Key Points

			The autonomic nervous system regulates body temperature, circulation, respiration, digestion, metabolism, and bladder and sexual function.
			Autonomic nervous system disorders are important but underrecognized causes of symptoms.
			The symptoms of autonomic nervous system dysfunction often are nonspecific. Autonomic nervous system dysfunction may be hard to confirm by clinical examination.
			Laboratory testing is valuable to confirm autonomic nervous system dysfunction.
			Autonomic nervous system dysfunction can be restricted to one organ or may be widespread, involving all organs innervated by the autonomic nervous system.
			Treatment is largely symptomatic and is directed to the specific symptoms of the autonomic nervous system dysfunction.

Structure and Function

The autonomic nervous system (ANS) consists of two main divisions: sympathetic and parasympathetic (Fig. 1). Both have various centers in the brain, with descending pathways to the brain stem and spinal cord. Sympathetic nerve fibers leave through the thoracic and upper lumbar spinal nerve roots and enter the ganglia of the paravertebral sympathetic chain. Postganglionic fibers then travel with peripheral nerves and arteries to supply various organs and structures. Parasympathetic fibers leave the central nervous system (CNS) through some of the cranial and sacral spinal nerves to reach the parasympathetic ganglia, which are smaller than the sympathetic ganglia and are located close to their effector organs.

Figure 1 The peripheral autonomic nervous system. view larger image

The classic transmitters of the peripheral ANS are acetilcolina and noradrenaline (Fig. 2). Neuropeptides have been identified as important cotransmitters.

Figure 2 Classic neurotransmitters of the autonomic nervous system. Aadrenaline; AChAcetilcolina; NAnoradrenaline. view larger image

The ANS regulates bodily activities that are not under ordinary voluntary control (eg, temperature, circulation, respiration, digestion, metabolism, and the activity of the genitourinary system). The two divisions of the ANS often function as physiologic antagonists, and it is the balance of their activities that maintains good function in an organ.

Heart rate mainly is controlled by parasympathetic (vagus) nerves, with less input from the sympathetic nerves. Blood pressure mainly is regulated by the sympathetic system. Both are reflexly activated by the baroreceptors. The gastrointestinal tract is innervated by the enteric nervous system, to which both ANS divisions contribute. This system controls gut motility, secretions, and blood flow. The storage and elimination of urine depend on the integrated activity of the bladder and the urethral sphincters. Both sympathetic and parasympathetic nerve fibers contribute. The ANS also controls sexual function: penile or clitoral engorgement, glandular secretion, emission, and ejaculation. In the eyes, the ANS supplies the pupils, the ciliary muscles controlling accommodation, and the tear glands. Autonomic fibers to the skin innervate the sweat glands and blood vessels and are thus important in temperature regulation.

Clinical Evaluation

Symptoms suggesting autonomic dysfunction are listed in Table 1. The clinical examination for autonomic dysfunction is limited. One of the few reliable signs is orthostatic hypotension (systolic blood pressure fall > 20 mm Hg, diastolic blood pressure fall > 10 mm Hg, or both when the patient goes from lying to standing). The postural fall may be immediate or delayed and occasionally becomes apparent only after exercise. Careful examination of the pulse rate on standing may show a lack of tachycardia in a patient with disordered cardiac innervation, but usually an electrocardiogram is required to detect this feature. Abnormally reacting pupils may be readily detected, but dryness of the eyes, mouth, or skin is often difficult to ascertain clinically.

Table 1   Symptoms of autonomic dysfunction

Postural faintness or loss of consciousness

Gastrointestinal dysfunction

Bloating

Diarrhea

Constipation

Rectal incontinence

Bladder dysfunction

Sexual dysfunction

Poor erections

Impaired ejaculation

Decreased or increased sweating

Dry mouth or dry eyes

Blurring of near vision

Cold or discolored extremities

Tests of ANS function

Tests of autonomic function (Table 2) are gradually becoming more readily available in laboratories dedicated to ANS testing [1].

Table 2   Tests of autonomic nervous system function
Function	Type of test
Heart rate	Measures the reduced heart rate response to standing, to deep breathing, and to Valsalva maneuver
Blood pressure	Uses a continuous noninvasive monitor that records blood pressure following changes of posture on a tilt table and/or from lying/standing and/or during Valsalva maneuver, also prolonged tilt-table testing for vasovagal syncope
Sweating	Determines the areas of sweating by the change in color of heat-sensitive powders on the skin after whole-body warming
	Evaluates responses to injected or iontophoresced sweat-stimulating chemicals (Acetilcolina or pilocarpine)
	Uses bioelectric skin potentials (sympathetic skin responses)
Gut motility	Transit times are evaluated radiologically by barium meal studies, radiopaque pellets, and chemical markers
Bladder	Uses a urodynamic battery of tests
	Cystometrography
	Urethral pressure profiles
	Uroflowmetry
	Pudendal nerve conduction studies
	Sphincter electromyography
Sexual function	Evaluates nocturnal erections by penile tumescence testing in a sleep laboratory
	Measures blood pressure in the penis using Doppler techniques
	Determines prolactin levels; if elevated, a pituitary prolactinoma is present
	Uses intracavernous papaverine injections to produce erections in patients with psychogenic or neurogenic impotence but not with arterial insufficiency
Pupils	Shows brisk constriction with dilute pilocarpine in Adies pupils
	Produces pupillary dilatation with hydroxyamphetamine drops in Horners syndrome when damage lies in the central nervous system
Lacrimation	Uses Schirmer strips (a thin band of absorbent paper is inserted into the lower eyelid for 5 min); moistening of less than 5 mm is abnormal

Clinical Syndromes

Clinical disorders of the ANS can be conceptualized in a manner similar to other neurologic disorders. They may involve the CNS or the peripheral nervous system, or both; they may be focal or restricted (eg, Horners syndrome) or involve the ANS diffusely; therefore, they are called generalized dysautonomias (eg, pure autonomic failure). Dysautonomias also can be considered primary (degenerative disorders) or secondary to traumatic, vascular, or other identifiable causes.

Orthostatic Hypotension

Orthostatic hypotension has many causes, only some of which involve the ANS (Table 3). Patient history and examination often reveal the cause, but some individuals require extensive medical and neurologic investigations to establish the etiology.

Table 3   Disorders associated with orthostatic hypotension

Central nervous system disorders

Multiple system atrofia

Parkinsons disease

Wernickes encephalopathy

Posterior fossa tumors

Brain stem lesions

Spinal cord lesions

Peripheral nervous system disorders

Diabetes mellitus

Pure autonomic failure

Acute dysautonomia

Peripheral neuropathies (acute or chronic)

Medications

Antihypertensive agents

Diuretics

Antianginal medications

Phenothiazines

Levodopa

Impaired circulation

Hypovolemia

Anemia

Electrolyte disturbances (metabolic or hormonal)

Adrenal insufficiency

Pheochromocytoma

Orthostatic hypotension of the elderly

Vasovagal (Neurocardiogenic) Syncope

Vasovagal syncope is an acute hemodynamic event that consists of bradycardia and hypotension resulting in a marked reduction in cardiac output and cerebral perfusion. Episodes may be triggered by the sight of blood or needles or by other stimuli (reflex syncopes) but often occur spontaneously. The cause is unknown. There appears to be a sudden excess of vagal impulses to the heart (producing bradycardia) and a concomitant withdrawal of sympathetic vasoconstrictor impulses to the blood vessels (producing hypotension) [2]. Recording the pulse and blood pressure during a prolonged tilt of 60?or more on a tilt table often reproduces these events and is a useful diagnostic test [3].

Multiple System Atrofia

Multiple system atrofia (MSA) is a progressive neurologic disorder with prominent autonomic dysfunction [4,5]. When ANS features predominate, the term Shy-Drager syndrome is used. When parkinsonian features predominate, the disorder is often designated striatonigral degeneration. When ataxia and corticospinal tract involvement are prominent, the disorder is often labeled olivopontocerebellar atrofia. All conditions are thought to be variants of a widespread CNS degenerative disorder, the cause of which is unknown. MSA is relentlessly progressive, with death occurring within 7 years of onset.

Pure Autonomic Failure

Pure autonomic failure is a chronic disorder that produces mainly orthostatic hypotension, male sexual dysfunction, and bladder dysfunction. Some patients develop, over time, the somatic neurologic features of MSA.

Parkinsons Disease

About 10% of patients with Parkinsons disease have dysautonomic symptoms. Orthostatic hypotension may be unmasked or worsened by the medications used to treat Parkinsons disease.

Diabetes Mellitus

Diabetic patients can develop various dysautonomias: restricted or generalized, symptomatic, or those detected only by special tests [6,7]. They often are associated with generalized peripheral neuropathy. Orthostatic hypotension can be a serious problem. Cardiac innervation also can be affected, producing a resting tachycardia, a fixed heart rate, and reduced heart rate variations on lying to standing. This abnormal cardiac innervation may contribute to the sudden and unexplained deaths in patients with diabetic autonomic neuropathy. Gastric atony causes abdominal distention, nausea, and vomiting. Midgut and lower gut dysfunction causes diarrhea that is often intermittent, worse at night, and associated with abdominal cramps and anorectal incontinence. It is uncertain whether bacterial overgrowth or autonomic neuropathy is the more important cause; improvement with antibiotics suggests the former. Sexual dysfunction affects up to 40% of diabetic men. The principal cause is probably autonomic neuropathy, but vascular factors may contribute. Sexual function in diabetic women is thought to be normal. Some patients develop atonic bladders caused by the loss of bladder sensation and detrusor and sphincter dysfunction. Urinary tract infections with fibrosis and scarring worsen the situation. Decreased sweating distally in the limbs is common in patients with diabetic polyneuropathy but is of little importance. Gustatory sweating (excessive sweating on the face or torso when eating, sometimes only specific foods) can be troublesome. Hypoglycemic unawareness, with a lack of sweating and tachycardia, also is caused by dysautonomia.

Orthostatic Hypotension of the Elderly

Orthostatic hypotension of the elderly is an underdiagnosed cause of dizziness, unsteadiness, syncope, and falls. Causes are multifactorial, including aging changes in the ANS, medications, prolonged recumbency, and concurrent illness.

Chronic Alcoholism

Many alcoholic patients are asymptomatic, but tests of autonomic function often reveal abnormalities. There is a divergence of opinion about the occurrence and frequency of orthostatic hypotension in alcoholics [8]. It has been reported to be frequent in those with Wernickes encephalopathy and chronic liver disease. Hypothermia is common and has been attributed both to the vasodilator effects of alcohol and to dysfunction of hypothalamic thermoregulatory mechanisms. Decreased sweating contributes to accidental hyperthermia in hot climates. Erectile impotence is frequent in alcoholics, but it more often results from psychogenic or endocrinologic causes than ANS dysfunction.

Spinal Cord Lesions

Autonomic abnormalities vary with the time after the injury or disease onset and with the extent and cause of the damage. Trauma is the most common cause, but similar problems occur in patients with myelopathies caused by multiple sclerosis, acute or subacute transverse myelitis, vascular disease, syringomyelia, and spinal cord compression. A complete transection of the spinal cord above T6 destroys the descending vasomotor pathways to the abdominal vascular bed and legs; thus resting blood pressure is low, and orthostatic hypotension can be a problem. In patients with lesions below T6, blood pressure disturbances are less severe.

Autonomic dysreflexia is a frequent problem in quadriplegics or paraplegics. This disorder consists of episodic hypertension accompanied by bradycardia, sweating above the level of the spinal cord lesion, and headache. These attacks often are precipitated by distention of the bladder or bowel, stimulation of the skin below the level of the lesion, or reflex spasms of the lower limb muscles. Other autonomic abnormalities in quadriplegics and paraplegics include bladder and male sexual dysfunction and reduced bowel motility. Damage to the lower spinal cord or cauda equina produces variable weakness and sensory loss in the legs and sacral area, atonic bladder with urinary retention, anorectal incontinence, and sexual dysfunction.

Peripheral Neuropathies

Autonomic dysfunction occurs in many patients with Guillain-Barr syndrome and includes hyperactivity or hypoactivity of sympathetic and parasympathetic functions. Major fluctuations in blood pressure are common. Hypotension can be caused by even low doses of vasoactive drugs; therefore hypertension must be treated cautiously. Sinus tachycardia is frequent, and various cardiac arrhythmias may occur; the latter may be responsible for sudden death in some patients. Bladder dysfunction and paralytic ileus also may occur. The dysautonomic abnormalities are at their maximum during the peak period of paralysis.

Acute dysautonomias present with varying combinations of sympathetic and parasympathetic abnormalities [9]. They are thought to be similar in cause to Guillain-Barr syndrome (an acute immune-mediated phenomenon) but with the brunt of the damage being to the autonomic rather than the somatic nerves.

Dysautonomic symptoms and signs are uncommon in most chronic polyneuropathies. The major exception is amyloid neuropathy [10]. This neuropathy occurs in certain types of familial amyloidosis or in immunocyte dyscrasias with amyloidosis. The ANS dysfunction is relentlessly progressive, with death occurring within 5 years of diagnosis, which is made by biopsy of nerve, rectal mucosa, or abdominal wall adipose tissue.

Peripheral Nerve Injuries

A major nerve lesion causes hypohidrosis, vasomotor impairment, and trophic skin changes in the cutaneous distribution of the nerve. Sometimes, excessive vasoconstriction in response to emotion or cold occurs. Causalgia is a distinct syndrome that follows a partial or complete lesion of a peripheral nerve. It consists of these autonomic disturbances as well as severe pain. The sympathetic nervous system is thought to be involved in causing these symptoms, although the mechanism is unclear.

Reflex Sympathetic Dystrophy

Reflex sympathetic dystrophy (RSD) includes entities such as shoulder-hand syndrome and Sudecks atrofia. The clinical features resemble causalgia, but it is best to restrict causalgia to denote the syndrome that follows a nerve injury. The most common cause of RSD is a limb fracture. Other local causes include soft tissue trauma, tendinitis, bursitis, and shoulder dislocation. Visceral injury or diseases such as myocardial infarction and carcinoma of the lung also can cause RSD, as can CNS lesions such as cerebral infarctions. In approximately one third of patients, there is no identifiable antecedent event or cause. Despite the vasomotor and sweating abnormalities that implicate involvement of the peripheral ANS, there is no firm evidence that this disorder involves the ANS; the responses to treatments such as chemical sympathectomy with intravenous guanethidine and surgical sympathectomy are inconsistent [11].

Treatment

In many patients with disorders of the ANS no specific treatment of the underlying disease is available; therefore treatments are aimed at relieving symptoms [12].

Orthostatic Hypotension

Patients who are symptom free can be left untreated. Medications that can cause or aggravate orthostatic hypotension should be stopped (see Table 3). Patient education is important; patients can do many things for themselves to help control symptoms [13]. They should learn to sit awhile on the side of their bed before standing. Before rising from a chair, they should exercise their feet and legs. Elevating the head of the bed improves early morning blood pressure, and some patients have been maintained satisfactorily for years by this method solely. Salt content of the patients diet should be increased unless there is a contraindication, such as congestive heart failure. Elastic stockings, if they extend to include the thighs, may help; custom-fitted ones that extend to the midabdomen are even more effective but are very uncomfortable. Orthostatic hypotension is often worse after meals; thus patients should be aware of the increased danger of standing and exercising at that time. Alcohol with meals may add to the hypotension.

Drugs for treating orthostatic hypotension are listed in Table 4. Doses should be titrated depending on the response. Fludrocortisone is the drug of choice for most patients; supine hypertension, hypokalemia, and congestive heart failure are side effects. Midodrine is a recent and very promising medication [6]. Side effects include supine hypertension, gastrointestinal complaints, and urinary urgency. If these two medications, alone or in combination, prove unsatisfactory, then treatment becomes a trial-and-error approach using other medications listed in Table 4.

Table 4   Medications for the treatment of orthostatic hypotension*
Mode of action	Agent	Dosage
Fluid expansion	Fludrocortisone	0.05 mg twice daily to
		0.2 mg three times per day
Vasoconstriction	Fludrocortisone	As above
	Midodrine	2.510 mg three times per day
Prevention of vasodilation	Indomethacin	25 mg three times per day
	Flurbiprofen	50 mg three of four times per day
	Metoclopramide	510 mg three times per day
Prevention of diuresis	Desmopressin acetate nasal spray	10 g twice daily
Prevention of splanchnic vasodilation	Octreotide	50100 g subcutaneously twice daily
*Some drugs have more than one mode of action.

Gastrointestinal Dysfunction

In patients with gastroparesis, acceleration of gastric emptying can be achieved with metoclopramide. Other treatments include bethanechol, domperidone, and cisapride (Table 5). These medications may improve coexisting constipation; stool bulk expanders, laxatives, or enemas also can be used. Diarrhea can be treated with antibiotics, such as tetracycline, as well as routine antidiarrhea agents, such as codeine and loperamide. Profound rectal incontinence in some patients with severe ANS dysfunction, particularly in those with spinal cord damage, can be a major problem. Continual leakage often produces sacral ulcers. A colostomy should be considered in this situation.

Table 5   Medications for the treatment of gastrointestinal autonomic symptoms
Clinical sign	Agent	Dosage
Gastroparesis	Metoclopramide	520 mg 30 min before meals and at bedtime
	Bethanechol	1050 mg three times per day
	Domperidone	1520 mg three or four times per day
	Cisapride	510 mg three or four times per day
Constipation	Laxatives
	Enemas
Diarrhea	Tetracycline	250 mg four times per day
	Codeine	1530 mg three times per day
	Loperamide	2 mg two or three times per day
	Diphenoxylate hydrochloride atropine sulfate	2.55 mg three or four times per day
	Clonidine	200 g four times per day

Bladder Dysfunction

Superimposed urinary tract infections must be treated. Urodynamic tests can help to determine the type of chronic neurogenic bladder dysfunction (the failure to store or to void). Failure to store urine is caused by either detrusor hyperreflexia or sphincter weakness (Table 6). Detrusor hyperreflexia may respond to a muscarinic cholinergic blocking agent, although inability to void may then become a side effect that could then be dealt with by intermittent catheterization. Tricyclic antide-pressants reduce bladder contractility and increase sphincter activity; therefore imipramine taken at night can improve urine storage during sleep. a-adrenergic agonists may increase urinary sphincter activity, but urinary drainage, such as a condom catheter in men or an indwelling catheter in women, often is required when sphincter hypoactivity is severe.

Table 6   Medications for the treatment of autonomic bladder dysfunction
Disorder	Agent	Dosage
Failure to store urine
Detrusor hyperreflexia	Propantheline	1530 mg four times per day
	Oxybutynin chloride	5 mg two to four times per day
Sphincter hypoactivity	Ephedrine	2550 mg four times per day
Both	Imipramine	1025 mg every night
Failure to void urine
Detrusor hypoactivity	Bethanechol	1050 mg three times per day
Urethral sphincter spasm	Prazosin	15 mg three times per day

Failure to void urine results from bladder-sphincter dyssynergia and other causes (see Table 6). Detrusor hypofunction can be managed by suprapubic tapping or compression and with bethanechol. Prazosin sometimes reduces urethral sphincter spasm. When these treatments fail, the best alternative is intermittent catheterization, which is much safer than an indwelling catheter. When this option is not practical, as, for example, in a patient with reduced manual dexterity, an indwelling catheter can be used in women and in some men, or surgical division of the urethral sphincters followed by condom catheter drainage can be used in men.

Male Sexual Dysfunction

Satisfactory erections often can be achieved with papaverine or prostaglandin E1 injections into the corpora cavernosa of the penis [14]; or intraurethral insertion of a pellet that contains prostaglandin E1 (alprostadil). Penile prostheses are either semirigid and malleable or inflatable. Both types of prostheses are associated with an impressively high degree of user satisfaction. However, the recently released oral agent sildenafil (Viagra; Pfizer, New York, NY) is rapidly replacing many of the older remedies because it is more convenient and painless [15,16].

Key References

Recently published papers of outstanding interest, as identified in References and Recommended Reading, have been annotated.

	Younger DS, Rosoklija G, Hays AP: Diabetic peripheral neuropathy. Semin Neurol 1998, 18: 95- 104. [PubMed abstract] [Related articles]

An excellent review of the diagnosis and management of clinicopathologic neuropathic syndromes occuring with diabetes.

	Kloner RA: Viagra: What every physician should know. Ear Nose Throat J 1998, 77: 783- 786.

This article covers the basic medical considerations involved when prescribing sildenafil (Viagra).

References and Recommended Reading

Recently published papers of particular interest have been highlighted as:

Of interest

Of outstanding interest

1.	Low PA: Laboratory Evaluation of Autonomic Function. In Clinical Autonomic Disorders, edn 2. Low PA, ed. New York: Lippincott-Raven; 1997: 179- 208.

2.	Kaufmann H: Neurally mediated syncope: Pathogenesis, diagnosis, and treatment. Neurology 1995, 45: S12- S18.

3.	Benditt DG, Ferguson DW, Grubb BP, et al.: Tilt table testing for assessing syncope. J Am Coll Cardiol 1996, 28: 263- 275. [PubMed abstract] [Related articles]

4.	Schatz IW, Bannister R, Kaufmann H: Consensus statement on the definition of orthostatic hypotension, pure autonomic failure and multiple system atrofia. Clin Auton Res 1996, 6: 125- 126.

5.	Wenning GK, Ben-Shlomo Y, Magalhäes M, et al.: Clinical features and natural history of multiple system atrofia: Ananalysis of 100 cases. Brain 1994, 117: 835- 845.

6.	Hilsted J, Low PA: Diabetic Autonomic Neuropathy. In Clinical Autonomic Disorders, edn 2. New York: Lippincott-Raven; 1997: 487- 508.

7.	Younger DS, Rosoklija G, Hays AP: Diabetic peripheral neuropathy. Semin Neurol 1998, 18: 95- 104. [PubMed abstract] [Related articles]

8.	Stewart JD: Causes and Evaluation of Male Sexual Dysfunction. In Clinical Autonomic Disorders, edn 2. New York: Lippincott-Raven; 1997: 269- 276.

9.	Low PA, McLeod JG: Autonomic Neuropathies. In Clinical Autonomic Disorders, edn 2. New York: Lippincott-Raven; 1997: 463- 486.

10.	Reilly MM: Genetically determined neuropathies. J Neurol 1998, 245: 6- 13. [PubMed abstract] [Related articles]

11.	Wilson PR: Reflex Sympathetic Dystrophy. In Clinical Autonomic Disorders, edn 2. New York: Lippincott-Raven; 1997: 537- 544.

12.	Freeman R, Miyawaki E: The treatment of autonomic dysfunction. J Clin Neurophysiol 1993, 10: 61- 82. [PubMed abstract] [Related articles]

13.	Robertson D, Davis TL: Recent advances in the treatment of orthostatic hypotension. Neurology 1995, 45: S26- S32. [PubMed abstract] [Related articles]

14.	Stewart JD: Management of male sexual dysfunction. In Clinical Autonomic Disorders, edn 2. Low PA, ed. New York: Lippincott-Raven; 1997: 803- 807.

15.	Kloner RA: Viagra: What every physician should know. Ear Nose Throat J 1998, 77: 783- 786.

16.	Mobley DF, Baum N: When patients request the impotence pill. Postgrad Med 1998, 104: 55- 66. [PubMed abstract] [Related articles]

Select Bibliography

	Low PA, ed.: Clinical Autonomic Disorders. New York: Lippincott-Raven; 1997.

	Robertson D, Low PA, Polinsky RJ, eds.: Primer on the Autonomic Nervous System. San Diego: Academic Press; 1996.

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