Multiple system atrophy: clinical presentation and diagnosis

Multiple system atrophy (MSA) describes a relatively uncommon, debilitating disorder that is frequently misdiagnosed as Parkinson's disease. Patients with MSA show various combinations of parkinsonism, cerebellar ataxia, pyramidal signs and progressive autonomic failure, especially cardiovascular and urologic autonomic dysfunction. Few treatment options exist. Although some patients initially respond well to dopaminergic treatment for their parkinsonian symptoms, striatal degeneration occurs, and levodopa often becomes ineffective. Thus, physicians may provide only symptomatic treatment and support for patients with MSA. In this paper, we present a case study of a 68-year-old woman who came to the Vanderbilt Movement Disorders Clinic with severe autonomic dysfunction and parkinsonism, previously diagnosed as Parkinson's disease. Following autonomic function tests as well as clinical evaluation, she was diagnosed with MSA and began treatment for orthostatic hypotension and micturition dysfunction.     

Composite autonomic scoring scale for laboratory quantification of generalized autonomic failure

An autonomic reflex screen, which consisted of a quantitative sudomotor axon reflex test, orthostatic blood pressure and heart rate response to tilt, heart rate response to deep breathing, the Valsalva ratio, and beat-to-beat blood pressure measurements during phases II and IV of the Valsalva maneuver, tilt, and deep breathing, was used to develop a 10-point composite autonomic scoring scale of autonomic function. The scheme allots 4 points for adrenergic and 3 points each for sudomotor and cardiovagal failure. Each score is normalized for the compounding effects of age and sex. Patients with a score of 3 or less on the composite autonomic scoring scale have only mild autonomic failure, those with scores of 7 to 10 have severe failure, and those with scores between these two ranges have moderate autonomic failure. The sensitivity and specificity of the method were assessed by evaluating the composite autonomic scoring scale in four groups of patients with known degrees of autonomic failure: 18 with multisystem atrophy, 20 with autonomic neuropathy, 20 with Parkinson's disease, and 20 with peripheral neuropathy but no autonomic symptoms. The composite scores (means +/- SD) for these four groups, respectively, were as follows: 8.5 +/- 1.3, 8.6 +/- 1.2, 1.5 +/- 1.1, and 1.7 +/- 1.3. Patients with symptomatic autonomic failure had scores of 5 or more, those without symptomatic autonomic failure had scores of 4 or less, and no overlap existed in these groups. Thus, autonomic laboratory tests should be useful in grading the degree of autonomic failure.     

Postprandial hypotension and orthostatic blood pressure responses in elderly Parkinson's disease patients

OBJECTIVE: To investigate the change in systolic blood pressure (SBP) induced by meals and to compare their impact on the orthostatic SBP response in elderly Parkinson's disease with that in control patients. DESIGN: Ten elderly patients suffering from Parkinson's disease were compared with 10 age-matched elderly control patients. METHODS: The postprandial SBP change was measured by means of ambulatory blood pressure monitoring with the patient in the supine position. Orthostatic SBP responses were measured the next day by means of active standing and passive head-up tilting tests performed before and after the patients had their lunch. RESULTS: In Parkinson's disease patients, a postprandial SBP drop of 27 mmHg in the supine position was found compared with a drop of 8 mmHg in controls. In Parkinson's disease patients, that drop was moderately correlated to the orthostatic SBP responses and significantly correlated to the preprandial supine baseline SBP level. The orthostatic fall in SBP was greater with passive than with active standing and with both it was greater in Parkinson's disease patients than in the control subjects. The fall in orthostatic blood pressure was reduced by a previous meal. In contrast, there was no difference in orthostatic heart rate responses between the patients and the controls. CONCLUSIONS: Parkinson's disease patients demonstrated a significant postprandial drop in SBP and a tendency towards orthostatic hypotension, which was not worsened by the meal, probably owing to a stronger sympathetic activation. Postprandial supine SBP change and orthostatic SBP responses were only moderately associated in Parkinson's disease patients. In addition to autonomic dysfunction, an increased baseline SBP level might contribute to both phenomena.     

Collection and transfusion of blood and blood components in the United States, 1989

A poor response to L-DOPA in addition to parkinsonian, cerebellar, and autonomic signs is commonly regarded as indicative of clinical multiple system atrophy (MSA). We compared the motor response to a single oral administration of 250 mg L-DOPA/25 mg carbidopa in eight MSA patients and eight Parkinson's disease (PD) patients with the "on-off" phenomenon, evaluating L-DOPA peripheral pharmacokinetics. Motor response was consistently good in all PD patients, but only four MSA patients had a (moderate) response. Pharmacokinetic parameters did not differ between the groups. The varying extent of putaminal damage could be responsible for the differing motor response to L-DOPA in MSA patients.     

Nocturnal blood pressure and relation to vasoactive hormones and renal function in hypertension and chronic renal failure

The purpose of this study was to assess the blood pressure profile and to measure vasoactive hormones in patients with essential hypertension (n=61), secondary hypertension (n=32) and chronic renal failure (n=32) matched with healthy control subjects (n=35), and to study the relationship between circadian changes in blood pressure and baseline levels of vasoactive hormones and renal function. Non-invasive, automatic blood pressure measurement was performed for 24 or 48 h. Venous plasma concentrations of renin, angiotensin II, aldosterone, arginine vasopressin, atrial natriuretic peptide and endothelin were measured. The mean 24-h blood pressure was higher in all groups of hypertensive patients than in control subjects. The nocturnal blood pressure fall was preserved in essential hypertension, in contrast to secondary hypertension in which it was attenuated. In the patients with chronic renal failure the 24-h mean blood pressure was the same as in the controls. Night-time blood pressure was higher among the chronic renal failure patients than in the control group, and the nightly blood pressure fall in both diastolic and systolic blood pressure was reduced. Plasma concentrations of renin activity, arginine vasopressin, atrial natriuretic peptide, aldosterone and endothelin were significantly increased in secondary hypertension and chronic renal failure, compared to essential hypertension and control subjects. Plasma angiotensin II was increased in chronic renal failure compared to essential hypertension and controls. Estimated creatinine clearance and nightly blood pressure dips were inversely correlated in essential and secondary hypertension, i.e. with a decreasing renal function both systolic and diastolic nightly blood pressure dips were gradually attenuated. In the whole group of patients the nightly systolic and diastolic blood pressure dips were negatively correlated to basal plasma renin activity, plasma aldosterone and atrial natriuretic peptide levels, i.e. the higher the basal plasma hormone level the lower the blood pressure dip. In conclusion, patients with essential hypertension have elevated but normally configured 24-h blood pressure profiles, and patients with different kinds of secondary hypertension have elevated 24-h blood pressure profiles and attenuated nightly systolic and diastolic blood pressure falls. The more the renal function is reduced and the more the plasma levels of renin and aldosterone are increased, the more the nocturnal fall in blood pressure is reduced. It is suggested that the attenuated or absent decrease in nocturnal blood pressure in secondary renal hypertension is caused by an abnormally increased secretion of vasoactive hormones and/or by so far unknown factors released from the diseased kidney.     

Decrease of medullary catecholaminergic neurons in multiple system atrophy and Parkinson's disease and their preservation in amyotrophic lateral sclerosis

We investigated the number of tyrosine hydroxylase (TH)-immunoreactive neurons in the C1 and A2 regions of the medulla, the sites of the baroreflex arc, in 7 patients with multiple system atrophy (MSA), 8 with Parkinson's disease (PD), 9 with amyotrophic lateral sclerosis (ALS), and 12 age-matched normal subjects to analyze the relationship between cardiovascular dysfunction and medullary catecholaminergic neurons. Orthostatic hypotension (OH) was marked in all the MSA patients and moderate in three PD patients. Three of the five ALS patients who had been on respirators showed lability of blood pressure; paroxysmal hypertension and nocturnal hypotension without compensatory tachycardia. All the MSA patients showed extremely marked decrease of TH-immunoreactive neurons in both the C1 and A2 regions. In the patients with Parkinson's disease, numerous TH-immunoreactive neurons contained Lewy bodies that were immunostained by antibody to TH. TH-immunoreactive neurons were decreased very markedly in the A2 regions of two patients with OH, and three patients without OH showed fairly marked decreases in the C1 or A2 region. In contrast, the number of TH-immunoreactive neurons in ALS was the same as in normal subjects. In MSA and some PD patients, orthostatic hypotension may partly be due to the involvement of the medullary catecholaminergic neurons. The lability of blood pressure in ALS probably is not related to the medullary catecholaminergic neurons.     

Consensus statement on the diagnosis of multiple system atrophy

We report the results of a consensus conference on the diagnosis of multiple system atrophy (MSA). We describe the clinical features of the disease, which include four domains: autonomic failure/urinary dysfunction, parkinsonism and cerebellar ataxia, and corticospinal dysfunction. We set criteria to define the relative importance of these features. The diagnosis of possible MSA requires one criterion plus two features from separate other domains. The diagnosis of probable MSA requires the criterion for autonomic failure/urinary dysfunction plus poorly levodopa responsive parkinsonism or cerebellar ataxia. The diagnosis of definite MSA requires pathological confirmation.     

Recurrent torticollis due to cervical osteochondroma. Case report and review of the literature]

A patient is presented who had bilateral abductor vocal fold paralysis pathologically proven to be due to multiple system atrophy (MSA) in the absence of other neurological features. MSA is a degenerative neurological condition that includes olivopontocerebellar atrophy, Shy-Drager syndrome and striatonigral degeneration. The usual predominant features of MSA are cerebellar ataxia, autonomic dysfunction and Parkinsonism. Stridor is present in over one third of patients and has been reported previously as a presenting symptom in MSA: however previously reported patients have always gone on to develop other neurological symptoms. The usual investigations of bilateral abductor vocal fold paralysis caused by MSA will not reveal the pathological process and we believe that magnetic resonance imaging (MRI) of the medulla and brain stem and autonomic function tests are probably the investigations of choice. It is a worthwhile exercise attempting to identify MSA as the cause of stridor as the prognosis is good in the medium term if appropriate support is offered.     

Ambulatory blood pressure, nocturnal blood pressure reduction and plasma catecholamines

OBJECTIVE AND DESIGN: Controversial data have been reported on plasma catecholamines in hypertensives. Aims of this study were to find whether 24-hour ambulatory blood pressure was correlated with circulating catecholamines and to investigate whether nocturnal blood pressure reduction was associated with baseline plasma catecholamines. Samples for catecholamine determination were obtained in 34 consecutive male subjects after a 30-minute rest and before ambulatory blood pressure monitoring. RESULTS: Hypertensive patients (n = 22; 24-hour blood pressure: 145 +/- 14/94 +/- 6 mm Hg) showed similar norepinephrine and epinephrine levels when compared with normotensives (n = 12; 24-hour blood pressure: 124 +/- 6/81 +/- 6 mm Hg), and higher dopamine values (hypertensives: 64.6 +/- 58; normotensives: 26.2 +/- 31 pg/ml; p < 0.05). A positive correlation was observed between dopamine and diastolic nocturnal blood pressure (p < 0.05) while a negative correlation was found between dopamine and nocturnal diastolic blood pressure reduction (p < 0.025). No significant relationship was observed between both norepinephrine and epinephrine, and 24-hour blood pressures. CONCLUSIONS: Since previous reports have documented malfunctioning of dopaminergic system in hypertension, the higher levels of circulating plasma dopamine found in hypertensive patients in the present study may account for a peripheral compensatory increase. The correlation between dopamine and nocturnal blood pressure fall seems to indicate that the impairment of dopaminergic system may influence the 24-hour blood pressure profile, affecting the nocturnal blood pressure reduction.     

Physiologic basis of pulmonary edema during intestinal reperfusion

The ventrolateral portion of the intermediate reticular formation of the medulla (ventrolateral medulla, VLM), including the C1/A1 groups of catecholaminergic neurons, is thought to be involved in control of sympathetic cardiovascular outflow, cardiorespiratory interactions, and reflex control of vasopressin release. As all these functions are affected in patients with multiple systems atrophy (MSA) with autonomic failure, we sought to test the hypothesis that catecholaminergic (tyrosine hydroxylase [TH]-positive) neurons of the VLM are depleted in these patients. Medullas were obtained at autopsy from 4 patients with MSA with prominent autonomic failure and 5 patients with no neurological disease. Patients with MSA had laboratory evidence of severe adrenergic sudomotor and cardiovagal failure. Tissue was immersion fixed in 2% paraformaldehyde at 4 degrees C for 24 hours and cut into 1-cm blocks in the coronal plane from throughout the medulla. Serial 50-microm sections were collected and one section every 300 microm was stained for TH. There was a pronounced depletion of TH neurons in the rostral VLM in all cases of MSA. There was also significant reduction of TH neurons in the caudal VLM in 3 MSA patients compared with 3 control subjects. In 2 MSA cases and in 2 control subjects, the thoracic spinal cord was available for study. There was also depletion of TH fibers and sympathetic preganglionic neurons (SPNs) in the 2 MSA cases examined. Thus, depletion of catecholaminergic neurons in the VLM may provide a substrate for some of the autonomic and endocrine manifestations of MSA.     

Paclitaxel changes sympathetic control of blood pressure

Paclitaxel has become part of standard therapy in the treatment of ovarian and breast cancer. Concern has been raised about the effects of paclitaxel on cardiovascular function. Therefore, this study of the effects of paclitaxel on autonomic cardiovascular control was initiated. Eighteen women treated for ovarian or breast cancer were examined with autonomic cardiovascular function tests, once before the treatment and once after the second course of paclitaxel. Heart rate and blood pressure variability and changes in heart rate and blood pressure responses to the tests were measured. Baroreflex sensitivity was calculated from the Valsalva manoeuvre non-invasively. Paclitaxel did not change heart rate variability at rest compared with the pretreatment level. However, medium frequency variability of blood pressure was smaller after treatment with paclitaxel. Paclitaxel treatment did not impair the heart rate and blood pressure responses to the autonomic function tests. The results do imply that paclitaxel alters sympathetic control of blood pressure. Nevertheless, paclitaxel does not appear to precipitate autonomic cardiac neuropathy.     

Multiple system atrophy and visuospatial function.

An appropriate battery of tests of visuospatial function was given to 10 adult patients with multiple system atrophy, to 10 adult patients with idiopathic Parkinson's disease, and to 18 adult normal control Ss. Members of the 3 groups were matched for age, educational level, and Verbal IQ. Comparison of results showed that, unlike the patients with Parkinson's disease and the control Ss, patients with multiple system atrophy were impaired in their ability to discriminate between angles and to match angles, but showed no other visuospatial deficits. These results indicate a need for further study of this matter on a larger scale. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Electrophysiological tests of autonomic function in patients with idiopathic autonomic failure syndromes

Three electrophysiological tests of autonomic function were performed in patients with autonomic nervous system dysfunction to define test sensitivities and specificities. The skin sympathetic response, Valsalva ratio, and heart rate variation with deep breathing were studied in 10 patients with multiple system atrophy (MSA) and in 7 patients with pure (also called progressive or primary) autonomic failure (PAF); control subjects were 17 normal individuals of similar age. Thirteen patients had abnormal skin sympathetic responses, and 16 had abnormal Valsalva ratios. Fourteen patients had an abnormal variation of the heart rate with deep breathing. Taking the three tests together, binary logistic regression for distinguishing between patients and normal subjects correctly classified 91% of the 33 individuals for whom there were complete data with sensitivity of 88% and specificity of 94%. However, only 69% of the patients could be correctly classified by a logistic regression for discriminating between MSA and PAF. Electromyography (EMG) studies showed that 7 of 8 patients with MSA but only 2 of 7 patients with PAF (both multiparous women) had denervation of the rectal sphincter muscle. The EMG study is, therefore, valuable in men, but has a high false positive rate in women, probably because of pudendal nerve injury from parturition.     

The hypertension of autonomic failure and its treatment

We studied the incidence and severity of supine hypertension in 117 patients with severe primary autonomic failure presenting to a referral center over a 9-year period. Patients were uniformly characterized by disabling orthostatic hypotension, lack of compensatory heart rate increase, abnormal autonomic function tests, and unresponsive plasma norepinephrine. Fifty-four patients had isolated autonomic impairment (pure autonomic failure). Sixty-three patients had central nervous system involvement in addition to autonomic impairment (multiple-system atrophy). Patients were studied off medications, in a metabolic ward, and on a controlled diet containing 150 mEq of sodium. Fifty-six percent of patients had supine diastolic blood pressure > or =90 mm Hg. The prevalence of hypertension was slightly greater in females (63%) than in males (52%). Potential mechanisms responsible for this hypertension were investigated. No correlation was found between blood volume and blood pressure. Similarly, plasma norepinephrine (92+/-15 pg/mL) and plasma renin activity (0.3+/-0.05 ng/mL per hour) were very low in the subset of patients with pure autonomic failure and supine hypertension (mean systolic/diastolic pressure, 177 +/- 6/108 +/- 2 mm Hg, range 167/97 to 219/121). Supine hypertension represents a challenge in the treatment of orthostatic hypotension. We found these patients to be particularly responsive to the hypotensive effects of transdermal nitroglycerin. Doses ranging from 0.025 to 0.1 mg/h decreased systolic blood pressure by 36+/-7 mm Hg and may effectively treat supine hypertension overnight, but the dose should be individualized and used with caution.     

Analysis of Parkinson's disease and related syndromes using 123I-IMP-SPECT with the ARG method

We studied regional cerebral blood flow (rCBF) in 8 patients with non-demented Parkinson's disease (PD). 1 patient with progressive supranuclear palsy (PSP), 1 patient with multiple system atrophy (MSA), and 7 normal control subjects using single photon emission computed tomography (SPECT) with the IMP-ARG method. Regions of interest were studied in the cerebral cortex (upper frontal, lower frontal, temporal, occipital, parietal), thalamus, basal ganglia, and cerebellum. In patients with PD, rCBF was normal in 4/8, and decreased in occipital lobe in 4/8. In patient with PSP, rCBF was decreased in the upper and lower frontal lobes, and in the cerebellum. In patient with MSA, rCBF was diminished in the cerebellum. The results of our study were almost compatible with the conventional rCBF study by positron emission tomography (PET), however, the decrease of rCBF in occipital lobe had rarely been reported, suggesting that might be related to visuospatial dysfunction in Parkinson's disease.     

Ambulatory blood pressure measurement in type-II diabetic patients with autonomic neuropathy

The aim of our study was to access the 24-hr ambulatory blood pressure (BP) in diabetic patients with autonomic neuropathy (AN). Twenty-two NIDDM patients without hypertension, being treated with sulfonylureas, were studied. The 24-hr ambulatory blood pressure recordings were performed using portable non-invasive automatic system. Autonomic neuropathy was assessed by standard cardiovascular reflex tests. There were ten patients with and 12 without AN, matched for age, body mass index, duration of diabetes and glycemic control. Mean BP increased at night in four of the subjects with AN and decreased in the remaining 18 patients. The group of subjects with nocturnal increases in BP had more severe autonomic nerve dysfunction compared with those with decreases in nocturnal BP. No significant difference between clinical and ambulatory day-time measurements was found. In three patients with AN after 5 weeks intensified therapy. 24-hr BP did not show any significant difference.     

Power spectral analysis of heart rate variability during graded head-up tilting in patients with vasodepressor syncope

1. Two groups of age- and sex-matched subjects, eight healthy controls and 10 patients, suffering from recurrent vasodepressor syncope, participated in a study to examine autonomic function and sequential changes in power distribution of heart rate (HR) variability during graded head-up tilt. 2. The following autonomic function tests were performed: valsalva ratio, HR responses to deep breathing and posture, BP responses to sustained handgrip and postural change. Each subject was tilted at 15 degrees, 30 degrees, 45 degrees, 60 degrees and 80 degrees head-up, each for 15 min, or until symptoms occurred. The eight control subjects completed the tilt study without any symptoms, while all 10 patients developed presyncope and/or syncope at various tilt angles. 3. Resting blood pressure (BP) was lower in the patient group, while resting HR, autonomic function tests and resting HR variability components were similar in the two groups. 4. The control group showed a progressive increase in low frequency power component (LF) from supine to end tilt (delta LF 20.06 +/- 14.50%) and a progressive fall in high frequency (HF) component (delta HF - 24.62 +/- 10.64%). In contrast, in the patient group, LF fell during tilt in the presyncope period (delta LF - 10.57 +/- 12.93%, P < 0.01 vs control group). HF and HF:LF ratio responses did not differ significantly in the two groups. 5. At end tilt, the increase in plasma noradrenaline was significantly greater in the control group than in the patient group (delta NA 0.83 +/- 0.27 vs 0.28 +/- 0.14 pmol/mL, P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Autonomic nervous system dysfunction in elderly hypertensive patients with abnormal diurnal blood pressure variation: relation to silent cerebrovascular disease

To investigate the relationships among diurnal blood pressure (BP) variations and autonomic nervous system dysfunction, we assessed heart rate variability (HRV) using power spectral analysis of the 24-hour RR interval in 51 asymptomatic elderly hypertensive patients with various patterns of nocturnal BP fall. The extreme-dippers with marked nocturnal BP fall (n=16) had lower asleep low-frequency power (LF)/high-frequency power (HF) ratios (a relative index of sympathetic nervous system activity), while the nondippers without nocturnal BP fall (n=18) had lower awake LF/HF ratios and asleep/awake ratio for HF (an index of parasympathetic nervous activity), when compared with dippers with appropriate nocturnal BP fall (n=17). The incidence of multiple lacunar infarction detected by brain magnetic resonance imaging was 56% in the extreme-dippers and 38% in the nondippers, and both were markedly higher than that (6.3%) in the dippers (both P<.01). There was no significant relationship between the BP level and any HRV parameter for either the daytime or nighttime period. The asleep/awake ratio for systolic BP was significantly correlated with the asleep/awake ratio for HF (r= -.363, P<.01) and with the asleep/awake ratio for the LF/HF ratio (r=.540, P<.001), regardless of whether multiple lacunar infarction was present. In conclusion, the autonomic nervous system activity is not related to high BP level per se, rather its diurnal variation is more important as a determinant of the diurnal BP patterns, regardless of the presence or absence of cerebrovascular disease.     

Clinical and laboratory indices that enhance the diagnosis of postural tachycardia syndrome

OBJECTIVE: To identify clinical and laboratory indices that improve the diagnosis of the postural tachycardia syndrome (POTS). DESIGN: We assessed associations of orthostatic intolerance by using multivariate regression analysis. MATERIAL AND METHODS: We evaluated autonomic symptoms and autonomic function in 30 patients with POTS, 30 patients with mild orthostatic intolerance, and 19 age- and gender-matched control subjects. Indices of parasympathetic and sympathetic functions were analyzed on the basis of (1) autonomic function tests (head-up tilt), (2) oscillations at respiratory and nonrespiratory frequencies (0.01 to 0.09 Hz) in R-R interval and blood pressure (Wigner distribution), and (3) deterministic component (rescaled range analysis). RESULTS: The four clinical and laboratory indices that independently supported the diagnosis of POTS are as follows: (1) orthostatic heart rate during the first minute of head-up tilt, (2) autonomic deficit (adrenergic autonomic score), (3) loss of spectral powers in R-R interval during head-up tilt at the fifth minute, and (4) severity of orthostatic dizziness, fatigue, palpitations, and shortness of breath. CONCLUSION: Enhancing the sensitivity and specificity of the diagnosis of POTS should be possible by using these four indices. A hyperadrenergic state and distal neuropathy, affecting adrenergic sympathetic cardiovagal fibers, seem to be involved in the pathophysiology of POTS. Certain features suggest brain-stem dysregulation.     

Relationship between blood pressure and renal function

RENAL DAMAGE CAUSED BY HYPERTENSION: Renal vasoconstriction seems to be a key factor in the origin of arterial hypertension and accounts for the decrease in renal blood flow commonly observed in patients with hypertension. An inverse correlation has been found between renal blood flow and clinic blood pressure levels in established hypertension. Other features of renal damage attributable to high blood pressure have also been correlated with clinic blood pressure levels. Microalbuminuria is a good example of an alteration in renal function that depends in part on blood pressure levels. EFFECTS OF ANTIHYPERTENSIVE AGENTS: Antihypertensive agents can prevent or ameliorate renal vascular damage secondary to arterial hypertension, including renal failure. Ambulatory blood pressure monitoring is an excellent method of studying blood pressure levels in relation to end-organ damage and the blood pressure response to antihypertensive agents. Preliminary studies using this technique indicate that changes in renal function are closely correlated with the average daily blood pressure in arterial hypertension. CONCLUSIONS: Further studies are needed on the mechanisms of renal deterioration and on how to preserve renal function in arterial hypertension.