MULTIPLE SYSTEM ATROPHY AND PURE AUTONOMIC FAILURE
Sir Roger Bannister and Phillip A. Low
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.
Shy and Drager  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. .
The first cases of pure autonomic failure (PAF) were described by Bradbury and Eggleston  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.
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."
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 .
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.  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 . 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.
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).
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.
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 . 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.
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).
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.
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 of sympathetic function make use of Cannon's law of denervation supersensitivity . 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 . There is a similar increase in the number of b‑receptors on lymphocytes . 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)
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.
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  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.
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.
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 . 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.
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.
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).
The most effective treatment for incontinece is with clean intermittent catheterization. Anticholinergic medication is reserved for the subject with detrusor hyperreflexia.
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 . 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.
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 *
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.
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
Disorder Kingdom United States
Number 19 20
Supine (pg/ml) 119 + 19 76 + 18
Tilt (pg/ml) 135 + 21 *
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.
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
Prognosis Good Good Bad
Lesion Mainly Postganglionic Mainly preganglionic;
postganglionic Somatic Central
Supine plasma Reduced Reduced Normal
EMG Normal ± abnormal Usually normal
Table 42-3: Clinical Features of PAF and MSA based on 2 large programs
UK NIH UK NIH
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%
Modified from Bannister et al 1988