MULTIPLE SYSTEM ATROPHY AND PURE AUTONOMIC FAILURE
Sir
Roger Bannister and Phillip A. Low
SUMMARY
1. Multile-system atrophy (MSA), because
of the multiple involvement of the central nervous system, is quite distinct clinically
from pure autonomic failure in which the central nervous system is unaffected.
2. Striatonigral, olivopontocerebellar,
and pyramidal forms of MSA exist.
3. Key magnetic resonance imaging findings
in patients with MSA consist of cerebellar atrophy and changes in the
posterolateral putamen that reflect a loss of neurons. The changes are
typically manifested as T2 hypodensity or linear lateral hyperdenities.
4. A characteristic finding on positron
emission tomography is reduced uptake of - F-dopa in the caudate and putamen.
5. The natural history of pure autonomic
failure is one of slow progression over some 10 to 15 years, while MSA patients
usually do not survive more than 6-8
years from the time of diagnosis.
6. Treatment of orthostatic hypotension
with fludrocortisone, head-up tilt, vasoactive agents or DDAVP may be partially
effective.
HISTORY
Shy and
Drager [23] were the first to describe other neurologic features with autonomic
failure, the syndrome now called MSA (MSA). It is appropriate to quote from
their original description. "The full syndrome comprises the following
features; orthostatic hypotension, urinary and rectal incontinence, loss of
sweating, iris atrophy, external ocular palsies, rigidity, tremor, loss of
associated movements, impotence, the findings of an atonic bladder and loss of
rectal sphincter tone, fasciculations, wasting of distal muscles, evidence of a
neuropathic lesion in the electromyogram that suggests involvement of the
anterior horn cells, and the finding of a neuropathic lesion in the muscle
biopsy. The date of onset is usually in the 5th to 7th decade of life. "
At this
stage, olivopontocerebellar atrophy (OPCA) had not been linked with autonomic
failure. Though Shy and Drager noted degeneration of the intermediolateral cell
column in their pathologic report, credit for first specifically linking this
finding with the presenting features of postural hypotension rests with
Johnson, et al. [13].
The first
cases of pure autonomic failure (PAF) were described by Bradbury and Eggleston
[6] as "idiopathic orthostatic hypotension" because of their
presenting features. This term is misleading because it stresses only one
feature of autonomic failure and ignores the more usually associated neurologic
disturbances of bladder and sexual function and sweating. The term pure
autonomic failure is now accepted generally for this syndrome.
MULTIPLE-SYSTEM ATROPHY
Definition
A Consensus Panel convened by the American Autonomic
Society and co-sponsored by the American Academy of Neurology, defined MSA as
"a sporadic, progressive, adult onset disorder characterized by autonomic
dysfunction, parkinsonism, and ataxia in any combination. The features of this
disorder include: 1.Parkinsonism (bradykinesia with rigidity or tremor or
both), usually with a poor or
unsustained motor response to chronic levodopa therapy. 2. Cerebellar or
corticospinal signs. 3. Orthostatic hypotension, impotence, urinary
incontinence or retention, usually preceding or within 2 years after the
onset of the motor symptoms.
Characteristically, these features cannot be explained by medications or other
disorders. Parkinsonian and cerebellar features commonly occur in combination.
However, certain features may
predominate. When Parkinsonian features
predominate the term striatonigral degeneration is often used. When cerebellar
features predominate, sporadic OPCA is often used. When autonomic failure
predominates, the term Shy-Drager syndrome is often used. These manifestations
may occur in various combinations and evolve with time."
Prevalence
Multiple
system atrophy has increased in importance with the recognition that it occurs
much more frequently than had been hitherto suspected. At the National Hospital
Parkinson's Disease Brain Bank, which accepts for research purposes the brains
of patients who were managed as Parkinson's disease or parkinsonian-like
syndromes, about one-fifth prove to have the pathologic changes typical of MSA.
Clearly there are several factors in the selection of such cases that are
likely to distort the true incidence of this disorder. The clinical diagnosis
of Parkinson’s disease might have included patients with parkinsonism. Most
cases were not diagnosed by movement disorder or autonomic neurologists. The
prevalence of MSA does appear to have been underestimated. The prevalence of
MSA in the population may be on the order of between 5 and 15 per 100,000 [10].
Clinical Features
Age of onset
is in late middle age to old age. The 2 largest series (n>50 in each)
indicate median age of onset of 53 years (range 33-76; Wenning et al 1994;
n=100), and a mean of 60.3 years (SD 9.3; Sandroni et al 1991; n=73). The male
to female ratio is 2:1 (Wenning et al 1994; Sandroni et al 1994). Patients with
MSA present most commonly with symptoms of autonomic failure and parkinsonism.
There are usually features which suggest that the patient does not have
Parkinson's disease. Three differences distinguish MSA from Parkinson’s
disease. These are the atypical nature of the parkinsonian features, the
involvement beyond the extrapyramidal system, and the characteristic autonomic
features. Among the extrapyramidal symptoms, rigidity, bradykinesia, and ataxia
predominate over tremor, which is usually absent or minimal (Sandroni et al
1991; Wenning et al 1994). The response to levodopa is often absent, poor, or
poorly sustained. Wenning et al reported that 29% had a good or excellent
levodopa response at some stage, although only 13% maintained this response.
Orofacial and choreodystonic movements as side effects of treatment at this
stage, although the characteristic change is the absence of this response, and
they generally do not suffer “on-off” type phenomenon. Wenning et al reported
dyskinesias in 53% of treated patients. Sandroni et al (1991) reported lower
values for both levodopa response and dyskinesias. Dyskinesias correlated well
with levodopa response and occurred in 16% of MSA. Much of the difference
relates to criteria for MSA. Many of the cases accepted by Wenning et al (1994)
would have been defined as nonspecific MSA (n=75) or less likely
Parkinsonism-plus (n=54) in the Mayo series. Levodopa aggravates orthostatic
hypotension, and may provoke orthostatic symptoms. Mild pyramidal signs may be
present. Some patients may have additional cerebellar or bulbar involvement.
These features raise the possibility of more widespread involvement of the
central nervous system and hence the possible diagnosis of MSA. Following the
Consensus Conference, terms such as Parkinsonism-plus and non-specific MSA
should be discarded.
The true
diagnosis of MSA is made by the presence of autonomic failure. Orthostatic
hypotension is the rule, present at first evaluation or within a year of
development of parkinsonism. Orthostatic hypotension in patients with MSA is
usually less severe than that seen in patients with PAF. Symptoms of
orthostatic hypotension consist of lightheadedness, tiredness, ataxia, which
worsens in proportion to the severity of fall in blood pressure, blurred
vision, retrocollic aching. Of interest is that in about half the patients the
most common symptom or observation is orthostatic cognitive impairment (Low et
al 1995). These patients may look dazed, and may have trouble concentrating or
thinking clearly. Symptoms are often worse on arising, especially following
excessive nocturia (Mathias et al 1986). blood pressure falls following a meal
(see below), and orthostatic hypotension may be aggravated. Symptoms may also
worsen with exercise (Smith et al 1995), duration of standing and with a rise
in core temperature (Low et al 1995).
In a
study on early morning orthostatic hypotension, Mathias et al (1986) recorded
day and night urine volume, morning and evening body weight, and supine and
sitting blood pressure in five patients with chronic autonomic failure. All had
nocturnal polyuria, overnight weight loss, and a pronounced postural fall in
blood pressure, with lowest levels in the morning. Desmopressin (2-4 micrograms
given intramuscularly at 8 pm) reduced nocturnal polyuria, diminished overnight
weight loss, raised supine blood pressure, and
reduced the postural fall, especially in the morning. The excessive
nocturia might be related to an abnormal circadian rhythm of plasma
antidiuretic hormone, which is paradoxically higher during the day than at
night in these patients (Ozawa et al 1993).
Patients
with chronic orthostatic hypotension may be remarkably tolerant of very low
orthostatic blood pressures, developing no symptoms, especially when the
condition becomes chronic. This improvement in orthostatic tolerance appears to
be related to an expansion of the
autoregulated range into lower blood pressures (Thomas and Bannister 1980;
Brooks et al 1989). Within this range, cerebral blood flow remains constant in
the face of changing systemic blood pressure by a change in cerebral arteriolar
tone. Thomas and Bannister (1980) demonstrated that cerebral blood flow was maintained in response to head up tilt
down to a systolic pressure of 60 mm
Hg. Recent studies have combined transcranial doppler (TCD) with cerebral blood
flow recordings. Flow velocity, measured by TCD, becomes reduced when cerebral
arteriolar tone increases. It was demonstrated that blood flow was maintained
by a change in cerebral arteriolar tone (Brooks et al 1989). Cerebral
autoregulation in MSA may be a more dynamic process than originally conceived,
and could change from day to day (Shinohara et al 1978). With severe
orthostatic hypotension, autoregulation fails, and reversal of flow at the
end-diastolic phase on the Doppler flow image using duplex ultrasonography
occurs, as has been demonstrated for both the common carotid and vertebral
arteries (Yonehara et al 1994). This reversal can be corrected when effectively
treated by pressor agents.
The
circadian BP rhythm is characterized by a nocturnal fall and a diurnal rise,
and has been suggested to be mediated mainly by the circadian rhythm of
sympathetic tone (Imai et al 1990a,b). Ambulant BP recordings, initally using
intra-arterial recordings and subsequently using non-invasive measurements,
have demonstrated a consistent circadian trend in BP that was the inverse of
the normal pattern in widespread autonomic failure, with the highest pressures
at night and the lowest in the morning. These recordings of low BP seem to
correlate with symptoms of orthostatic hypotension (Mann et al 1983; Tochikubo
et al 1987; Imai 1990a,b). Increased alpha-receptor number and decreased cyclic
AMP production, which occurs in PAF have been suggested to contribute to its
supine hypertension, and an increase in alpha-receptor number may also
contribute to the supine hypertension of MSA (Kafka et al 1984), analagous to
the situation in essential hypertension.
The BP
response to exercise is impaired in both MSA and PAF (Smith et al 1995). With
exercise, BP increases in normal
subjects, but paradoxically falls
markedly in MSA and PAF, with a delayed recovery; The fall in BP is largely due
to a fall in systemic vascular resistance.
The
brain bears the brunt of the ischemic effects of orthostatic hypotension.
Rarely, other regions are apparently affected. Severe angina associated with
orthostatic hypotension has been reported. This patient had angina in
association with normal coronary arteries (Silverberg et al 1979). Vertigo is
not uncommon (Low et al 1995) and is presumed to be due to ischemia of the
vestibular end organ. Electronystagmographic abnormalities were reported in 3
patients with MSA with normal brain stem evoked potentials (Ohashi et al 1991).
Rarely it is associated with Meniere’s syndrome (Hinton et al 1993).
While
symptoms of orthostatic hypotension has attracted the most attention,
cholinergic dysfunction is an integral part of the disorder (Cohen et al 1987;
Khurana et al 1994; Sandroni et al 1991). Symptoms include constipation,
impotence, nocturia, hesitancy in micturition, anhidrosis, and xerostomia.
Constipation is the rule and can be refractory to treatment. Rectal
incontinence can also occur, often accompanied by urologic symptoms. Bladder
symptoms may mimic prostatism. Patients have frequency, nocturia, hesitancy,
poor stream and difficulty in bladder emptying. Many of these patients present
to the neurologist following a failure of transurethral prostatic resection to
relieve their urologic symptoms. Micturition is increasingly defective, with
overflow incontinence due to uninhibited detrusor activity and sphincter
weakness. In the male, sexual function is lost early in the disease, with
failure of erection first then failure of ejaculation. Cystometry/mictometry,
if done, will be abnormal in patients with impotence or urologic symptoms
(Rydin et al 1981). With progression of the symptoms, incontinence and/or
retention develops.
Beck et
al (1994) recently reviewed genitourinary dysfunction in 62 cases of MSA and
their experience is representative of the experience of many autonomic
clinicians. All patients had abnormal urethral or anal sphincter electromyography. Impotence occurred in 96%
of the men and was the first symptom alone in 37%. Urinary symptoms resulted
from a combination of detrusor hyperreflexia and urethral sphincter weakness
followed by failure of detrusor contraction. In men these symptoms simulated
those of outflow obstruction so that 43% underwent prostatic or bladder neck
surgery before the correct diagnosis was made. Stress incontinence occurred in
57% of the women and of these half had undergone surgery. The results of
surgery in both sexes were poor.
Dysarthria is common in MSA (Bassich et al 1984; Hanson et al 1983), and
may be due to cerebellar, striatal or mixed dysfunction (Linebaugh 1979).
Abductor paralysis of the vocal cords is reported to be relatively common
(Williams et al 1979; Hanson et al 1983). The sequence of involvement is
typically increased snoring followed by
episodes of inspiratory and expiratory stridor and sometimes, sleep apnoea. Respiratory failure or sleep
apnea can be relieved by tracheostomy. This complication can occur in some
patients with relatively early disease, and can uncommonly antedate autonomic
failure (Martinovits et al 1988; Bawa et al 1993), its presence should be
sought. Voice alterations in patients
with MSA might be distinguishable from that of Parkinson’s disease. Hanson et
al (1983) found that laryngeal stridor, hoarseness, intermittent glottal fry
and slow speech rate were found to be discriminating symptoms of MSA.
Electromyographic
evidence of denervation of the posterior crico-arytenoid muscle, the sole
abductors of the cords, is consistently
found; the interarytenoid muscle or crico-pharyngeal sphincter can also be
involved (Guindi et al 1981). Clinical and pathological findings have been
reported in three cases of MSA with laryngeal stridor severe enough to require
tracheostomy (Bannister et al 1981). Histological studies showed a marked
atrophy of the posterior crico-arytenoid muscles, with changes suggestive of
denervation (Bannister et al 1981; Guindi et al 1981) but despite this finding,
no clear evidence of any motor cell loss in the nuclei ambigui was obtained.
Multiple
system atrophy is associated with both obstructive (upper airways) and central
apnea, which can be life threatening. Nocturnal snoring, and sleep apnea are
common and are related to upper airways obstruction (Munschauer et al 1990).
Patients can die suddenly during sleep (Munschauer et al 1990). Chokroverty et
al (1978) reported a tilt-table polygraphic study in four patients with MSA who
developed periodic apnoea in the erect posture. In one patient reduced
hypercapneic ventilatory response and necropsy findings of neuronal loss and astrocytosis in the pontine tegmentum
suggested dysfunctional respiratory neurones in the brainstem. One patient had
Cheyne-Stokes respiration during the late stage of the illness.
Marked
muscular wasting, often with fasciculations with electromyographic and
pathologic confirmation of anterior horn disease, but without sensory loss, can
occur in MSA (Montagna et al 1983). Apraxia of lid opening occurs but is not
specific for MSA (Lepore et al 1985). The patient has difficulty in lid
elevation accompanied by vigorous frontalis contraction and no evidence of
ongoing orbicularis oculi contraction. Ocular assessment shows restricted
conjugate movements, though less than that seen in progressive supranuclear palsy.
The pupils may show alternating anisocoria.
Cognition
in unimpaired in the majority of MSA patients. In about 20% mild cognitive
impairment does seem to be present (Sandroni et al 1991). Psychiatric
manifestations are less common and are probably non-specific, comprising
depression, anxiety, and in general reflect an exaggeration of the patient’s premorbid state.
Types of Multiple System
Atrompy
The
following three principal forms of motor disturbance occur in MSA but are
entirely absent in PAF:
1. Striatonigral
Degeneration
The term
striatonigral degeneration was first used by Adams, et al. [1] to describe
patients with a parkinsonian syndrome possessing special pathologic features.
Many physicians consider the disorder clinically indistinguishable from
Parkinson's disease, and, in hindsight, these patients, especially if autonomic
defects had been sought and found, could now be classified as having MSA. In
this disease, there is a predominance of rigidity without much tremor, which is
associated with progressive loss of facial expression and limb akinesia. The
limbs show rigidity on examination, without the classic "cogwheel" or
"lead pipe" rigidity of Parkinson's disease. The facial expression is
often less affected than that in patients with Parkinson's disease. Patients
have difficulty in standing, walking, or turning, and difficulty feeding
themselves. Salivation is reduced. As a result of akinesia, the speech becomes
faint and slurred. The gait becomes slow and clumsy, superficially resembling
that seen in patients with Parkinson's disease, with an attitude of stooping
and often extreme cervical flexion which makes forward gaze difficult.
2. Olivopontocerebellar
Atrophy
In the
olivopontocerebellar form of MSA, not included in Shy and Drager's original
clinical description of only two cases, there is a prominent disturbance of
gait with truncal ataxia which frequently makes it impossible for the patient
to stand without support. In addition, there is marked slurring of speech with
irregularity of speed of diction. There may also be a mild or moderate
intention tremor affecting the arms and legs. This form of MSA is distinct from
familial OPCA, in which the associated clinical features may include optic
atrophy, retinitis pigmentosa, chorea, cataracts, and areflexia [12].
Neuropathy is more consistently present in familial OPCA.
3. Pyramidal Lesion
In both
striatonigral degeneration and OPCA there may be a pyramidal increase in tone,
together with impaired rapid hand and foot movements and exaggerated deep
tendon reflexes and bilateral extensor planter responses. It is, of course,
difficult to detect a pyramidal disturbance of tone in the presence of the
extrapyramidal disturbance. Primitive reflexes, such as the palmomental reflex,
may also be present.
Peripheral Neuropathy
There is
reasonably good agreement on the frequency of electrophysiologic generalized
neuropathy in MSA. Cohen et al (1987)
found electrophysiologic evidence of neuropathy in 7/36 patients with MSA
(19%). Sandroni et al (1991) reported a figure of 23% in 75 patients with MSA.
Pramstaller et al (1995) reported a
frequency of 18% mixed sensorimotor axonal neuropathy. Another 23% showed EMG
evidence of chronic partial denervation. Clinically, the neuropathy is usually
subclinical or mild, but can occasionally be moderately severe. The pathologic
alterations are uncertain. Reports have been few and contradictory. One sural
nerve biopsy was reported to show a marked reduction in large myelinated fiber
with complete sparing of unmyelinated fibers (Galassi et al 1982) while another
reported a selective loss of small nerve fibers (Tohgi et al 1982). Our own
experience is that the neuropathy is that of a low grade axonal polyneuropathy
with non-specific sural nerve changes. In 10 patients with chronic autonomic
failure, the sympathetic perivascular nerve plexuses from quadriceps muscle
biopsies were studied by catecholamine fluorescence and electronmicroscopy.
There was almost complete absence of catecholamine fluorescence and fewer than
normal numbers of small granular (noradrenergic) vesicles in all nerves
studied. The most marked depletion of noradrenergic vesicles was seen in two of
the patients with PAF (Bannister et al 1981).
Postprandial Hypotension
In
patients with autonomic failure, ingestion of food can sometimes substantially
lower BP (Da Costa et al 1985). In one patient with autonomic failure, BP fell
rapidly to 80/50 mm Hg after food ingestion and remained low for up to 3 hours,
even while the patient was in the supine position (Fig. 38‑2). Clearly
postcibal hypotension can be a major clinical problem for patients with
autonomic failure. Glucose appears to be the major factor in food; lipid has a
smaller, slower hypotensive effect, with a minimal change caused by protein
alone. The hypotensive effect of glucose does not result from its osmolality,
because an isocaloric, isosmotic, and isovolemic solution of glucose causes
only minimal changes in BP. Insulin probably has a role in the hypotension
induced by carbohydrate ingestion, but neurotensin, which has vasodilatory
effects, as well as other vasoactive intestinal polypeptides may contribute to
the vasodepressive effect of food in these patients [Da Costa et al 1985; 17].
Insulin
has a hypotensive effect that appears to be independent of hypoglycemia
(Mathias et al 1987). An associated problem in patients with generalized
autonomic failure is the absence of sympathetic manifestions of hypoglycemia.
Insulin is known to open up arteriovenous shunts in peripheral nerve (Kihara et
al 1994). The increase in splanchnic-mesenteric capacitance is not different in
patients with autonomic failure when compared with normals; the fall in BP is
due to the loss of compensatory mechanisims (Kooner et al 1989). The
hypotension was prevented by the peptide release inhibitor, octreotide, with no
change in cardiac index or in peripheral blood flow, suggesting an effect on
the splanchnic vasculature, probably through inhibiting release of
vasodilatatory pancreatic and gut peptides (Raimbach et al 1989; Fig. 38‑3).
CLINICAL FEATURES OF PURE
AUTONOMIC FAILURE
The age
of onset of PAF is typically in middle age. Most cases are diagnosed between
the ages of 50 and 70 years (Thomas and Schirger 1963). In the series of 26 cases by Cohen et al
(1987), ages ranged from 51-80 years, mean 67 years, with a mean duration of
symptoms of 39 months.The symptoms of PAF are insidious in their onset, with
mild symptoms concealed for years because of autonomic compensatory mechanisms.
Patients may start with symptoms of vague orthostatic weakness, postural
dizziness, or faintness that can very easily be overlooked or result in erroneous
referral to a psychiatrist, and not a neurologist. The crux of the diagnosis
is the demonstration of postural hypotension on standing, still often
neglected by physicians as a useful test. Some patients with autonomic failure
first have bladder symptoms or impotence and defective sweating, not postural
hypotension. Constipation is common (Polinsky et al 1981), but other
gastrointestinal symptoms are uncommon. A Horner’s syndrome can occur (Polinsky
et al 1981). These symptoms of PAF are similar for the autonomic failure
associated with MSA described above. There are some subtle differences in the
orthostatic hypotension of PAF when compared with MSA. The orthostatic
hypotension tends to be more pronounced and the symptoms tend to be more
prominent, probably related to the greater mobility of patients with PAF.
Postprandial orthostatic hypotension tends to be more severe.
INVESTIGATION
.
The 2
most characteristic findings in MSA are either putamen hypointensity (Fig 4) or
slit-like lateral putamen hyperintensity on T2 weighted images studied on a
high field strength system. The putamen hypodensity, especially along their
lateral and posterior portions (Pastakia 1986; Fulham et al 1991) correlates
with rigidity (Brown et al (1987) and with neuronal loss in these nuclei
reported on postmortem examinations. Other changes in MSA include cerebellar
and pontine atrophy (Savoiardo et al 1994; Abe et al 1983; Fulham et al 1991).
Stern et al (1989) reported, in a prospective study that moderate to severe
putaminal hypointensity distinguished MSA from Parkinson’s disease, but did not
distinguish among the different system atrophies and degenerations. Less common
findings are an anterior globose hyperintensity (Konagaya et al (1994),
occurring in about half the patients, and least common a T1-hypointensity. Lang
et al (1994) related the "slit-like void signal" observed in the
putamen to pathologic alterations in 3 patients with MSA. They reported that
the MRI change is typical of striatonigral degeneration, and that their
histochemical studies support the concept that increased iron deposition in the
putamen is responsible for this MRI picture. The MRI changes are helpful in
distinguishing MSA from Parkinson’s disease. The test is useful, but a negative
study does not exclude the diagnosis of MSA. It does not appear to reliably distinguish
between MSA and progressive supranuclear palsy Savoiardo et al (1985, 1994).
Positron Emission Tomography
F‑Dopa
is a positron‑emitting tracer analog of levodopa. When administered
intravenously, it is transported across the blood‑brain barrier and
stored as F‑dopamine in caudate and putamen synaptosomes. Using positron
and emission tomography (PET), the kinetics of F‑dopa uptake in patients
with MSA have been studied. There is reasonable correlation of the results of
PET with functional impairment Those patients with clinical evidence of
striatonigral degeneration showed significantly reduced influx rate constants
(K) for the uptake of F‑dopa into the caudate and putamen [7]. Short
duration of disease, or mild parkinsonism, is associated with normal PET scan,
while increased severity and duration of parkinsonism is associated with
reduced [18F]6-fluoro-1-dopa uptake, suggesting impaired nigrostriatal
dopaminergic function (Bhatt et al 1990).
Brooks et al (1990) used 18F-dopa and S-11C-nomifensine
(NMF) as positron emitting tracers whose caudate and putamen uptake reflects
striatal dopamine storage capacity and the integrity of dopamine reuptake
sites, respectively. Using these two tracers, they evaluated the integrity of
the presynaptic striatal dopaminergic system with PET in 10 subjects with MSA,
13 age-matched controls, 8 subjects with L-dopa responsive Parkinson's disease
(PD), and 7 subjects with PAF. They reported that both MSA and PD patients
showed a parallel decline of striatal dopamine storage capacity and reuptake
site integrity, probably reflecting a loss of nigrostriatal nerve terminals.
Caudate function was relatively preserved in PD compared with MSA. The majority
of PAF patients have an intact nigrostriatal dopaminergic system.
Benzodiazepine binding was largely preserved in the
cerebral hemispheres, basal ganglia, thalamus, cerebellum, and brainstem in
patients with MSA of either striatnigral or OPCA varieties (Gilman et al 1995).
Autonomic Function Tests
Detailed
studies have been done in the clinical autonomic laboratory, where the focus
has been on the severity and distribution of autonomic failure, and in the
research laboratory, where the emphasis has been on pathophysiologic mechanisms
(Aminoff et al 1972; Wilcox and Aminoff 1976; Cohen et al 1987; Kuroiwa et al
1983, 1987; Low 1993b; Khurana 1994). Cardiovascular reflex responses to
standing and to the Valsalva manoeuver are typically preserved in patients with
Parkinson's disease but are grossly defective or absent in patients with MSA
(Wilcox and Aminoff 1976). Cohen et al (1987) evaluated 62 consecutive patients
who presented to the Mayo Autonomic Reflex Laboratory; 26 patients were PAF and 36 patients, MSA. Patients were well
matched in age (67 vs 66 years), duration (39 vs 36 months), and severity of autonomic failure.
Postganglionic sudomotor and vasomotor functions were studied using the
quantitative sudomotor axon reflex test and supine plasma norepinephrine. The
distribution and severity of autonomic failure were assessed by the percent of
anterior surface anhidrosis on the thermoregulatory sweat test, by heart rate
responses to deep breathing and the Valsalva maneuver, and by BP recordings.
Severe and widespread anhidrosis was found in both PAF and MSA patients, 91 and
97% respectively of body surface being anhidrotic. Postganglionic sudomotor
failure occurred at the forearm in 50% each of PAF and MSA patients and at the
foot in 69% and 66% of PAF and MSA patients, respectively. However,
postganglionic sudomotor function was preserved in some MSA patients with
anhidrosis on thermoregulatory sweat test, indicating a preganglionic lesion.
Vagal abnormalities were found in 77% and 81% of PAF and MSA patients. More
recently, we have developed the composite autonomic scoring scale (CASS) that
corrects for the confounding effects of
age and gender (Low 1993a). This scale assigns autonomic failure from 0
(normal) to 10 (maximal impairment), with subscores for sudomotor, cardiovagal
and adrenergic deficits. Using CASS, we compared the scores in MSA and
Parkinson’s disease. MSA has CASS of 8.5±1.3 (SD), significantly higher
(P<0.001) than Parkinson’s disease (1.5±1.1; Fig 5).
Yokota
et al (1993) recorded sympathetic skin responses in 87 patients with various
types of cerebellar degeneration. Sympathetic skin responses were abnormal in
most patients with MSA, sporadic OPCA, and
striatonigral degeneration, whereas sympathetic skin responses were
normal in patients with familial OPCA, sporadic cerebellar atrophy, and familial
cerebellar atrophy.
Baser et
al (1991) measured sweat production evoked by the sympathetic skin response to
electrical stimulation, and by intradermal methacholine in patients with MSA,
PAF, and in normal subjects. Patients
with PAF and MSA produced significantly
less sweat than controls. They found that sympathetic skin response was less
sensitive than the sweat test, and can occur in the absence of normal sweat
gland function.
Kuroiwa
et al (1983) studied BP alterations, mean R-R interval, and R-R interval
variance in patients with Parkinson's
disease, spinocerebellar degeneration, and MSA. They reported a modest
correlation between indices of sympathetic function (orthostatic hypotension
with anhidrosis [p < 0.05]), parasympathetic function (reduction of R-R
interval variance while resting supine with bladder-bowel dysfunction [p <
0.05]). Most non-invasive tests were abnormal, including reduced heart rate
variation and are frequently associated with orthostatic hypotension and
sphincter disturbance (Kuroiwa et al 1987).
Khurana
et al (1994) undertook a detailed multi-organ evaluation of cholinergic
function on 11 patients with MSA. A battery of twelve tests was employed to
assess cholinergic function. Six tests demonstrated pupillary, lacrimal, salivary,
urinary bladder, sexual and sudomotor dysfunction in the majority of patients.
Cardiac vagal function as studied by the heart rate response to deep breathing,
the Valsalva manoeuver, cold face test, and atropine test was affected in all
patients. Oesophageal motility was abnormal in six patients. Cholinergic
dysfunction in MSA patients was widespread but of variable severity and
distribution. Subcutaneous administration of the parasympathomimetic agent
bethanechol demonstrated hyperresponsiveness of lacrimal, salivary,
oesophageal, bowel, bladder and sudomotor functions. It was suggested that MSA
was primarily a preganglionic cholinergic disorder with transsynaptic
degeneration accounting for the development of postganglionic cholinergic as
well as adrenergic dysfunction.
Polinsky
et al (1982) evaluated pancreatic polypeptide and catecholamine responses to
insulin-induced hypoglycemia in 8 patients with PAF, 7 with MSA, and 11 healthy
subjects. Normal subjects exhibited rapid and substantial elevations in plasma
epinephrine, norepinephrine, and pancreatic polypeptide concentrations in
response to insulin hypoglycemia. In contrast, patients with MSA and PAF
exhibited impaired catecholamine and pancreatic polypeptide responses to
insulin hypoglycemia, indicating involvement of the parasympathetic nervous
system. There was no correlation between the catecholamine and pancreatic
polypeptide responses in either the normal subjects or the patients.
Plasma Norepinephrine
The
plasma norepinephrine level is an important but relatively insensitive measure
of sympathetic efferent function. Patients with PAF almost always have a much
lower resting level than do patients with MSA, but neither show a rise on
head-up tilt or standing because of the block of baroreceptor pathways. Figure
38‑1 compares the plasma norepinephrine values in normal subjects,
patients with autonomic failure, and patients with the congenital disorder of
dopamine b‑hydroxylase deficiency. Table 38‑1 shows the
plasma norepinephrine levels in a group of patients with autonomic failure
from the National Hospital for Neurology and Neurosurgery (U.K.) and the National
Institutes of Health (U.S.). The Mayo data is similar. Supine plasma free
norepinephrine values were significantly reduced in PAF (p < 0.001), but not
in MSA, patients (Cohen et al 1987). Standing plasma norepinephrine values were
reduced in both PAF (p < 0.001) and MSA (p < 0.001) patients.
Sleep Laboratory Recordings
Several
types of sleep abnormalities have been described in the Sleep Laboratory.
Guilleminault et al (1981) reported sleep apnea, both obstructive and central
in type, as well as disturbances of the respiratory oscillator in 10 patients
with MSA. The observed respiratory irregularities were not associated with the
usual cardiac response, because of autonomic failure. Other abnormalities
include a reduction in total sleep time, increased sleep latency and awakening
periods during the night, and reductions of rapid eye movement (REM) and NREM
sleep (Martinelli et al 1981). In contrast to a reduction in BP during all
sleep stages, arterial BP of MSA patients rose progressively during NREM sleep
stages and show a further increase in REM sleep with sudden phasic swings of
systemic arterial pressure (Martinelli et al 1981; Coccagna et al 1985; Tulen
et al 1991). These patients may also hve REM sleep behaviors, described as
wild, dream-enacting behaviors during REM sleep with a loss of the usual atonia
of submental muscles (Sforza et al 1988). A disinhibited locomotor system
during sleep appears to be responsible
for this REM parasomnia. Pathologic changes in the brainstem in regions
responsible for respiratory rhythmogenesis are mild or absent (Chester et al
1988).
Evoked Potentials
Patients
with MSA have abnormal brain stem potentials in contrast to normal findings
with Parkinson's disease and PAF (Prasher and Bannister 1986). These workers
surmised that the most likely area involved was the superior olivary complex. A
subsequent study supports this notion. Uematsu et al (1987) related brainstem
auditory evoked responses (BAERs) to CT findings of pontine atrophy in 11
patients with MSA and 10 patients with olivopontocerebellar atrophy. The
prolongation of I-III interpeak latencies in 6 patients with MSA and in 6 patients
with olivopontocerebellar atrophy correlated well with the degree of the
pontine atrophy estimated from the CT scan. In addition prolongation of I-III
interpeak latency was noted in patients with the striatonigral but not OPCA
pattern of involvement.
Urologic Evaluation
Patients
with PAF and MSA have well-defined abnormalities on EMG-cytometry. Three
abnormalites have been described (Wheeler et al 1985; Salinas et al 1986; Kirby
et al 1986). First, almost all patients have profound urethral dysfunction, due
to poor proximal urethral sphincter tone, which causes bladder neck
incompetence. In addition, the function of the striated component of the
urethral sphincter is impaired, presumably due degeneration of Onuf’s nucleus,
and affects at least 90% of patients
(Salinas et al 1986; Kirby et al 1986; Pramstaller et al 1995). Second,
there is the loss of the ability to initiate a voluntary micturition reflex
(detrusor areflexia), affecting about two-thirds of patients (Salinas et al
1986). This may reflect the degeneration of neurons in pontine and medullary
nuclei and in the sacral intermediolateral columns. In addition, these studies
have demonstrated a significant reduction in the density of
acetylcholinesterase-containing nerves in bladder muscle. The third abnormality
is involuntary detrusor contractions in response to bladder filling (detrusor
hyperreflexia), affecting approximately one patient in three (Salinas et al
1986). It is suggested that these may be the result of a loss of inhibitory
influences from the corpus striatum and substantia nigra.
Urodynamic studies are reported to
differential MSA from Parkisnon’s disease (De Marinas et al 1993). Urethral
sphincter EMG is reported to be helpful in differentiating MSA from Parkinson’s
disease (Eardley et al 1989), showing detrusor hyperreflexia with reduction of
maximal cystometric capacity. In a recent study Pramstaller et al (1995)
reported that 90% of patients with MSA had an abnormal sphincter EMG; the test
appears to be highly sensitive and specific in differentiating MSA from
Parkinson’s disease. Similar evidence of denervation is obtainable from anal
sphincter EMG (Sakuta et al 1978). EMG of anal sphincter muscles will
differentiate amyotrophic lateral sclerosis from Shy-Drager syndome. In 30 patients
with ALS, EMG of the external sphincter muscle was essentially normal, with no
signs of denervation. In eight cases of Shy-Drager syndrome, however, motor
unit potentials of the anal sphincter had highly polyphasic forms of long
duration and high amplitude (Sakuta et al 1978).
Diagnosis of MSA
The
definition by the Consensus Panel, described earlier, is reasonable. In summary
the diagnosis of MSA is based on the clinical features of CNS involvement of
the systems described above coupled with the presence of clinical autonomic
failure. Clinical autonomic features that are useful in the clinical setting
are the early onset of orthostatic hypotension and bowel and bladder
involvement. There are certain clinical features that help differentiate the
parkinsonism of MSA from Parkinson's disease. These include the relative
absence of tremor, the poor response to levodopa, the absence of
levodopa-induced dyskinesias, and the aggravation of orthostatic hypotension by
levodopa. Where autonomic laboratory evaluation is available, patients with MSA
have a characteristic pattern of involvement. They have severe and widespread
impairment of sudomotor, adrenergic (both peripheral and cardiac) and
cardiovagal function. When a thermoregulatory sweat test is done these patients
will have in excess of 40% (typically >60%) of anterior surface anhidrosis,
in contrast to patients with Parkinson's disease, who have <40% anhidrosis.
The severity and distribution of autonomic failure is much milder in
Parkinson's disease. The composite autonomic scoring scale (CASS) score in MSA
exceeds 7, while the score is <5 in Parkinson's disease (Figure 43-4). There
is some evidence that patients with a worse autonomic failure score will
progress more rapidly (Sandroni et al 1991).
The
charge of the autonomic clinician is to make the diagnosis of MSA, using the
criteria discussed above. The next step is to evaluate the distribution and
severity of autonomic failure, since there is some suggestion that patients who
fulfill the diagnosis of MSA will have a range of outlooks. In the largest
retrospective review of patients studied at the Mayo Autonomic Reflex
Laboratory, where all patients were evaluated with a similar panel of tests,
including quantitative sudomotor testing, the severity and distribution of
autonomic failure at presentation was predictive of the rate of progression.
Patients with the striatonigral form of MSA with severe autonomic failure (often
designated Shy-Drager syndrome), who had orthostatic hypotension at onset of
the illness have a poor prognosis, while patients with less severe involvement,
with orthostatic hypotension developing years after the neurologic disorder may
progress less rapidly (Sandroni et al 1991).
Diagnosis of PAF
The
major emphasis on publications on PAF has been on a comparison with MSA,
because of the necessity in differentiating 2 conditions with different
prognoses (see below), and because they provide models of postganglionic versus
preganglionic autonomic disease. The Consensus panel definition is reasonable
but incomplete, resulting in the designation of all autonomic failures that do
not have CNS involvement, and not differentiate idiopathic peripheral autonomic
neuropathies from PAF. In practice there a necessary second step, to
differentiate PAF from the idiopathic autonomic neuropathies. Systematic
prospective evaluation of non-CNS causes of orthostatic hypotension remain to
be reported. Some suggestions on the differential diagnosis of PAF from IAN is
shown on table 43-2. The onset of PAF
is insidious whereas it is acute or subacute in IAN, and follows a viral
infection in 50% of cases (Suarez et al 1994). The onset in IAN is
characteristic with a constellation of autonomic symptoms including
gastrointestinal failure, with pain and distension, retention of urine and
cardiovascular failure. The cases with restricted autonomic failure are more
problematic. Helpful diffentiating points are the common presence of some
sensory symptoms (although the EMG is typically normal of only mildly
abnormal), the prominence of abdominal colic, the common involvement of the pupil, and the antedenct viral
infection.
Pharmacologic Tests
Pharmacologic
tests of sympathetic function make use of Cannon's law of denervation supersensitivity
[2]. Trendelenburg showed experimentally that, after complete postganglionic
section, there was supersensitivity to the neurotransmitter norepinephrine, if
this was given intravenously, but a lack of response to tyramine. Polinsky et
al (1981), in a classic pharmacologic dissection study of MSA versus PAF,
defined the distinctive differences. Greater-than-normal slopes of the
stimulus-response curves in patients with MSA and PAF were found and considered
consistent with deficient reflex modulation (Polinsky et al 1981; Baser et al
1991). Patients with PAF showed a shift to the left of the plasma
norepinephrine-BP curves, indicating "denervation supersensitivity"
observed previously by Trendelenburg, and is due to an increase in the density
of postsynaptic alpha-receptors. This was consistent with the deficient plasma
norepinephrine response to tyramine in these patients. Some studies have
reported supersensitivity to norepinephrine in MSA (Wilcox and Aminoff 1976;
Bannister et al 1979). This is supported by radioligand binding studies (a‑adrenergic receptor
agonist [3H]dibydroergocryptine for receptors on platelets and
[3H]dihydroalprenolol binding for b‑receptors on Iymphocytes). In MSA, there is a
sixfold increase in the number of a‑receptors on platelets [9]. There is a similar
increase in the number of b‑receptors
on lymphocytes [5]. Although this is an indirect estimate of receptors in blood
vessels and in the heart, there is a striking correspondence between extreme
norepinephrine supersensitivity and the low plasma levels of norepinephrine.
The increase is seen in both MSA and PAF (Kafka et al 1984).
Patients
with PAF and MSA may complain of feeling light-headed after alcohol ingestion
particularly on assumption of the upright posture. Alcohol was shown to lower
supine BP and dilate the superior mesenteric artery with no change in muscle or
cutaneous blood flow in these patients (Chaudhuri et al 1994). Alcohol also
enhances the fall in BP during head-up tilt.
As
expected spectral analysis of RR interval and systolic BP demonstrates a marked
reduction in power of all frequencies and of baroreflex gain in PAF (Furlan et
al 1995). Kingwell et al (1994) related
spectral analysis to microneurography and norepinephrine measurements. They
concluded that heart rate variation at 0.1 Hz depends on factors in addition to
cardiac sympathetic nerve firing rates, including multiple neural reflexes, cardiac adrenergic receptor
sensitivity, postsynaptic signal transduction, and electrochemical coupling,
and is not directly related to cardiac norepinephrine spillover, which is a
more direct measure of the sympathetic nerve firing rate.
In spite
of severe and widespread denervation, plasma renin response to standing can
remain intact, suggesting that plasma renin activity can be independent of
sympathetic nervous activity and may be mediated by renal baroreceptors
(Mathias et al 1977). However, generalized autonomic failure is usually
associated with a loss of the renin mechanism (Baser et al 1991; Biaggioni et
al 1993).
The
adrenal medullary response to hypoglycemia in patients with orthostatic hypotension appears to be impaired
(Polinsky et al 1980; Sasaki et al 1983). There did not seem to be a difference
between the responses of PAF vs MSA. in their deficient epinephrine response.
The glucose counterregulatory factors (eg, glucagon, epinephrine, growth
hormone, cortisol, and norepinephrine) to insulin-induced hypoglycemia appear
to be also reduced in MSA (Sasaki et al 1983).
Afferent and Central Pathways
While
detailed studies have been available on the dissection of efferent pathways,
studies on afferent or central pathways have been more indirect. The strategy
adopted has been to use a number of non-neural afferent stimuli that stimulates
portions of the central neuraxis, such as the hypothalamus or pituitary, and
measure their products. These include growth hormone, prolactin and vasopressin (which can be stimulated by
alterations in osmolarity), clonidine and hypoglycemia.
The
diurnal variation of growth hormone secretion is impaired (Hasen et al 1982),
as is its response to clonidine (da Costa et al 1984). Multiple system atrophy
patients had normal values but failed to rise in response to clonidine (da
Costa et al 1984). Konagaya et al (1985) evaluated the serum growth hormone and
prolactin responses to dopaminergic stimulation or dopamine receptor blockade
in 9 patients with MSA. The impaired responses suggested pituitary dopaminergic
involvement.
Patients
with MSA have a severely blunted response of plasma arginine vasopressin to the
stimulus of head-up tilt (Williams et al 1985; Puritz et al 1983; Kaufmann et
al 1992). The rise of plasma arginine vasopressin (AVP) with upright posture is
modulated by central dopamine and opioid receptors. Patients with MSA may have
depletion of brain dopamine and opioid peptides (Puritz et al 1983).In contrast
the increment in AVP in response to tilt-up is normal in PAF (Kaufmann et al
1992), indicating normal functioning of the efferent connections from the
osmoreceptors within the hypothalamus.
Patients
with MSA have intact plasma epinephrine responses to nicotinic adrenal stimulation
with arecholine, while PAF lack this response; both conditions are associated
with impaired ACTH response (Polinsky et al 1991). The lack of this response in
patients with pure autonomic failure is
consistent with peripheral sympathetic dysfunction. The appearance and exacerbation of tremor, vertigo, and
pathological affect in the MSA group suggest that some central cholinergic
receptors remain functional.
Plasma
beta-endorphin, and corticotropin (ACTH) responses during insulin-induced
hypoglycemia are significantly impaired in patients with MSA, in contrast to
normal levels in PAF patients (Polinsky et al 1987). The strong correlation
between beta-endorphin and ACTH levels is consistent with their common origin.
CSF 3‑methoxy‑4‑hydroxyphenylglycol
(MHPG) is reduced in both MSA and PAF (Polinsky et al 1984). However only PAF
is associated with a reduced plasma MHPG. In MSA, abnormal function of central
noradrenergic pathways seems to cause the low CSF MHPG levels. In
orthostatichypotension, the decreased CSF MHPG results from the diminished
plasma MHPG levels.It is possible to correct CSF MHPG levels for the
contribution from plasma free MHPG to provide an index of central
norepinephrine metabolism.
Neurochemistry of MSA and
PAF (Chapter 45)
PATHOLOGIC DIAGNOSIS
Pathology of multiple
system atrophy and PAF
The neuropathology of MSA consists of neuronal cell loss
and gliosis, without Lewy bodies or neurofibrillary tangles, in multiple
pigmented nuclei (Shy and Drager 1960; Bannister & Oppenheimer 1972; Daniel
1992): Cell populations that are severely and nearly always affected are
a. Subtantia
nigra and putamen
b. Inferior
olives
c. Pontine
nuclei
d. Cerebellar
Purkinje cells
e. Onuf's
nucleus
f. Locus
ceruleus
g. Intermediolateral
column cells
There
have been a number of pathologic studies of autonomic failure [13, 20, 24].
Brainstem abnormalities have also been noted, with loss of pigment in the
melanin‑containing nuclei which are derived from the basal plate of the
primitive neural tube, including the dorsal nucleus of the vague, the locus
coeruleus (Tomonaga 1983), and the nucleus tractus solitarius.
Neurochemically, a common feature was a profound depletion in dopamine and
noradrenaline from brain regions which are normally rich in these catecholamines.
Central cholinergic systems appeared to be involved also, but to a variable
degree (24). Cell populations that are commonly but less severely affected are
the caudate, pallidum, pyramidal tract, and vestibular nuclear complex (Sung et al 1979; Daniel 1992). Cells that
are only sometimes affected are the thalamus, subthalamic nucleus, cerebral
cortex, Edinger-Westphal nucleus, dentate nucleus, arcuate nucleus, optic
nerve/tract, Clarke's nucleus, sympathetic ganglia, sensory ganglia and
peripheral nerve (Daniel 1992).
Parkinson's
disease in contrast, has a more restricted neuropathology, with neuronal loss
in the substantia nigra and Lewy bodies in pigmented nuclei and in autonomic
neurons including intermediolateral column and postganglionic neurons
(Jellinger 1989), where the depletion is modest, in keeping the only minor or
mild autonomic failure (Aminoff and Wilcox 1971; Sandroni et al 1991a).
Pure
autonomic failure is unassociated with substantial CNS involvement and is likely
to be a postganglionic disorder (Bannister 1993). A modest reduction in
intermediolateral column neurons has been reported (20; Low et al 1978). Lewy
bodies may be found in patients with PAF. These are inclusion bodies that contain
remnants of melanin from the oxidation of catecholamines which are a
characteristic finding in Parkinson's disease, with which autonomic failure
is on rare occasions associated.
Spinal Cord
In
almost all patients carefully studied, MSA has been associated with at least
75 percent reduction in the number of sympathetic preganglionic neurons in the
intermediolateral cell columns of the spinal cord, corrected for age (Low et
al 1988; Bannister and Oppenheimer 1972; Kennedy and Duchen 1977). Correction
for age is important since there is a 5-8% attrition of preganglionic neurons
per decade from the third decade onwards (Low et al 1977). Ventral spinal root
axons segregate into distinct groups of large, intermediate and small
myelinated axons, corresponding to alpha, gamma and preganglionic axons. Axonal
loss occurred predominantly in thin, myelinated fibers that correspond mainly
to autonomic preganglionic axons (Low et al 1978; Sobue et al 1986).
Intermediate and large myelinated fibers, mainly gamma and alpha axons, were
also involved, but to a lesser degree. Neuronal and axonal loss was more
prominent in caudal segments and less in rostral segments. Axonal degeneration
in single teased fibers was seen frequently in ventral spinal roots (Sobue et
al 1986).
There
are 3 groups of sacral motor neurons, the posterolateral motor neuron column
(PL), inferior intermediolateral nucleus (IML) and cell group X of Onuf (Onuf).
Morphometry disclosed a marked depletion of IML, Onuf and somatic motor neurons
in MSA (Konno et al 1986). In contrast, in ALS there is a severe loss of
somatic motor neurons, a modest reduction of IML neurons, and normal or only
modest reduction in Onuf’s neucleus (Konno et al 1986; Mannen et al 1982).
In MSA, small-sized myelinated fibers of thoracic corticospinal
tract appear to be markedly reduced, while large-sized myelinated fibers remain
well preserved (Sobue et al 1987).
Some
reduction in intermediolateral cell counts have been reported in PAF
(Oppenheimer 1980; Low et al 1978; van Ingelghem et al 1994). The changes tend
to be much milder than those of MSA, merging with the effects of aging. Low et
al (1978) reported intermediolateral column neuron and corresponding axon
counts and morphometry in 2 patients with MSA and one with PAF. The
intermediolateral column (ILC) neuron cell
body counts were reduced to 17% of control levels in SDS and 52% of
control levels in Iorthostatic hypotension. The B fiber counts in the
corresponding ventral spinal root were reduced to 21% and 41% in SDS and
Iorthostatic hypotension, respectively.
Ganglionic Changes in
Autonomic Failure
Matthews
[19] has found differences in the ganglionic pathology between patients with
PAF and those with MSA. In the latter, the neurons of the sympathetic ganglia
are not severely reduced in number and do not appear grossly abnormal. There is
evidence to suggest a severe deficiency of preganglionic endings on the
ganglia, and possibly overdriving of surviving endings. In PAF, on the other
hand, the packing density of ganglionic neurons is severely reduced, in one
instance up to 25 percent of the number reported for normal ganglia, though the
surviving ganglia did not appear to be grossly abnormal pathologically.
Nosology
While
these disorders are typically clinically distinct, there is considerable
heterogeneity, and controversy on nosology (Quinn 1989). MSA is often
misdiagnosed as Parkinson's disease, even by experienced neurologists. Patients
who present with apparent Parkinson’s disease may evolve into MSA, although
autonomic function tests may distinguish them ab initio (Sandroni et al 1991).
Patients with typical features of Parkinson’s disease may have additional
neurologic involvement (such as corticospinal tract involvement, cerebellar
signs or some evidence of autonomic failure), when the term Parkinsonism-plus
is somtimes used (Sandroni et al 1991a). These patients have autonomic findings
that are intermediate in seveirity between MSA and Parkinson’s disease. About
10% of patients with apparent PAF may evolve into MSA (Thomas and Schirger
1970). Although the polar groups appear distinct, many cases are more difficult
to classify when strict criteria are used. For instance in the study by
Sandroni et al (1991a), where strict criteria for MSA were used (requiring the
presence of orthostatic hypotension and/or urogenital autonomic failure on
first evaluation), many cases fell into the category of non-specific
multisystem degeneration. In the British Parkinsonism Study, where a
neuropathologic "gold standard" was used, approximately 20% of
clinical Parkinson's disease had the neuropathologic features of MSA (Quinn
1989). However, as discussed earlier, the premorten evaluation was variable.
Even the neuropathologic features may merge. For instance, Parkinson's disease
itself has pathologic alterations beyond the nigra-striatum (Jellinger 1991)
and Lewy bodies can be seen is some cases of MSA (Quinn 1989). Transitional changes where features of
Parkinson's disease with Lewy bodies in the substantia nigra and locus ceruleus
and striato-nigral degeneration and olivo-ponto-cerebellar atrophy were evident
in both cases (Sima et al 1987).
The simplest
interpretation of these observations is that the two forms of autonomic
failure, PAF and MSA, result from the loss of ganglionic and of preganglionic
neurons, respectively. The lesser loss of intermediolateral column cells in
PAF could be a retrograde neuronal death consequent upon target deprivation.
The possibility cannot be excluded that the loss of intermediolateral neurons
in MSA itself might be due to disruption of the retrograde trophic influences
imposed on them by ganglionic neurons.
Pathogenetic Mechanisms
Argyrophilic
cytoplasmic inclusions of oligodendrocytes have been described in cases of MSA
(Fig 43-6), with phenotypes of sporadic olivopontocerebellar atrophy,
striatonigral degeneration, and the Shy-Drager syndrome (Papp et al 1989, 1992,
Costa and Duykaerts 1993). The subject has been recently reviewed (Costa and
Duykaerts 1993). The oligodendroglial cytoplasmic inclusions are immunolabeled
with antiubiquitin antibodies. Ultrastructurally, they appear as
granule-associated filaments. More recently, similar argyrophilic inclusion
bodies have been reported in the cytoplasm of neurons and in both
oligodendroglial and neuronal nuclei of MSA brains. Neuronal and
oligodendroglial cytoplasmic inclusions have identical ultrastructural
characteristics, but different antigenic properties. Oligodendroglial
cytoplasmic inclusions are reported to be recognized by anti-ubiquitin,
anti-alpha- and anti-beta-tubulin, and anti-tau antibodies, whereas neuronal
cytoplasmic inclusions were stained only by anti-ubiquitin antibody (Papp et al
1992). The chemical nature of the inclusions is largely unknown. The fraction
containing glial cytoplasmic inclusions-bearing cells contains a 32 kDa and a
40 kDa protein, both of which were specifically recognized by anti-ubiquitin
and anti-alpha B-crystallin antibodies, neither of which was found in the same
fraction derived from control brain (Tamaoka et al 1995). These immunochemical
results suggest that ubiquitinated alpha B-crystallin is present in glial
cytoplasmic inclusions from the brains of patients with MSA. Their significance
remains controversial: they could be a primary event in the course of the degenerative
process or merely an epiphenomenon of some disordered cytoskeletal metabolism
(Costa and Duykaerts 1993).
The
current opinion is that these inclusions are present in all cases of MSA but
that the presence of these inclusions are not specific to MSA (Daniels et al
1995). These workers found inclusions in all of 56 brains with MSA; 3 of 7 with
corticobasal degeneration, and 2 of 18 with PSP. They have also been found in 2
of 22 with hereditary OPCA (Nakazato et al 1990; Gilman et al in press) and in
a patient with chromosome 17-linked dementia (Sima et al 1994).
Recently,
antibodies in human CSF against specific brain regions in vitro have been
detected in patients with a variety of neurodegenerative disorders. These
studies suggest that specific CSF antibodies may be markers of system-specific
degeneration. Thus, a CSF antibody in Alzheimer's disease reacts against rat
cholinergic septal neurons (McRae-Degueurce et al 1987), and a CSF antibody in
patients with Parkinson's disease reacts against dopaminergic neurons of the
rat substantia nigra/ventral tegmental area (Carvey et al 1991). More recently,
Polinsky et al. (1991) reported that CSF immunoreactivity to rat locus ceruleus
occurred in a significantly greater number of samples from MSA patients
compared to control subjects or patients with PAF. Other brain regions
infrequently showed immunoreactivity. These findings suggest that degeneration
in MSA may release antigen(s) that induce antibodies against locus ceruleus
neurons. Less specific immunologic alterations, representing antibody
attachmment to degenerating fibers have been described (Yamada et al 1990).
In a
study of 60 patients with MSA, their relatives, and an identical number of
controls, MSA patients had
significantly more potential exposures to metal dusts and fumes, plastic
monomers and additives, organic solvents, and pesticides than the control
population (Nee et al 1991). These findings were interpreted are possibly
consistent with the hypothesis that MSA develops as a result of a genetically
determined selective vulnerability in the nervous system to environmental
insults or toxins.
There is
no clear evidence of inherited MSA or of
HLA association. Original work on PAF in which 16 patients with PAF had a frequency of the HLA antigen Aw32 13
times more common than in healthy controls (Bannister et al 1983) was not
confirmed in a subsequent study in either MSA or PAF (Nee et al 1989).
TREATMENT OF AUTONOMIC FAILURE
The
management of orthostatic hypotension in MSA and PAF is covered in detail in
chapter 55. We will summarize treatments specifically applied to MSA and PAF.
L-DOPS: DL-threo-3,4-dihydroxyphenylserine (DL-threo-DOPS) is a
norepinephrine precursor, currently unavailable in the United States. Anecdotal
reports of its efficacy in reducing orthostatic hypotension have appeared
(Sakoda et al 1985), and the improvement is reported to be associated with an
increase in muscle sympathetic nerve activity induced by tilt-up (Kachi et al
1988) and in improving cerebral blood flow (Matsubara et al 1990). Both the D-
and L-enantiomers can be measured in human plasma and urine (Boomsma et al
1988). The drug has been claimed to be beneficial in reducing L-DOPA related
orthostatic hypotension.(Yoshida et al 1989).
Beta-receptor Agonists: In a single case report, prenalterol, a selective beta
1-adrenoreceptor agonist, was reported to improve supine and standing BP, and
relieve symptoms (Goovaerts et al 1984). Haemodynamically, prenalterol resulted
in a substantial increase in standing cardiac output, primarily due to its
chronotropic effects. Prenalterol additionally stimulates the renin-aldosterone
system and restores the normal diurnal pattern of water and sodium excretion.
One reported problem is the development of complex ventricular ectopic beats
developed at higher doses (Goovaerts et al 1984).
MAOs with Tyramine: The combination of monoamine oxidase inhibitor with
tyramine (Nanda et al 1976) or other amines (Davies et al 1979) can increase BP
in patients with MSA and PAF. Most experts now consider this combination
unacceptable. These patients can develop hypertensive crises with certain foods
such as cheese.
Indomethacin: Indomethacin and related nonsteroidal anti-inflammatory
drugs are reported to improve BP (Kochar et al 1978; Goldberg and Robertsone
1985; possibly by inhibiting vasodilator prostaglandins (Kochar et al 1978;
Tsuda et al 1983; Goldberg and Robertson 1985). All reports are uncontrolled
reports of a small number of patients.
An increase of 20-30 mm Hg diastolic BP is typical for doses of 75-150 mg/day
(Kochar et al 1978; Goldberg and Robertosn 1985), but some authors have not
observed a rise in standing BP (Davies et al 1980). Clinical experience is that
indomethacin and ibuprofen have similar efficacies, and that the benefits are
modest in MSA and PAF. The drug increased the pressor supersensitivity to
intravenous noradrenaline and angiotensin II, while reducing supine plasma
renin activity to 50% (Davies et al 1980).
Ibopamine: Ibopamine, a dopaminergic prodrug with weak agonist
activity on a- and b-adrenoceptors has been
studied in 3 patients with PAF (Rensma et al 1993). Orthostatic tolerance was
reported to improve as soon as 10-30 min after administration of ibopamine and
lasted 20-50 min. a-Adrenoceptor
blockade with phentolamine abolished the effect of ibopamine. Ibopamine
appeared to be potent but to have highly variable interindividual
pharmacokinetics.
Beta-blockers: Although beta blockers have been used in the treatment of
MSA (Brevetti et al 1981), its efficacy is questionable. Xamoterol, a
cardioselective b-1-adrenoceptor partial
agonist, has been reported to be effective on postural hypotension (West et al
1990; Obara et al 1992). Xamoterol is reported to lessen the total number of
symptomatic episodes of orthostatic hypotension over 24 hours (West et al
1990). However episodes of severe hypertension (defined as a systolic
intra-arterial BP above 200 mmHg) were
more frequent with xamoterol (West et al 1990), and the rise in BP was greater
at night (Obara et al 1992).
Dopamine Agonists: Dopamine agonists can be used in MSA in an attempt to
ameliorate the extrapyramidal features of the disease. L-dopa has a central
hypotensive effect and a peripheral vasoconstrictor effect. The use of L-dopa
can result in a modest improvement in orthostatic hypotension, especially if
combined with a volume expander or a vasoconstrictor (Steiner et al 1974;
Aminoff et al 1973). Lisuride, an ergolene derivative with dopamine receptor
agonist properties has been used in the treatment of MSA (Lees and Bannister
1981). A modest reduction in
orthostatic hypotension occurred in two patients.
The use
of Sinemet in MSA is reasonable if there is an increase in mobility or speech.
Benefits tend to be modest and are usually obainable with relatively small
doses. Most patients do not need doses in excess of 25/250 t.i.d. The directly
acting dopamine agonists and Pergolide do not appear to confer any extra
benefits (Kurlan et al 1985).
Midodrine: Midodrine, a peripheral alpha-adrenergic agonist, causes
veno- and arteriolar vasoconstriction. It is almost completely absorbed after
oral administration and undergoes enzymatic hydrolysis to form its
pharmacologically active metabolite, des-glymidodrine (McTavish and Goa 1989).
It does not cross the blood-brain barrier. Comparative studies have shown
midodrine to be clinically at least as effective as other sympathomimetic
agents (norfenefrine, etilefrine, dimetofrine and ephedrine) and dihydroergotamine in this regard. Jankovic et al
(1993) reported the findings of a recent multicenter study of the safety and
efficacy of midodrine therapy in 97 patients with neurogenic orthostatic
hypotension. These included 18 patients with MSA and 20 with PAF. Following one
week of placebo therapy, the patients were randomized into 4 groups for a 4
week study; placebo, 2.5 mg, 5 mg, or 10 mg three times daily. These patients
demonstrated a 27 +/- 8% (22 mmHg) increase in standing systolic BP for the 10
mg dose. Symptoms or fainting, blurred vision, improved energy level, standing
time, and depressed feelings were also significantly improved even at lower
doses (p < 0.05 or less). Side effects were mild. Midodrine was considered
an effective and safe agent for the treatment of neurogenic orthostatic
hypotension (Jankovic et al 1993; Gilden et al 1993).
In a
double-blind, randomized dose response study (Wright et al 1995), 15 patients
with neurogenic orthostatic hypotension, comprising PAF, MSA; and autonomic
neuropathies, (5 males; 10 females; mean age 63 years) were randomized to a
single oral dose, 4-way crossover study of placebo and midodrine (2.5, 10,
20mg). BP was measured repeatedly supine and standing for 6h. A global symptom
relief score was given by the investigator and patient separately. Midodrine
resulted in a log-linear dose-dependent improvement in 1h postdose BP
(p<0.01). Global symptom relief (both patient and investigator) favored
midodrine 10mg and 20 mg compared with placebo (p<0.05). The blood level of
a single dose of midodrine was sustained for approximately 2 hours and of
desglymidodrine for about 4h. Midodrine 10mg & 20mg resulted in supine
hypertension in 20% & 47% of patients. The 10 mg dose of midodrine appeared
to be both efficacious and safe in the treatment of orthostatic hypotension,
and a tid regimen is supported by the study.
A
randomized double-blind, multicenter study comparing midodrine with placebo has
been completed in neurogenic orthostatic hypotension (Low et al 1995). We
compared midodrine 10 mg t.i.d. with placebo in patients with symptomatic
neurogenic orthostatic hypotension (orthostatic hypotension). One hundred and
seventy patients (M=F=85) with orthostatic hypotension were randomized to midodrine 10 mg tid, or placebo in a 6 week
study, comprising a single blind run-in and
washout at week 1 and 5 and 6, with an intervening double-blind period
(weeks 2 to 4). The patients included 40 patients with MSA and 37 with PAF. The
primary endpoints were improvement in standing systolic BP, symptoms of
lightheadedness and a global symptom relief score (by the investigator and
patient separately). Midodrine resulted in a significant improvement in
standing systolic BP by the end of the first week, an improvement in symptoms
by the end of the second week, and global symptom relief (both patient and
investigator) at all evaluated time-points. The main side effects were those of
pilomotor reactions, bladder dysfunction and supine hypertension. The 10 mg tid
dose of midodrine appeared to be both efficacious and safe in the treatment of
neurogenic orthostatic hypotension.
Vasopressin: Vasopressin administered either as a nasal spray or
intravenously, improves orthostatic BP (Kochar 1985). Two sprays are
administered intranasally. Patients with PAF may have a supersensitive pressor
response to arginine vasopressin (Williams et al 1986).
A
different use of vasopressin analogs to reduce nocturnal diuresis was reported
by Mathias et al (1986). Desmopressin (DDAVP) is a vasopressin‑like substance
that specifically acts on the V2‑receptors on the renal tubules, which
are responsible for the antidiuretic effect of vasopressin. It has virtually
no activity on the V1, receptors, which are responsible for the
vasoconstriction induced by vasopressin. Intramuscular DDAVP injection prevents
nocturnal polyuria, induces overnight weight loss, and raises the supine BP in
the morning, thus easing the symptoms resulting from postural hypotension
[18]. Studies with intranasally administered DDAVP indicate that it is also
effective. Doses between 5 and 40 µg, given at bedtime as a single dose, are of
benefit in preventing both nocturia and morning postural hypotension (Fig. 38‑4).
DDAVP has can, however, cause hyponatremia. Therefore, DDAVP must be used
cautiously, with monitoring of osmolality and plasma sodium level on a six‑weekly
basis.
Octreotide:
The somatostatin analog octreotide reduces splanchnic
capacitance and reduces orthostatic hypotension in patients with PAF and MSA
(Hoeldtke and Israel 1989). Octreotide requires subcutaneous adminstration.
Some patients in whom octreotide failed to stabilize upright BP had a
satisfactory response to the drug after pretreatment with dihydroergotamine
(Hoeldtke and Israel 1989). Side-effects are usually nausea or abdominal cramps
after moderate doses (greater than 1.0 micrograms/kg). The pressor response is
not accompanied by an increase in the plasma norepinephrine level (Weiss et al
1990).
Sympathetic neural
prosthesis: Polinsky et al (1983) reported on
a prototype electromechanical analogue of the sympathetic division of the
baroreceptor reflex arc that was used to maintain BP automatically in two
patients with neurogenic orthostatic hypotension. The device prevented significant and sustained reductions
in mean BP when the patients were tilted up to 85 degrees. Upon achieving the
preset mean BP, the device maintained this pressure with a standard error of less than 2 mm Hg. Similar results were
obtained when the patients were walking. The device did not cause supine
hypertension during the trials.
Non-pharmacologic Approaches
These
have included the use of compression garments (Chapter 56), anti-gravity suit
(Brook 1994) postural training (Hoeldtke et al 1988) and physical countermaneuvers.
Drug therapy, combined with performing isometric exercises on a tilt table,
whose angle was gradually increased during three weeks, made it possible for a
patient with severe orthostatic hypotension the walk (Hoeldtke et al 1988).
Physical countermaneuvers will increase standing BP and standing time, largely
by an increase in peripheral resistance (Bouvette et al 1996).
Urologic
The most effective treatment for
incontinece is with clean intermittent catheterization. Anticholinergic medication
is reserved for the subject with detrusor hyperreflexia.
Fludrocortisone
Another
line of treatment which is usually helpful is oral fludrocortisone. In a
smaller dose (0.1 mg) than necessary to increase blood volume, fludrocortisone
appears to increase the sensitivity of blood vessels to very small amounts of
norepinephrine which may still be capable of being released in autonomic
failure [8]. A study was undertaken to assess a standard sodium intake; in it,
the body weight of subjects did not change over the 14 days when the drug was
given, so there is no reason to believe that the results are an effect of the
change in blood volume. Larger doses of fludrocortisone (0.2-0.4 mg) increase
blood volume, usually with a delay of about 1 to 2 weeks. A significant problem
is supine hypertension. Many patients are thought to respond better to a small
dose of fludrocortisone combined with the judicious use of vasopressor drugs.
This combination better sustains BP at periods of greatest need and by avoiding
vasopressors after 6PM, supine hypertension can be minimized.
Anesthetic Management
There
are particular problems associated with anesthesia in patients with generalized
autonomic failure. The choice between local, regional and general anesthesia is
less important than careful preoperative evaluation, careful operative control
of blood volume, BP and posture. Anesthesia may be associated with profound
hypotension and some of the signs of anaesthesia may be absent (Malan and Crago
1979). The response to cardiac depressant drugs and reduction of circulating
blood volume may be exaggerated due to absence of compensatory mechanisms. The
response to vasoactive agents is unpredictable.
Adequate
cardiovascular monitoring and the maintenance of BP with intravenous fluids is
essential (Bevan 1979; Malan and Crago 1979; Hutchinson and Sugden 1984).
Sympathomimetic drugs, if used at all, should be administered in very dilute
solutions to avoid hypertension from denervation hypersensitivity (Bevan 1979).
Certain anesthetics might be more hypotensive than others. A profound fall in
arterial pressure during anaesthesia induced with thiopentone has been
demonstrated (Saarnivaara et al 1983), while anaesthesia induced with ketamine,
maintained with nitrous oxide in oxygen and supplemented with fentanyl,
diazepam and suxamethonium did not cause a fall in arterial pressure. In the
postoperative period, orthostatic hypotension may be severe and their control
requires volume expansion, postural training by graduated elevation of the head
of the bed, and the careful use of vasoconstrictors.
PROGRESSION OF PURE
AUTONOMIC FAILURE
Studies
of PAF have been almost invariably done comparing this condition with MSA.
Information on the clinical features, progression, and outcome is actually
quite limited. Some patients with PAF have continued relatively symptom free
for many years, with standing BPs in the region of 80 mm Hg. The natural
history of PAF is that of a slow progression taking place over some 10 to 15
years. A comparison of the course of PAF with that of MSA in 2 large programs
are summarized in Table 43-3. Some
cases may be non-progressive (Thomas and Schirger 1963).
Prognosis of Multiple
System Atrophy
Most
patients with classic MSA do not survive longer than 7 years from the time of
diagnosis of the disease. Wenning et al (1994) however, reported a median
survival of 9.5 years, calculated by Kaplan-Meier analysis. Similar results
have been reported (Saito et al 1994), and the sporadic OPCA variety has been
suggested to have a longer survival than the striatonigral variety (Saito et al
1994). The differences in survival by different investigators likely relates to the criteria used to
define MSA. Their downhill course is marked by increasing rigidity, urinary
incontinence, and sometimes marked stridor, which may require tracheostomy.
The extrapyramidal features rarely respond to levodopa (in the form of
levodopa with a dopamine decarboxylase inhibitor), probably because the central
defect of norepinephrine as well as dopamine prevents effective levels of dopamine
being achieved. Death in patients with autonomic failure with MSA is frequently
due, after some six years on average, to respiratory obstruction or failure
after worsening movement disorder, akinesia, and bladder disorder. With the
appreciation of a spectrum of severities, a attempt has been made to relate the
severity and distribution of autonomic and non-autonomic involvement to
outcome. We reviewed the clinical and autonomic features of all patients with
extrapyramidal and cerebellar disorders studied in the Mayo Autonomic Reflex
Laboratory from 1983 to 1989 (Sandroni et al 1991). Orthostatic BP reduction,
percentage of anhidrosis on thermoregulatory sweat test, quantitative sudomotor
axon reflex test, forearm response and heart rate response to deep breathing
strongly regressed with severity of clinical involvement. The severity and
distribution of autonomic failure at the time of first evaluation was
predictive of a greater rate of progression 2 years later. Saito et al (1994)
came to the same conclusion. They concluded that the earlier and the more
severe the involvement of the autonomic nervous system, and to a lesser extent
the striatonigral system, the poorer the prognosis.
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Table
38-1. Plasma Norepinephrine in Autonomic Failure
Disorder United Kingdom United
States
Pure autonomic failure Number 19 20
Supine (pg/ml) 119 + 19 76 + 18
Tilt (pg/ml) 135 + 21 *
Autonomic failure
and multiple
system atrophy
Number 15 37
Supine (pg/ml) 279 + 38 265
+ 21
Tilt (pg/ml) 334 + 50 *
*No
values because standing attempted for 5 minutes, and, because many patients
were unable to stand for this long, measurements were unreliable and were not
taken.
Taken
from: Bannister, R., Mathias, C., and Polinsky, R. Clinical features of
autonomic failure, B. Autonomic failure: a comparison between UK and US
experience. In: Bannister, R. (editor). Autonomic Failure, 2nd ed. Oxford:
Oxford University Press, 1988, with permission of Oxford University Press.
FIGURE LEGENDS
Fig.
43‑1. Supine systolic and diastolic blood pressure before and after a
standard meal in a group of normal subjects (stippled area, with + SEM bars)
and in a patient (I.R.) with autonomic failure. The normal subject's blood
pressure does not change after a meal. In the patient, there is a rapid fall in
blood pressure to levels around 80/50 mm Hg, which remain low in the supine
position over the 3‑hour observation period. (From Mathias and Bannister
[171. Reproduced by permission of Oxford University Press.)
Fig.
43‑2. Mean arterial blood pressure (MAP) in 7 patients with chronic
autonomic failure after oral glucose given following pretreatment with either
placebo (open circles) or the somatostatin analogue, SMS 201995 (Octreotide)
50 ~g subcutaneously (filled circles) given 30 minutes (first arrow) before the
glucose. In the placebo cases, glucose caused a substantial fall in blood
pressure. The reverse wasrely survive more than 6 years from the time of
diagnosis.
Fig
43-3. MRI of a 63 year old female patient with MSA showing putamen
hypodensity. (MRI was provided by courtesy of Dr Joseph Jankovich, Baylor
College of Medicine, Houston, Texas).
Fig
43-4. Composite autonomic scoring scale (CASS) scores for patients with MSA,
autonomic neuropathy (), Parkinson’s disease, and neuropathy (non-autonomic).
Fig.
43‑5. Mean levels (+SEM) of plasma norepinephrine, adrenaline, and
dopamine in 10 normal subjects, 12 patients with multiple‑system atrophy
(MSA), and 8 patients with PAF (PAF). Individual values on the first occasion
in Patients 5 and 6 (1 and 2, respectively, in figure) with dopamine beta-hydroxylase
(DBH) deficiency are indicated. The astensk indicates undetectable levels,
which were below 5 pa/ml for norepinephrine and adrenaline and 20 pa/ ml for
dopamine. (From Mathias, C. J., and Bannister, R. Dopamine beta‑hydroxylase
deficiency and other genetically determined autonomic disorders: A. Clinical
features. In: Bannister, R., and Mathias, C. (editors). Autonomic Failure, 3rd
ed. Oxford: Oxford University Press, 1992. Reproduced by permission of Oxford
University Press.)
Fig.
43-6 Glial cytoplasmic inclusions in a patient with MSA (Gallyas stain. x1500).
Courtesy of Dr Joseph Parisi, Department of
Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota).
Table
42--1. Plasma Norepinephrine in Autonomic Failure
¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾
United
Disorder Kingdom United States
¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾
Pure autonomic
failure
Number 19 20
Supine
(pg/ml) 119 + 19 76 + 18
Tilt
(pg/ml) 135 + 21
*
Autonomic failure
and multiple
system atrophy
Number 15 37
Supine
(pg/ml) 279 + 38 265 + 21
Tilt
(pg/ml) 334 + 50
*
¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾
*No
values because standing attempted for 5
minutes,
and, because many patients were unable
to
stand for this long, measurements were unreliable
and
were not taken. Taken from: Bannister, R.,
Mathias,
C., and Polinsky, R. Clinical features of
autonomic
failure, B. Autonomic failure: a
comparison
between UK and US experience. In:
Bannister,
R. (editor). Autonomic Failure, 2nd ed.
Oxford:
Oxford University Press, 1988, with
permission
of Oxford University Press.
Table
42-2: Differentiation of PAF, autonomic neuropathy and MSA
____________________________________________________________________
Parameter PAF Autonomic
Neuropathy MSA
______________________________________________________________________
Onset Insidious Acute or subacute
Insidious
First
symptom Orthostatic
hypotension Constellation of Sx Orthostatic
hypotension
or
bladder involvement
Gastrointes- Absent, Usually
present Uncommon
tinal
symptoms except constipation
CNS
involvemt Absent Absent Present
Somatic Absent Often present but
Present in
neuropathy mild 14-20%
Pain Absent Often present
Absent
Autonomic Limited Widespread Relatively
widespread
system
review involvement involvement involvement
Progression Slowly ? non-progressive Inexorably
progressive progressive
Prognosis Good Good Bad
10%-> MSA
Lesion Mainly Postganglionic Mainly
preganglionic;
postganglionic Somatic Central
Supine
plasma Reduced Reduced Normal
norepinephrine
EMG Normal ± abnormal
Usually normal
C
Table
42-3: Clinical Features of PAF and MSA based on 2 large programs
¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾
PAF MSA
¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾
UK NIH UK NIH
¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾
N 24 22 73 44
Age
(years) 58±10 (38-78) 47±3
(25-68) 54±10 (34-74) 51±1(25-67)
Duration
(years) 9 ±1 (2-16) 14 ±2
(5-31) 3 ± 2 (1-8) 8 ± 1
(2-15)
Orthostatic
hypotension (%) 92% 73% 74% 30%
Urinary
(%) 27% 0% 52% 18%
Impotence
(males; %) 94% 55% 83% 48%
¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾¾
Modified
from Bannister et al 1988