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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Requests To Purchase Bulk Reprints (minimum, 100 copies): Barbara Hudson,
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