ARTICLE: Primary Autonomic Failure: Three Clinical Presentations of One Disease?

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http://www.annals.org/issues/v133n5/full/200009050-00014.html

Primary Autonomic Failure: Three Clinical Presentations of One Disease?

Horacio Kaufmann, MD

Pages 382-384

Ann Intern Med. 2000;133:382-384.

Three neurodegenerative diseases of unknown cause involve primary autonomic

failure. These diseases are pure autonomic failure, in which autonomic

impairment (that is, orthostatic hypotension and bladder and sexual

dysfunction) occurs alone; Parkinson disease, in which autonomic failure is

combined with an extrapyramidal movement disorder; and multiple-system

atrophy (also called Shy-Drager syndrome), in which autonomic failure is

combined with an extrapyramidal or cerebellar movement disorder or both (1).

During the early stages of multiple-system atrophy, autonomic deficits may

be the sole clinical manifestation; therefore, the disease may resemble pure

autonomic failure. However, after a variable period that can be as long as

several years, extrapyramidal or cerebellar deficits or both invariably

develop. In Parkinson disease, extrapyramidal motor problems are the

presenting feature; later in the disease process, patients may develop

severe autonomic failure, making it difficult to distinguish between

Parkinson disease and multiple-system atrophy. To further complicate the

distinction, some patients with multiple-system atrophy display motor

deficits similar to those seen in Parkinson disease before autonomic failure

is apparent.

In clinical practice, all of these possibilities lead to two main diagnostic

problems. First, it cannot be determined whether a patient who is thought to

have pure autonomic failure and whose only finding is autonomic failure will

develop more widespread nonautonomic neuronal damage and be found to have

multiple-system atrophy. Second, it may be difficult to determine whether a

patient with autonomic failure and a parkinsonian movement disorder has

Parkinson disease or multiple-system atrophy.

In addition to clinical criteria, several tests have been used to

distinguish among Parkinson disease, pure autonomic failure, and

multiple-system atrophy. For example, vasopressin release in response to

hypotension and growth hormone secretion in response to clonidine are

blunted in multiple-system atrophy but preserved in pure autonomic failure

and Parkinson disease. This is because brain stem-hypothalamic-pituitary

pathways are affected only by multiple-system atrophy (2, 3). Plasma

norepinephrine concentration while supine is low in patients with pure

autonomic failure but normal in patients with multiple-system atrophy

because postganglionic neurons are normal (4). Sphincter electromyography

shows denervation in multiple-system atrophy because the Onuf nucleus in

segments S2 to S4 of the spinal cord is affected; however, it is normal in

Parkinson disease (5). In addition, magnetic resonance imaging of the brain

shows abnormalities in the putamen only in multiple-system atrophy (6).

However, most if not all of these tests are frequently ambiguous, and

accurate methods to distinguish Parkinson disease from other diseases with

extrapyramidal involvement, particularly multiple-system atrophy, are

necessary. Differential diagnosis of extrapyramidal and autonomic disorders

is important because of prognostic purposes and because accurate diagnoses

are required when testing new surgical and pharmacologic therapies. In a

thorough and elegant study in this issue, Goldstein and colleagues (7) show

that sympathetic cardiac innervation is selectively affected in Parkinson

disease and pure autonomic failure but not in multiple-system atrophy. This

may be a useful diagnostic test that can distinguish between Parkinson

disease and multiple-system atrophy. Moreover, in a patient with apparent

pure autonomic failure, normal sympathetic cardiac innervation should

indicate probable development of multiple-system atrophy.

To visualize the sympathetic innervation of the heart, the investigators

used thoracic positron emission tomographic scanning after intravenous

infusion of 6-[18 F]fluorodopamine, a catecholamine taken up by sympathetic

postganglionic neurons and handled in a manner similar to the way in which

norepinephrine is handled. In addition, the investigators performed cardiac

catheterization to determine cardiac norepinephrine spillover, extraction of

[3 H]norepinephrine, and venous-arterial differences in levels of plasma

dihydroxyphenylglycol (DHPG, a marker of neuronal norepinephrine turnover)

and L-dopa (a marker of norepinephrine synthesis in sympathetic nerves). Of

29 patients with Parkinson disease, 9 had chronic orthostatic hypotension

(only 4 were taking L-dopa). Of the remaining 20 patients with Parkinson

disease (those without orthostatic hypotension), 15 were taking L-dopa. As

expected, most patients with multiple-system atrophy had orthostatic

hypotension, 5 of whom were taking L-dopa.

Goldstein and colleagues found that all patients with Parkinson disease and

orthostatic hypotension as well as most patients with Parkinson disease and

no orthostatic hypotension had loss of functional cardiac sympathetic nerve

terminals. This was shown by decreased myocardial concentration of 6-[18

F]fluorodopamine-derived radioactivity as well as decreased cardiac

extraction of [3 H]norepinephrine, norepinephrine spillover, and cardiac

venous-arterial differences in plasma levels of DHPG and L-dopa. Myocardial

concentrations of 6-[18 F]fluorodopamine-derived radioactivity were as low

in patients with Parkinson disease as in patients with pure autonomic

failure. In marked contrast, all patients with multiple-system atrophy had

normal 6-[18 F]fluorodopamine-derived radioactivity that was similar to that

in normal controls.

Similar results were seen in several studies from different laboratories

that used single photon-emission computed tomographic imaging with123

I-metaiodobenzylguanidine (8-10), as well as in an earlier study by

Goldstein and colleagues (11) that used 6-[18 F]fluorodopamine positron

emission tomography. However, these studies included a small number of

patients. More important, questions remained about the possibility that

chronic L-dopa treatment accounted for these findings in Parkinson disease.

In their present study, Goldstein and colleagues show that the abnormal

cardiac sympathetic innervation detected by positron emission tomography is

not related to long-term L-dopa administration: The defect was also evident

in patients with Parkinson disease who were not taking L-dopa. Moreover,

patients with multiple-system atrophy who were taking L-dopa had normal

cardiac sympathetic innervation.

Scanning of the heart with positron emission tomography distinguishes

between Parkinson disease and multiple-system atrophy because sympathetic

innervation is impaired in the former but not the latter. Goldstein and

colleagues' finding of loss of functional cardiac sympathetic nerve

terminals in Parkinson disease also confirms that the degenerative process

of this disease extends well beyond central dopaminergic systems to involve

peripheral catecholamine-containing neurons. The results further indicate

that multiple-system atrophy exclusively affects neurons in the central

nervous system. In multiple-system atrophy, sympathetic responses are

abnormal because peripheral autonomic neurons, although intact, are not

engaged by the central nervous system.

Despite all these clinical and pathologic differences, are these three

diseases different entities? The neuropathologic markers in multiple-system

atrophy are glial and neuronal cytoplasmic inclusions in the central nervous

system; peripheral sympathetic postganglionic neurons are spared (12). In

contrast, in Parkinson disease and pure autonomic failure, a different type

of cytoplasmic inclusion (Lewy bodies) is found in the central nervous

system as well as in peripheral autonomic ganglia and postganglionic

sympathetic neurons (13-15).

Recent findings suggest that the same neurodegenerative process underlies

multiple-system atrophy, Parkinson disease, and pure autonomic failure

because in all three, -synuclein accumulates in the neuronal cytoplasmic

inclusions. A gene encoding for -synuclein, a neuronal protein of unknown

function, is mutated in autosomal dominant Parkinson disease (16).

Nonfamilial Parkinson disease does not have the mutation, but -synuclein

accumulates in Lewy bodies in these patients, suggesting a toxic role for

aggregates of this protein (17). Of interest, it was recently reported that

cytoplasmic inclusions in multiple-system atrophy also stain positive

for -synuclein (18), and other researchers have found that Lewy bodies in

pure autonomic failure are strongly positive for -synuclein (Kaufmann and

coworkers. Unpublished data). Thus, abnormalities in the expression or

structure of -synuclein or associated proteins may cause degeneration of

catecholamine-containing neurons. It is therefore possible to speculate that

primary autonomic failure includes three clinical presentations of one

disease. Elucidation of the role of -synuclein in neuronal degeneration may

test this hypothesis. Meanwhile, tests that contribute to accurate diagnoses

of the different forms of autonomic failure will greatly facilitate

evaluation of new therapies.

Author and Article Information

From Mount Sinai School of Medicine; New York, NY 10029

Requests for Single Reprints: Horacio Kaufmann, MD, Mount Sinai School of

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