or chewing gum to encourage swallowing may decrease drooling in social situations. Treatment with Botulinum toxin injection into the salivary glands can be effective for patients with more severe symptoms of drooling. Glycopyrrolate is also effective in severe drooling and has only a limited ability to cross the blood-brain barrier, which reduces the risk of central anticholinergic side effects.
- Rhinorrhea: Ipratropium nasal spray, an anticholinergic agent, is effective.
- Sexual dysfunction:
- Men with erectile dysfunction may benefit from treatment with sildenafil one hour before sex. Sildenafil should be used cautiously in patients with orthostatic hypotension. Tadafil and vardenafil are effective as well.
- Women may benefit from urinating before sexual activity and vaginal lubricants.
- Orthostatic hypotension: It may occur as a feature of the disease itself or due to the medications used to treat Parkinson disease, including dopamine agonists, levodopa, and monoamine oxidase type B (MAO B) inhibitors.
- Cardiovascular: Anemia, cardiac arrhythmia, congestive heart failure, myocardial infarction, myocarditis, pericarditis, valvular heart disease, venous insufficiency
- Drugs: Alcohol, antiadrenergic medications, antianginals, antiarrhythmics, antidepressants, antihypertensives, antiparkinsonian agents, diuretics, narcotics, neuroleptics, sedatives
- Endocrine: Adrenal insufficiency, diabetes insipidus, hypoaldosteronism, hyperglycemia, hypokalemia, hypothyroidism
- Intravascular volume depletion: Blood loss, dehydration, shock, pregnancy/postpartum
- Miscellaneous: Acquired immunodeficiency syndrome (AIDS), anxiety, panic disorder, eating disorders, prolonged bed rest
The importance of autonomic dysfunction secondary to other diseases is related to the prognosis of the primary disease process, the severity of orthostatic symptoms, and its response to treatment. The primary forms of autonomic dysfunction, both peripheral and central, have a generally poor prognosis, especially those associated with parkinsonian symptoms or movement disorders. The mean age of onset of these primary syndromes is in the 6th decade, and survival five years after the neurologic symptoms is less than 50%.
Orthostatic hypotension, particularly when symptomatic, can lead to falling, which has significant associated morbidity, particularly in a frail elderly population. According to several population-based studies, orthostatic hypotension is a risk factor for cardiovascular and all-cause mortality, usually due to associated diseases and underlying causes. Orthostatic hypotension has been associated with the development of dementia and cognitive impairment, though the mechanisms underlying this association are uncertain. Recurrent episodes of hypotension and cerebral hypoperfusion may result in neuronal injury. It is associated with periventricular white matter lesion burden, which in turn is a marker of vascular cognitive impairment. In addition, cognitive impairment and orthostatic hypotension can be both prodromal manifestations of an underlying neurodegenerative disease, such as dementia with Lewy bodies.
Pearls and Other Issues
Autonomic dysfunction is a prevalent health problem that remains underdiagnosed, undertreated, and underappreciated across healthcare systems. In most cases, patients tend to have a late diagnosis when their symptoms are chronic and long-standing. The lack of acknowledgment from the general population and the medical community, diagnostic testing set in the development, and a finite set of extensively tested and validated drugs to offer, among other causes, make the field one of the most promising for research.
Autonomic dysreflexia is a severe, potentially life-threatening condition affecting the cardiovascular system of patients exposed to various risk factors - ranging from painful/noxious stimuli to more subtle conditions (e.g., bowel or bladder obstructions). It can lead to cardiac ischemia, brain hemorrhage, seizures, and even death. Therefore, clinicians should remain cognizant, depending on the specific patient and clinical constellation of symptoms.
Enhancing Healthcare Team Outcomes
The diagnosis and management of autonomic dysfunction are complex and usually require an interprofessional team comprising specialists such as a neurologist, endocrinologist, internist, urologist, and cardiologist. The treatment is symptomatic and usually requires medications, which also have adverse effects. The outcomes and quality of life with autonomic dysfunction are poor.
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