0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Contribution |

Prospective Differentiation of Multiple System Atrophy From Parkinson Disease, With and Without Autonomic Failure FREE

Axel Lipp, MD; Paola Sandroni, MD, PhD; J. Eric Ahlskog, MD, PhD; Robert D. Fealey, MD; Kurt Kimpinski, MD, PhD; Valeria Iodice, MD; Tonette L. Gehrking; Stephen D. Weigand, MS; David M. Sletten, BA; Jade A. Gehrking; Kim K. Nickander, BA; Wolfgang Singer, MD; Demetrius M. Maraganore, MD; Sid Gilman, MD; Gregor K. Wenning, MD, PhD; Clifford W. Shults, MD; Phillip A. Low, MD
[+] Author Affiliations

Author Affiliations: Departments of Neurology (Drs Lipp, Sandroni, Ahlskog, Fealey, Kimpinski, Iodice, Singer, Maraganore, and Low; Mss T. L. Gehrking, J. A. Gehrking, and Nickander; and Mr Sletten) and Biostatistics (Mr Weigand), Mayo Clinic, Rochester, Minnesota; Department of Neurology, University of Michigan, Ann Arbor (Dr Gilman); Universitätsklinik für Neurologie, Innsbruck, Austria (Dr Wenning); and VA Medical Center, San Diego, California (Dr Shults).


Arch Neurol. 2009;66(6):742-750. doi:10.1001/archneurol.2009.71.
Text Size: A A A
Published online

Objective  To report preliminary results of a prospective ongoing study of multiple system atrophy (MSA) and Parkinson disease (PD), with a large subset of patients with PD with autonomic failure (25%), to evaluate autonomic indices that distinguish MSA from PD.

Methods  We used consensus criteria, detailed autonomic studies (Composite Autonomic Symptom Scale, Composite Autonomic Scoring Scale, thermoregulatory sweat test, and plasma catecholamines), and functional scales (Unified MSA Rating Scale [UMSARS] I-IV and Hoehn-Yahr grading) on a prospective, repeated, and ongoing basis.

Results  We report the results of a study on 52 patients with MSA (mean [SD], age, 61.1 [7.8] years; body mass index (calculated as weight in kilograms divided by height in meters squared), 27.2 [4.6]; Hoehn-Yahr grade, 3.2 [0.9]; UMSARS I score, 21.5 [7.4]; and UMSARS II score, 22.7 [9.0]) and 29 patients with PD, including PD with autonomic failure (mean [SD], age, 66.0 [8.1] years; body mass index, 26.6 [5.5]; Hoehn-Yahr grade, 2.2 [0.8]; UMSARS I score, 10.4 [6.1]; and UMSARS II score, 13.0 [5.9]). Autonomic indices were highly significantly more abnormal in MSA than PD (P < .001) for the Composite Autonomic Scoring Scale (5.9 [1.9] vs 3.3 [2.3], respectively), Composite Autonomic Symptom Scale (54.4 [21.8] vs 24.7 [20.5], respectively), and thermoregulatory sweat test (percentage anhidrosis, 57.4% [35.2%] vs 9.9% [17.7%], respectively). These differences were sustained and greater at 1-year follow-up, indicating a greater rate of progression of dysautonomia in MSA than PD.

Conclusions  The severity, distribution, and pattern of autonomic deficits at study entry will distinguish MSA from PD, and MSA from PD with autonomic failure. These differences continue and are increased at follow-up. Our ongoing conclusion is that autonomic function tests can separate MSA from PD. Autonomic indices support the notion that the primary lesion in PD is ganglionic and postganglionic, while MSA is preganglionic.

Figures in this Article

Multiple system atrophy (MSA) is a sporadic multisystem progressive disorder characterized by autonomic failure, with orthostatic hypotension (OH), neurogenic bladder and erectile dysfunction, cerebellar ataxia, corticospinal dysfunction, and parkinsonism that may be poorly responsive to levodopa.1,2 A major clinical dilemma is whether a patient with parkinsonism has Parkinson disease (PD) or MSA, as the prognosis of MSA is much worse. Autonomic involvement is common in PD but is more variable in severity than MSA.35 Mild OH is relatively common in PD and occasionally severe OH can occur.6,7 In retrospective studies from the Mayo Clinic, we reported that, when quantitative methods were used, the severity and distribution of autonomic deficits appear to distinguish MSA from PD.4,5 In contrast to MSA, which is predominantly a preganglionic disorder, autonomic pathology in PD is primarily postganglionic,8 which can be explored in autonomic function tests. Postganglionic adrenergic neuropathy forms the basis of neuroimaging studies of the postganglionic axons of the heart with iodine-123 metaiodobenzylguanidine or other postganglionic adrenergic markers suitable for positron-emission tomography, whereas uptake is markedly reduced or absent in PD and usually normal in MSA.913

These studies and consensus criteria1 and their update2 have resulted in significant advances in the diagnosis of MSA. However, these approaches have been retrospective; lacking is a comprehensive prospective evaluation of autonomic function. As part of a National Institutes of Health–funded program project on MSA, we undertook a prospective study of patients with MSA and patients with PD who underwent full neurological and autonomic evaluation. We used standardized instruments to evaluate symptoms (Autonomic Symptom Profile), motor symptoms, including autonomic activities of daily living (Unified MSA Rating Scale [UMSARS]), and deficits (Composite Autonomic Scoring Scale [CASS] and percentage anhidrosis on the thermoregulatory sweat test [TST]). The Composite Autonomic Symptom Scale (COMPASS) provides a score of autonomic symptoms with appropriate weighting.14,15 We had 2 hypotheses. The first is that the severity, distribution, and pattern of autonomic failure at entry into the study will separate MSA from PD. The second is that, for MSA patients with mild autonomic failure, the increase in autonomic deficit documented at the first return visit (at the end of 1 year) will differentiate these patients from those with PD and will predict the rate of progression of MSA. The relevant indices are changes in CASS, TST percentage, and COMPASS score. We defined mild autonomic failure as autonomic deficits of TST (< 40%) and CASS (<4). Presumably, the more severe and rapid progression of autonomic failure reflects the more widespread and intense distribution of neuronal loss and glial cytoplasmic inclusions.

Because autonomic failure is part of the criteria for the diagnosis of MSA,1,2 we have gone to pains to match the severity of clinical autonomic failure between MSA and PD. We included PD patients with florid autonomic failure, as long as they fulfilled criteria for PD. Specifically, 6 of 29 patients with PD also had autonomic failure. Patients with PD with autonomic failure were indistinguishable from those with MSA in OH, who often had more severe OH than MSA.

PATIENTS
Parkinson Disease

We used criteria modified from those by Hughes et al,16 which clinically define definite PD. Patients were required to have 3 of the 3 cardinal features of PD (resting tremor, bradykinesia, and rigidity). We included PD patients with autonomic failure, defined as PD patients with severe and symptomatic OH that either preceded motor symptoms or comprised a dominant complaint. We excluded those with parkinsonism due to drugs (including neuroleptic drugs, α-methyldopa, reserpine, and metoclopramide) and other causes, dementia, and history of stroke, brain surgery for PD, and structural brain disease.

Multiple System Atrophy

We used the criteria from Gilman et al1,2 to identify patients with MSA. The diagnosis of probable MSA requires (1) the presence of OH (fall in systolic blood pressure of ≥30 mm Hg) and/or urinary incontinence (persistent involuntary partial or total bladder emptying accompanied by erectile dysfunction in men); and (2) parkinsonism or cerebellar ataxia that is poorly responsive to levodopa.

TESTS AND INSTRUMENTS

Patients stopped taking medications that could interfere with autonomic function for 5 half-lives of the drugs prior to autonomic testing. The TST is a modification of Guttmann’s17 quinizarin sweat test. An unclothed subject lies supine and his or her exposed body surface is covered with an indicator powder mixture.18,19 The body is warmed to 38°C; sweat is recognized by a change in color in the indicator. The sweat distribution is documented by digital photography. The digital images are processed by a pixel counter to derive an accumulative value for the area and percentage of anhidrosis.

The UMSARS is a validated, disease-specific scale that represents the diverse signs and symptoms of MSA.20 It can assess rates of progression and is sensitive to change over time.21 It has an activities of daily living score (UMSARS I, 12 questions) that evaluates motor (including autonomic) activities and the motor examination score (UMSARS II, 14 questions). Poorer health is signified by higher scores on the UMSARS.

The COMPASS is a test derived from the Autonomic Symptom Profile, which is a self-report instrument of 169 questions designed to provide an index of autonomic symptom severity.14 It yields 1 total score that reflects the overall severity of autonomic symptoms and 11 weighted subscale scores that assess severity of symptoms within the following domains: orthostatic intolerance, syncope, sexual failure (men only), bladder dysfunction, diarrhea, constipation, upper gastrointestinal symptoms, secretomotor dysfunction, sleep dysfunction, vasomotor symptoms, and pupillomotor symptoms. Autonomic Symptom Profile scores correlate with objective indices of autonomic function,14 and we have generated norms for the profile based on a sample of 245 healthy controls who completed the instrument.15 The change in COMPASS is a derivative of COMPASS and evaluates the change in symptoms over time on selected domains of symptoms. The focus is on 7 selected domains. We have made the instruments available to selected research centers.22,23

The CASS is the measure of autonomic deficits derived of postganglionic sudomotor, adrenergic, and cardiovagal function.24,25 Results are compared with those in a database of 557 normal subjects.26 A 10-point score, which corrects for the confounding effects of age and sex, is generated.27 It has 3 subscales: adrenergic (range, 0-4), sudomotor (range, 0-3), and cardiovagal (range, 0-3). Generally, a total CASS score of 3 or less indicates no or mild autonomic failure; scores from 4 to 6 indicate moderate autonomic failure; and scores from 7 to 10 indicate severe autonomic failure.

STATISTICAL ANALYSIS

Summary statistics are presented as mean (standard deviation [SD]). Comparisons of initial evaluations and measures at month 12 were based on Wilcoxon signed rank sum or Mann-Whitney U tests. Spearman estimates of correlation were determined. P values were not adjusted for multiple comparisons.

COMPARISON OF MSA WITH PD AT INITIAL EVALUATION

Patients were compared for age, sex, and body mass index (calculated as weight in kilograms divided by height in meters squared) (Table 1). Patients with PD were slightly older. Mean age was 61.1 [7.8] years in patients with MSA and 66.0 [8.1] years in patients with PD (P = .01). Duration of disease was estimated to be 7.2 [2.9] years in patients with MSA and 10.1 [5.1] years in patients with PD. There were 32 patients with parkinsonian type MSA and 20 with cerebellar type MSA.

Table Graphic Jump LocationTable 1. Demographics and Autonomic and Functional Scores at Baseline and Follow-up
AUTONOMIC SYMPTOMS AND FUNCTIONAL STATUS

The COMPASS score (Table 2) in patients with MSA was significantly greater (P < .001) than that of PD. Six of 11 domains were significantly more affected in MSA. Three of the domains related to blood pressure control (syncope, orthostatic intolerance, and vasomotor symptoms). The other 3 were domains focused on symptoms of disturbed secretomotor, bladder, and sleep function. These 6 domains, designated COMPASS select, were markedly different between MSA and PD and comprise the domains selected for focus in the subsequent analysis. For COMPASS select domains, scores in patients with MSA (47.7 [19.7]) were significantly higher than those in patients with PD (19.4 [16.0]) (P < .001).

Table Graphic Jump LocationTable 2. Autonomic Symptom Scores in Patients With MSA and PD at Baseline

Scores on UMSARS I, which evaluates functional status, were significantly greater (P < .001) at 21.5 [7.4] in patients with MSA than those with PD (10.4 [6.1]). The UMSARS II (Table 1) evaluates neurologic deficits; scores were also significantly different between MSA and PD (P < .001). The greater impairment in functional status in patients with MSA compared with those with PD was also reflected in Hoehn-Yahr (P < .001) and UMSARS IV (P < .001) grading.

AUTONOMIC FUNCTION TESTS

The CASS scores were significantly greater (P < .001) in MSA (5.9 [1.9]) than in PD (3.3 [2.3]) (Table 1 and Figure 1), indicating more severe and widespread autonomic failure in the former. The TST revealed more diffuse anhidrosis in MSA than PD (P < .001) with little overlap (Table 1 and Figure 1). Anhidrosis in MSA affected entire regions while that in PD and PD with autonomic failure tended to be distal, which is typical of a length-dependent neuropathic pattern. When the quantitative sudomotor axon reflex test component of the CASS was separately considered, postganglionic sudomotor involvement was not severe (52 patients with MSA, 1.75 [1.27]; 28 patients with PD, 0.79 [1.17]; P = .001). Orthostatic hypotension was common in PD and almost invariable in MSA (Figure 1). Supine norepinephrine and its orthostatic increment were not significantly different between MSA and PD.

Place holder to copy figure label and caption
Figure 1.

Results of baseline autonomic function tests. Autonomic symptoms (Composite Autonomic Symptom Scale [COMPASS] and COMPASS select) based on the Autonomic Symptom Profile and deficits (Composite Autonomic Scoring Scale [CASS] and thermoregulatory sweat test) are significantly greater in multiple system atrophy (MSA) than Parkinson disease (PD) (P < .001). Orthostatic hypotension is common in both but more so in MSA (P = .03), while orthostatic increment in plasma norepinephrine was not significantly different.

Graphic Jump Location

Figure 2 illustrates typical TST patterns in MSA, PD, and PD with autonomic failure. Patients with MSA (Figure 2A) shows regional and progressive anhidrosis not seen in PD or PD with autonomic failure. Patients with PD have a normal pattern or distal anhidrosis (Figure 2B) typical of postganglionic length-dependent denervation. Parkinson disease with autonomic failure is associated with either normal TST percentage (Figure 2C) or a pattern indicative of ganglionic and/or distal denervation (Figure 2D). Hence, while clinical autonomic failure in PD was indistinguishable from MSA, the distribution of anhidrosis was dramatically different.

Place holder to copy figure label and caption
Figure 2.

Representative thermoregulatory sweat test (TST) findings in multiple system atrophy (MSA) (A), Parkinson disease (PD) (B), and PD with autonomic failure (C and D). The regional (lower extremities) preganglionic sweat loss (abnormal TST response and a normal quantitative sudomotor axon reflex test [QSART] response) in 2002 with subsequent progression to global anhidrosis in 2005 is nearly pathognomonic of MSA. Distal sudomotor impairment with minimal progression is typical of PD. Note anhidrosis of distal feet and toes in 2004 and progression only to fingers during 4 years (B). A patient with PD with autonomic failure may have a normal TST (C) or may show a more extensive sudomotor deficit (D), which on further testing reveals a predominantly ganglionic (large truncal segmental sweat loss with reduced QSART values) or a postganglionic, length-dependant deficit (feet and fingers). Sweating is shown in purple.

Graphic Jump Location

When MSA is compared with the subset PD with autonomic failure (n = 6), the latter has a peripheral pattern of anhidrosis and a significantly lower TST percentage (MSA, 27.1% [34.9%] vs PD 10.9% [7.4%]; P = .01). Results of the other tests (UMSARS I, COMPASS select, and CASS) were not significantly different between MSA and PD with autonomic failure.

CORRELATIONS

Figure 3 shows the following correlations: autonomic deficits (CASS) correlate very well with autonomic symptoms (COMPASS) (ρ = 0.67) and with COMPASS select (ρ = 0.68) scores. Functional status evaluated by UMSARS I correlated well with both COMPASS select (ρ = 0.60) and CASS (ρ = 0.53) scores, suggesting that autonomic failure might be responsible for a significant part of functional deficits (Figure 2).

Place holder to copy figure label and caption
Figure 3.

Regression of autonomic deficits (Composite Autonomic Scoring Scale [CASS]) with autonomic symptoms (Composite Autonomic Symptom Scale [COMPASS] select and COMPASS) and functional status (Unified Multiple System Atrophy [MSA] Rating Scale [UMSARS]) and of autonomic symptoms (COMPASS select) with functional status (UMSARS I). PD indicates Parkinson disease.

Graphic Jump Location
PROGRESSION OF AUTONOMIC AND FUNCTIONAL STATUS

Autonomic and functional status progression is based on a preliminary analysis of 25 patients with MSA and 20 patients with PD who had completed follow-up evaluation at 12 months (Table 1 and Table 3). The change in autonomic symptoms (change in COMPASS), was almost 3-fold greater in MSA than PD (Table 3 and Figure 4). The change in COMPASS score was significantly greater (P = .008) in MSA (56.9 [45.9]) than PD (22.1 [32.8]). When only the 5 selected domains were used (change in COMPASS select), variance was less and the change in autonomic symptoms in MSA (49.8 [37.8]) was significantly greater (P = .007) than in PD (17.7 [26.5]) (Figure 4).

Place holder to copy figure label and caption
Figure 4.

Results at 1-year follow-up or last available autonomic data in patients with multiple system atrophy (MSA) or Parkinson disease (PD). Composite Autonomic Symptom Scale (COMPASS) change and COMPASS select change are based on a modified Autonomic Symptom Profile. CASS indicates Composite Autonomic Scoring Scale.

Graphic Jump Location
Table Graphic Jump LocationTable 3. COMPASS Change Scores in Patients With MSA and PD at 1-Year Follow-up

For the same patients, changes in UMSARS I and II scores continue to be more than 2 times greater in MSA than PD, progressing at a greater rate in MSA (Table 1 and Figure 4). Progression is well-exemplified in Figure 2, showing progressive anhidrosis in MSA that is not seen in PD.

The main findings of this prospective study to date are that functional status (UMSARS I) and especially certain select autonomic symptom domains (COMPASS select) and deficits (CASS and TST percentage) will distinguish PD from MSA. Additionally, another study in 12 months will further differentiate the 2 conditions, as MSA is characterized by a much more rapid progression of dysautonomia and functional status. This 2-step approach of systematic evaluation at entry and 1-year follow-up enhances the ability of the clinician to diagnose MSA with greater sensitivity and specificity.

While autonomic failure has long been recognized as being an integral component of MSA, much of the focus has been confined to the presence of OH and neurogenic bladder dysfunction. This study confirms both the observation that OH is almost invariably present in MSA4,5,28 and that it is also relatively common in PD,6,7 as it was present in 41.7% (baseline) and 29.4% (1-year follow-up) of patients with PD. The frequency of OH in PD should not be surprising, because OH is relatively common in persons with PD in this age group29,30; postganglionic adrenergic denervation is also present in PD.8,29,30 This study emphasizes the cautionary point that the presence of OH as the sole autonomic manifestation in PD is not a strong indicator of MSA.

The selection of autonomic function tests was done with 2 goals in mind. First, we selected tests that we hypothesized, based on preliminary data and autonomic pathophysiology, would discriminate between MSA and PD. Second, we chose tests that were currently available at clinical autonomic laboratories and were well-validated and reproducible, with a coefficient of variability less than 20%. Multiple system atrophy differs from PD in its involvement of hypothalamic regions responsible for thermoregulation,31,32 in addition to involvement of preganglionic neurons,33 so that the distribution of anhidrosis should be more diffuse. The finding in this study that diffuse anhidrosis is usually present in MSA confirms our earlier findings4,5 that there is more widespread anhidrosis in MSA than PD. The distribution of anhidrosis in PD supports the notion that the lesion is postganglionic in PD irrespective of severity of autonomic failure5,8 and serves as a reliable diagnostic test to differentiate PD with autonomic failure from MSA. The quantitative sudomotor axon reflex test results in MSA are significantly higher than those in PD, indicating that the denervated postganglionic axon undergoes some secondary changes. The values are typically less than 2, indicating that there are areas of anhidrosis revealed by TST that maintain a sweat response to quantitative sudomotor axon reflex test, supporting the presence of a preganglionic lesion in MSA. The reason for a lower score in PD reflects the much more restricted or absent area of anhidrosis in PD.

The subset of PD patients with autonomic failure in whom autonomic failure dominates the clinical phenotype is problematic to the clinician, as these patients may closely mimic those with MSA. When MSA is compared with the PD with autonomic failure subset, COMPASS select, UMSARS, and CASS scores are not significantly different, reflecting the influence of autonomic failure on these scores. On the other hand, the pattern of anhidrosis (peripheral or ganglionic in PD with autonomic failure and central-preganglionic in MSA) and anhidrosis percentage are significantly different in MSA. By combining quantitative sudomotoraxon reflex test and TST, we found that intact quantitative sudomotor axon reflex test in anhidrotic areas is typical of MSA and confirms a preganglionic site of the lesion.

Plasma norepinephrine measured in both supine and standing positions has been reported to differentiate a preganglionic from a postganglionic disorder.34,35 Supine norepinephrine is reduced in widespread postganglionic disorders, such as paroxysmal atrial fibrillation, and normal in a preganglionic disorder like MSA.34,35 In contrast, the latter condition is associated with a failure of norepinephrine to approximately double, because of widespread preganglionic failure disorder.34,35 The poor discriminatory value of norepinephrine or its intracellular metabolite, dihydroxyphenylglycol, indicates that PD is not characterized by sufficiently widespread postganglionic adrenergic failure to be regularly detectable by this test. This test does not have sufficient sensitivity for routine use to discriminate between MSA and PD.

The Autonomic Symptom Profile provides a comprehensive evaluation of autonomic symptoms and has been validated.14,15 The domains that are significantly different between MSA and PD are those on blood pressure control (syncope, orthostatic intolerance, and vasomotor symptoms) and dysfunctional secretomotor, bladder, and sleep. The high correlation of COMPASS select score with CASS score supports the notion that these autonomic symptoms are due to autonomic failure in MSA (and PD). Its high correlation with UMSARS I and II scores emphasizes that autonomic dysfunction affects activities of daily living and that autonomic dysfunction parallels neurologic deficits. The high discriminatory value of change in COMPASS scores throughout 12 months emphasizes that change in autonomic function over time is greater, almost 3-fold, than PD.

One potential limitation of our study is the reduced number of patients at follow-up compared with the number recruited. We have therefore not been able to test the second part of our hypothesis, that the rate of change of autonomic failure in those with initially mild autonomic deficits will distinguish MSA from PD. The main reasons for the inability to return for autonomic evaluation are death and incapacity. We minimized this problem by the use of UMSARS I and change in COMPASS score, which allows for an evaluation of autonomic symptoms and activities of daily living by telephone interview. The results at 1 year likely reflect an underestimate of deterioration in MSA, because the most common reason for inability to return was incapacity or death. The median time to death from entry in the study, according to Kaplan-Meier estimate of survival, was 2.1 years (not shown). Although we use consensus criteria,1 1 limitation is that the diagnosis of MSA is still an assumption. Five patients have died since starting the study. In all cases, patients who underwent brain autopsy studies had pathologically confirmed MSA, suggesting that the consensus criteria are relatively robust. Another limitation of the study is the relatively advanced stage of the disease when MSA diagnosis is made. This limitation reflects the strict set of criteria. We plan to explore the predictive value of our evaluative approach in cases of possible MSA within 4 years of onset.

Correspondence: Phillip A. Low, MD, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (low@mayo.edu).

Accepted for Publication: November 13, 2008.

Author Contributions:Study concept and design: Sandroni, Gilman, Shults, and Low. Acquisition of data: Lipp, Ahlskog, Fealey, Kimpinski, Iodice, T. L. Gehrking, Sletten, J. A. Gehrking, Maraganore, Gilman, and Low. Analysis and interpretation of data: Lipp, Fealey, Weigand, Sletten, Nickander, Singer, Wenning, and Low. Drafting of the manuscript: Sletten and Shults. Critical revision of the manuscript for important intellectual content: Lipp, Sandroni, Ahlskog, Fealey, Kimpinski, Iodice, T. L. Gehrking, Weigand, Sletten, J. A. Gehrking, Nickander, Singer, Maraganore, Gilman, Wenning, and Low. Statistical analysis: Weigand and Sletten. Obtained funding: Shults. Administrative, technical, and material support: Lipp, Fealey, Kimpinski, Iodice, T. L. Gehrking, Sletten, J. A. Gehrking, Nickander, Singer, Maraganore, Gilman, and Low. Study supervision: Wenning and Low.

Financial Disclosure: None reported.

Funding/Support: This work was supported in part by grants NS 32352, NS 44233, and NS 43364 from the National Institutes of Health, grant MO1 RR00585 from the Mayo Clinic's Center for Translational Science Activities, and the Mayo Clinic.

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Neurological Disorders and Stroke or the National Institutes of Health.

Gilman  SLow  PAQuinn  N  et al.  Consensus statement on the diagnosis of multiple system atrophy. J Neurol Sci 1999;163 (1) 94- 98
PubMed Link to Article
Gilman  SWenning  GKLow  PA  et al.  Second consensus statement on the diagnosis of multiple system atrophy. Neurology 2008;71 (9) 670- 676
PubMed Link to Article
Aminoff  MJWilcox  CS Assessment of autonomic function in patients with a Parkinsonian syndrome. Br Med J 1971;4 (5779) 80- 84
PubMed Link to Article
Cohen  JLow  PFealey  RSheps  SJiang  NS Somatic and autonomic function in progressive autonomic failure and multiple system atrophy. Ann Neurol 1987;22 (6) 692- 699
PubMed Link to Article
Sandroni  PAhlskog  JEFealey  RDLow  PA Autonomic involvement in extrapyramidal and cerebellar disorders. Clin Auton Res 1991;1 (2) 147- 155
PubMed Link to Article
Senard  JMRai  SLapeyre-Mestre  M  et al.  Prevalence of orthostatic hypotension in Parkinson's disease. J Neurol Neurosurg Psychiatry 1997;63 (5) 584- 589
PubMed Link to Article
Allcock  LMUllyart  KKenny  RABurn  DJ Frequency of orthostatic hypotension in a community based cohort of patients with Parkinson's disease. J Neurol Neurosurg Psychiatry 2004;75 (10) 1470- 1471
PubMed Link to Article
Braak  Hde Vos  RABohl  JDel Tredici  K Gastric alpha-synuclein immunoreactive inclusions in Meissner's and Auerbach's plexuses in cases staged for Parkinson's disease-related brain pathology. Neurosci Lett 2006;396 (1) 67- 72
PubMed Link to Article
Braune  SReinhardt  MSchnitzer  RRiedel  ALucking  CH Cardiac uptake of [123I]MIBG separates Parkinson's disease from multiple system atrophy. Neurology 1999;53 (5) 1020- 1025
PubMed Link to Article
Goldstein  DSHolmes  CLi  STBruce  SMetman  LVCannon  RO  III Cardiac sympathetic denervation in Parkinson disease. Ann Intern Med 2000;133 (5) 338- 347
PubMed Link to Article
Iwasa  KNakajima  KYoshikawa  HTada  ATaki  JTakamori  M Decreased myocardial 123I-MIBG uptake in Parkinson's disease. Acta Neurol Scand 1998;97 (5) 303- 306
PubMed Link to Article
Satoh  ASerita  TSeto  M  et al.  Loss of 123I-MIBG uptake by the heart in Parkinson's disease: assessment of cardiac sympathetic denervation and diagnostic value. J Nucl Med 1999;40 (3) 371- 375
PubMed
Raffel  DMKoeppe  RALittle  R  et al.  PET measurement of cardiac and nigrostriatal denervation in Parkinsonian syndromes. J Nucl Med 2006;47 (11) 1769- 1777
PubMed
Suarez  GAOpfer-Gehrking  TLOfford  KPAtkinson  EJO’Brien  PCLow  PA The autonomic symptom profile: a new instrument to assess autonomic symptoms. Neurology 1999;52 (3) 523- 528
PubMed Link to Article
Low  PABenrud-Larson  LMSletten  DM  et al.  Autonomic symptoms and diabetic neuropathy: a population-based study. Diabetes Care 2004;27 (12) 2942- 2947
PubMed Link to Article
Hughes  AJBen-Shlomo  YDaniel  SELees  AJ What features improve the accuracy of clinical diagnosis in Parkinson's disease: a clinicopathologic study. Neurology 1992;42 (6) 1142- 1146
PubMed Link to Article
Guttmann  L The management of the quinizarin sweat test (QST). Postgrad Med J 1947;23353- 366
Link to Article
Fealey  RDLow  PAThomas  JE Thermoregulatory sweating abnormalities in diabetes mellitus. Mayo Clin Proc 1989;64 (6) 617- 628
PubMed Link to Article
Low  PAWalsh  JCHuang  CY McLeod  JG The sympathetic nervous system in diabetic neuropathy: a clinical and pathological study. Brain 1975;98 (3) 341- 356
PubMed Link to Article
Wenning  GKTison  FSeppi  K  et al. Multiple System Atrophy Study Group, Development and validation of the Unified Multiple System Atrophy Rating Scale (UMSARS). Mov Disord 2004;19 (12) 1391- 1402
PubMed Link to Article
Geser  FWenning  GKSeppi  K  et al. the European MSA Study Group, Progression of multiple system atrophy (MSA): a prospective natural history study by the European MSA Study Group (EMSA SG). Mov Disord 2006;21 (2) 179- 186
PubMed Link to Article
Köllensperger  MStampfer-Kountchev  MSeppi  K  et al.  Progression of dysautonomia in multiple system atrophy: a prospective study of self-perceived impairment. Eur J Neurol 2007;14 (1) 66- 72
PubMed Link to Article
Schrag  ASelai  CMathias  C  et al.  Measuring health-related quality of life in MSA: the MSA-QoL. Mov Disord 2007;22 (16) 2332- 2338
PubMed Link to Article
Low  PA Composite autonomic scoring scale for laboratory quantification of generalized autonomic failure. Mayo Clin Proc 1993;68 (8) 748- 752
PubMed Link to Article
Low  PA Autonomic nervous system function. J Clin Neurophysiol 1993;10 (1) 14- 27
PubMed Link to Article
Low  PADenq  JCOpfer-Gehrking  TLDyck  PJO’Brien  PCSlezak  JM Effect of age and gender on sudomotor and cardiovagal function and blood pressure response to tilt in normal subjects. Muscle Nerve 1997;20 (12) 1561- 1568
PubMed Link to Article
Low  PACaskey  PETuck  RRFealey  RDDyck  PJ Quantitative sudomotor axon reflex test in normal and neuropathic subjects. Ann Neurol 1983;14 (5) 573- 580
PubMed Link to Article
Wenning  GKBen-Shlomo  YHughes  ADaniel  SELees  AQuinn  NP What clinical features are most useful to distinguish definite multiple system atrophy from Parkinson's disease? J Neurol Neurosurg Psychiatry 2000;68 (4) 434- 440
PubMed Link to Article
Lipsitz  LA Orthostatic hypotension in the elderly. N Engl J Med 1989;321 (14) 952- 957
PubMed Link to Article
Masaki  KHSchatz  IJBurchfiel  CM  et al.  Orthostatic hypotension predicts mortality in elderly men: the Honolulu Heart Program. Circulation 1998;98 (21) 2290- 2295
PubMed Link to Article
Benarroch  EESchmeichel  AMParisi  JE Depletion of mesopontine cholinergic and sparing of raphe neurons in multiple system atrophy. Neurology 2002;59 (6) 944- 946
PubMed Link to Article
Benarroch  EESchmeichel  AMSandroni  PLow  PAParisi  JE Differential involvement of hypothalamic vasopressin neurons in multiple system atrophy. Brain 2006;129 (pt 10) 2688- 2696
PubMed Link to Article
Low  PAThomas  JEDyck  PJ The splanchnic autonomic outflow in Shy-Drager syndrome and idiopathic orthostatic hypotension. Ann Neurol 1978;4 (6) 511- 514
PubMed Link to Article
Polinsky  RJKopin  IJEbert  MHWeise  V Pharmacologic distinction of different orthostatic hypotension syndromes. Neurology 1981;31 (1) 1- 7
PubMed Link to Article
Mathias  CJPolinsky  RJ Separating the primary autonomic failure syndromes, multiple system atrophy, and pure autonomic failure from Parkinson's disease. Adv Neurol 1999;80353- 361
PubMed

Figures

Place holder to copy figure label and caption
Figure 1.

Results of baseline autonomic function tests. Autonomic symptoms (Composite Autonomic Symptom Scale [COMPASS] and COMPASS select) based on the Autonomic Symptom Profile and deficits (Composite Autonomic Scoring Scale [CASS] and thermoregulatory sweat test) are significantly greater in multiple system atrophy (MSA) than Parkinson disease (PD) (P < .001). Orthostatic hypotension is common in both but more so in MSA (P = .03), while orthostatic increment in plasma norepinephrine was not significantly different.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Representative thermoregulatory sweat test (TST) findings in multiple system atrophy (MSA) (A), Parkinson disease (PD) (B), and PD with autonomic failure (C and D). The regional (lower extremities) preganglionic sweat loss (abnormal TST response and a normal quantitative sudomotor axon reflex test [QSART] response) in 2002 with subsequent progression to global anhidrosis in 2005 is nearly pathognomonic of MSA. Distal sudomotor impairment with minimal progression is typical of PD. Note anhidrosis of distal feet and toes in 2004 and progression only to fingers during 4 years (B). A patient with PD with autonomic failure may have a normal TST (C) or may show a more extensive sudomotor deficit (D), which on further testing reveals a predominantly ganglionic (large truncal segmental sweat loss with reduced QSART values) or a postganglionic, length-dependant deficit (feet and fingers). Sweating is shown in purple.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Regression of autonomic deficits (Composite Autonomic Scoring Scale [CASS]) with autonomic symptoms (Composite Autonomic Symptom Scale [COMPASS] select and COMPASS) and functional status (Unified Multiple System Atrophy [MSA] Rating Scale [UMSARS]) and of autonomic symptoms (COMPASS select) with functional status (UMSARS I). PD indicates Parkinson disease.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

Results at 1-year follow-up or last available autonomic data in patients with multiple system atrophy (MSA) or Parkinson disease (PD). Composite Autonomic Symptom Scale (COMPASS) change and COMPASS select change are based on a modified Autonomic Symptom Profile. CASS indicates Composite Autonomic Scoring Scale.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Demographics and Autonomic and Functional Scores at Baseline and Follow-up
Table Graphic Jump LocationTable 2. Autonomic Symptom Scores in Patients With MSA and PD at Baseline
Table Graphic Jump LocationTable 3. COMPASS Change Scores in Patients With MSA and PD at 1-Year Follow-up

References

Gilman  SLow  PAQuinn  N  et al.  Consensus statement on the diagnosis of multiple system atrophy. J Neurol Sci 1999;163 (1) 94- 98
PubMed Link to Article
Gilman  SWenning  GKLow  PA  et al.  Second consensus statement on the diagnosis of multiple system atrophy. Neurology 2008;71 (9) 670- 676
PubMed Link to Article
Aminoff  MJWilcox  CS Assessment of autonomic function in patients with a Parkinsonian syndrome. Br Med J 1971;4 (5779) 80- 84
PubMed Link to Article
Cohen  JLow  PFealey  RSheps  SJiang  NS Somatic and autonomic function in progressive autonomic failure and multiple system atrophy. Ann Neurol 1987;22 (6) 692- 699
PubMed Link to Article
Sandroni  PAhlskog  JEFealey  RDLow  PA Autonomic involvement in extrapyramidal and cerebellar disorders. Clin Auton Res 1991;1 (2) 147- 155
PubMed Link to Article
Senard  JMRai  SLapeyre-Mestre  M  et al.  Prevalence of orthostatic hypotension in Parkinson's disease. J Neurol Neurosurg Psychiatry 1997;63 (5) 584- 589
PubMed Link to Article
Allcock  LMUllyart  KKenny  RABurn  DJ Frequency of orthostatic hypotension in a community based cohort of patients with Parkinson's disease. J Neurol Neurosurg Psychiatry 2004;75 (10) 1470- 1471
PubMed Link to Article
Braak  Hde Vos  RABohl  JDel Tredici  K Gastric alpha-synuclein immunoreactive inclusions in Meissner's and Auerbach's plexuses in cases staged for Parkinson's disease-related brain pathology. Neurosci Lett 2006;396 (1) 67- 72
PubMed Link to Article
Braune  SReinhardt  MSchnitzer  RRiedel  ALucking  CH Cardiac uptake of [123I]MIBG separates Parkinson's disease from multiple system atrophy. Neurology 1999;53 (5) 1020- 1025
PubMed Link to Article
Goldstein  DSHolmes  CLi  STBruce  SMetman  LVCannon  RO  III Cardiac sympathetic denervation in Parkinson disease. Ann Intern Med 2000;133 (5) 338- 347
PubMed Link to Article
Iwasa  KNakajima  KYoshikawa  HTada  ATaki  JTakamori  M Decreased myocardial 123I-MIBG uptake in Parkinson's disease. Acta Neurol Scand 1998;97 (5) 303- 306
PubMed Link to Article
Satoh  ASerita  TSeto  M  et al.  Loss of 123I-MIBG uptake by the heart in Parkinson's disease: assessment of cardiac sympathetic denervation and diagnostic value. J Nucl Med 1999;40 (3) 371- 375
PubMed
Raffel  DMKoeppe  RALittle  R  et al.  PET measurement of cardiac and nigrostriatal denervation in Parkinsonian syndromes. J Nucl Med 2006;47 (11) 1769- 1777
PubMed
Suarez  GAOpfer-Gehrking  TLOfford  KPAtkinson  EJO’Brien  PCLow  PA The autonomic symptom profile: a new instrument to assess autonomic symptoms. Neurology 1999;52 (3) 523- 528
PubMed Link to Article
Low  PABenrud-Larson  LMSletten  DM  et al.  Autonomic symptoms and diabetic neuropathy: a population-based study. Diabetes Care 2004;27 (12) 2942- 2947
PubMed Link to Article
Hughes  AJBen-Shlomo  YDaniel  SELees  AJ What features improve the accuracy of clinical diagnosis in Parkinson's disease: a clinicopathologic study. Neurology 1992;42 (6) 1142- 1146
PubMed Link to Article
Guttmann  L The management of the quinizarin sweat test (QST). Postgrad Med J 1947;23353- 366
Link to Article
Fealey  RDLow  PAThomas  JE Thermoregulatory sweating abnormalities in diabetes mellitus. Mayo Clin Proc 1989;64 (6) 617- 628
PubMed Link to Article
Low  PAWalsh  JCHuang  CY McLeod  JG The sympathetic nervous system in diabetic neuropathy: a clinical and pathological study. Brain 1975;98 (3) 341- 356
PubMed Link to Article
Wenning  GKTison  FSeppi  K  et al. Multiple System Atrophy Study Group, Development and validation of the Unified Multiple System Atrophy Rating Scale (UMSARS). Mov Disord 2004;19 (12) 1391- 1402
PubMed Link to Article
Geser  FWenning  GKSeppi  K  et al. the European MSA Study Group, Progression of multiple system atrophy (MSA): a prospective natural history study by the European MSA Study Group (EMSA SG). Mov Disord 2006;21 (2) 179- 186
PubMed Link to Article
Köllensperger  MStampfer-Kountchev  MSeppi  K  et al.  Progression of dysautonomia in multiple system atrophy: a prospective study of self-perceived impairment. Eur J Neurol 2007;14 (1) 66- 72
PubMed Link to Article
Schrag  ASelai  CMathias  C  et al.  Measuring health-related quality of life in MSA: the MSA-QoL. Mov Disord 2007;22 (16) 2332- 2338
PubMed Link to Article
Low  PA Composite autonomic scoring scale for laboratory quantification of generalized autonomic failure. Mayo Clin Proc 1993;68 (8) 748- 752
PubMed Link to Article
Low  PA Autonomic nervous system function. J Clin Neurophysiol 1993;10 (1) 14- 27
PubMed Link to Article
Low  PADenq  JCOpfer-Gehrking  TLDyck  PJO’Brien  PCSlezak  JM Effect of age and gender on sudomotor and cardiovagal function and blood pressure response to tilt in normal subjects. Muscle Nerve 1997;20 (12) 1561- 1568
PubMed Link to Article
Low  PACaskey  PETuck  RRFealey  RDDyck  PJ Quantitative sudomotor axon reflex test in normal and neuropathic subjects. Ann Neurol 1983;14 (5) 573- 580
PubMed Link to Article
Wenning  GKBen-Shlomo  YHughes  ADaniel  SELees  AQuinn  NP What clinical features are most useful to distinguish definite multiple system atrophy from Parkinson's disease? J Neurol Neurosurg Psychiatry 2000;68 (4) 434- 440
PubMed Link to Article
Lipsitz  LA Orthostatic hypotension in the elderly. N Engl J Med 1989;321 (14) 952- 957
PubMed Link to Article
Masaki  KHSchatz  IJBurchfiel  CM  et al.  Orthostatic hypotension predicts mortality in elderly men: the Honolulu Heart Program. Circulation 1998;98 (21) 2290- 2295
PubMed Link to Article
Benarroch  EESchmeichel  AMParisi  JE Depletion of mesopontine cholinergic and sparing of raphe neurons in multiple system atrophy. Neurology 2002;59 (6) 944- 946
PubMed Link to Article
Benarroch  EESchmeichel  AMSandroni  PLow  PAParisi  JE Differential involvement of hypothalamic vasopressin neurons in multiple system atrophy. Brain 2006;129 (pt 10) 2688- 2696
PubMed Link to Article
Low  PAThomas  JEDyck  PJ The splanchnic autonomic outflow in Shy-Drager syndrome and idiopathic orthostatic hypotension. Ann Neurol 1978;4 (6) 511- 514
PubMed Link to Article
Polinsky  RJKopin  IJEbert  MHWeise  V Pharmacologic distinction of different orthostatic hypotension syndromes. Neurology 1981;31 (1) 1- 7
PubMed Link to Article
Mathias  CJPolinsky  RJ Separating the primary autonomic failure syndromes, multiple system atrophy, and pure autonomic failure from Parkinson's disease. Adv Neurol 1999;80353- 361
PubMed

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 32

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles
JAMAevidence.com

The Rational Clinical Examination
Make the Diagnosis: Parkinsonism

The Rational Clinical Examination
Original Article: Does This Patient Have Parkinson Disease?