ARTICLE: Autonomic Disorders and Their Recognition

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New England Journal of Medicine

March 6, 1997 -- Volume 336, Number 10

Autonomic Disorders and Their Recognition

by J. Mathias, D.Phil., D.Sc.

St. 's Hospital, Imperial College School of Medicine

London W2 1NY, United Kingdom

The autonomic nervous system, through the sympathetic and parasympathetic

pathways, supplies and influences every organ in the body. It closely

integrates vital processes, such as blood pressure and body temperature.

Its immense capability and flexibility depend on intricate neurologic

pathways, involving the action of numerous transmitters. As we approach the

centennial of the use of the term " autonomic nervous system, " which was

coined by Langley in 1898, we should ask whether autonomic disorders are

being sufficiently considered, suitably investigated, and appropriately

managed in clinical practice.

Awareness is the first step in recognition. Autonomic disorders may be

localized or generalized. (1) The former may indicate the presence of a

serious underlying disease, such as in Horner's syndrome, or a benign

condition, such as Holmes-Adie pupil. Some may be psychologically

distressing, such as excessive facial sweating while eating and excessive

salivation. Chagas' disease, a disorder occurring mainly in South America

(where 60 million people are infected with Trypanosoma cruzi), may target

the autonomic plexus intrinsic to the heart and gut. The syndromes of

primary chronic autonomic failure with widespread dysfunction usually have

features of common neurodegenerative disorders (Figure 1).

Generalized secondary dysfunction of the autonomic nervous system often

complicates neurologic disorders (spinal cord injury, familial amyloidotic

polyneuropathy, and Guillain-Barre syndrome) and an ever-increasing list of

diseases, including diabetes mellitus, cancer, human immunodeficiency virus

infection, and even the prion disorder known as fatal familial insomnia.

Drugs may cause autonomic dysfunction directly or through a neuropathy, as

in alcoholic neuropathy. Intermittent abnormalities characterize neurally

mediated syncope (vasovagal syncope in the young and carotid-sinus

hypersensitivity in the elderly). Autonomic disturbances may be present

from birth (as, for example, the Riley-Day syndrome and dopamine

(beta)-hydroxylase deficiency); their frequency increases with age.

Although often associated with underactivity, some cause problems through

overactivity, such as vagally induced bradycardia in neurally mediated

syncope and paroxysmal hypertension due to isolated spinal reflex activity

(autonomic dysreflexia) in patients with quadriplegia. Autonomic disorders

thus cause substantial morbidity and may be more common than currently

perceived.

The clinical manifestations of autonomic disorders are protean. Sympathetic

adrenergic failure can cause orthostatic hypotension and ejaculatory

failure, sympathetic cholinergic failure can cause anhidrosis, and

parasympathetic failure can cause a fixed heart rate, sluggish urinary

bladder and bowel, and erectile failure. Thus, patients may first be seen

by a generalist or by specialists ranging from neurologists and urologists

to cardiologists and even psychiatrists (Table 1). Features such as

orthostatic hypotension, sudomotor or temperature dysregulation, and

genitourinary dysfunction, however, should initiate consideration of an

autonomic disorder. A cardinal sign that can be assessed readily is

orthostatic hypotension. There may be a classic history of posturally

induced dizziness, visual disturbances, and syncope, worsened by factors of

daily life (food, exercise, and temperature) (1); however, in some patients

cerebrovascular autoregulation improves with time, and this may reduce the

symptoms.

When an autonomic disorder is suspected, the primary investigations should

determine whether autonomic function is normal or abnormal. There are

various screening tests, (3) currently best directed toward cardiovascular

autonomic assessment. If the results of these tests are abnormal, the site

of the lesion and the functional deficit need further evaluation.

Underlying and associated disorders, such as diabetes mellitus, need to be

excluded. The syndromes of primary autonomic failure may cause diagnostic

problems. In pure autonomic failure there are no other neurologic

manifestations, and the lesions are peripheral. (4,5) In patients with

drug-responsive Parkinson's disease, autonomic dysfunction is usually mild

(6) and may be associated with or unmasked by drugs; a small subgroup of

patients, however, have more severe autonomic failure, previously suspected

(7) and now confirmed by Goldstein et al., in a report in this issue of the

Journal, (5) as being of peripheral origin. Therefore, these syndromes

differ clinically and pathophysiologically from multiple-system atrophy, a

sporadic and progressive disorder with autonomic (especially genitourinary

and cardiovascular), parkinsonian, cerebellar, and pyramidal features,

occurring in any order and combination (Figure 1).

In multiple-system atrophy, neuropathological analysis indicates

predominantly central lesions, with preservation of sympathetic ganglia;

this finding is consistent with the normal basal serum norepinephrine

concentrations in affected patients, unlike the frequently low values in

patients with pure autonomic failure. (4) In the parkinsonian forms,

certain features (absence of tremor and a bilateral onset) differ from

those of Parkinson's disease, but in individual patients these differences

are not clinically meaningful. A response to antiparkinsonian therapy alone

may not distinguish multiple-system atrophy from Parkinson's disease, since

two thirds of patients have an initial response (8); drug side effects and

a diminishing motor response over time reduce the proportion with responses

to less than a third. Computed tomography, magnetic resonance imaging, and

positron-emission tomography of the brain (9) with magnetic resonance

spectroscopy of basal ganglia (10) may be useful to identify groups of

affected patients but not necessarily individual patients. Electromyography

of the urethral and anal sphincter is helpful but invasive. (11)

Distinguishing multiple-system atrophy from Parkinson's disease and other

parkinsonian syndromes such as progressive supranuclear palsy may be

particularly difficult and may account for the fact that up to 25 percent

of patients given a diagnosis of Parkinson's disease in life are found to

have multiple-system atrophy at autopsy. (8) Noninvasive investigations

providing both diagnostic and pathophysiologic information may be of value

in distinguishing between these disorders in their early stages. The

response of serum growth hormone to clonidine, which is dependent on

central stimulation of (alpha)2-adrenergic receptors, is impaired in

multiple-system atrophy (12) but preserved in pure autonomic failure and

Parkinson's disease. (13) The presence of a neurocardiac defect on

positron-emission tomography in patients with multiple-system atrophy and

sympathetic failure provides further evidence of the site and nature of the

disorder.

Whether the subdivision proposed by Goldstein et al. (5) of the autonomic

failure in multiple-system atrophy into sympathetic and parasympathetic

forms will be helpful remains to be determined. Their use of the term

" Shy-Drager syndrome " for multiple-system atrophy with sympathetic

neurocirculatory failure (5) will certainly be contentious, since both

sympathetic and parasympathetic failure are described in the classic paper

of Shy and Drager (14) and are often observed in clinical practice when

sought after in this relentlessly progressive disease.

Do recognition and evaluation influence clinical management? A precise

diagnosis, along with a comprehensive evaluation of the functional deficit,

is essential for determining the prognosis in both secondary and primary

autonomic disorders (for example, the prognosis is good in pure autonomic

failure, favorable in Parkinson's disease, and poor in multiple-system

atrophy (15)), for anticipating complications (such as the need for a

tracheostomy for apnea in multiple-system atrophy), and for making

therapeutic decisions. Simple interventions may help, such as the

withdrawal of a drug causing complications or the unblocking of a urinary

catheter (a common cause of autonomic dysreflexia in quadriplegia). More

complex interventions currently under evaluation include liver

transplantation to reduce the level of variant transthyretin in familial

amyloidotic polyneuropathy. (16) In many patients, the quality of life may

be improved substantially by reducing orthostatic hypotension, eliminating

urinary incontinence, alleviating gastrointestinal disturbances, and

treating sexual dysfunction. There are also nonautonomic considerations;

for example, antiparkinsonian drugs are less effective in multiple-system

atrophy than in Parkinson's disease, and interventional procedures such as

intracerebral fetal nigral grafts are less likely to succeed. The

implications of recognition are therefore considerable.