The main findings of this prospective study to date are that functional status (UMSARS_1) and especially certain select autonomic symptom domains (COMPASS_Select) and deficits (CASS; TST%) will distinguish PD from MSA. Additionally, a repeat study in 12 months will further differentiate the two conditions, since MSA is characterized by a much more rapid progression of dysautonomia and functional status. This two-step approach of systematic evaluation at entry and at one year 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 presence of OH and neurogenic bladder. This study confirms both the observation that OH is almost invariably present in MSA4, 5, 15
but that OH is also relatively common in PD,6, 7
being present in 41.7% (baseline) and 29.4% (1-year). The frequency of OH in PD should not be surprising, since OH is relatively common in PD subjects of this age group37, 38
and there is, additionally, postganglionic adrenergic denervation in PD.9, 37, 38
This study emphasizes the cautionary point that the presence of OH as the sole autonomic manifestation in PD is not a strong red flag for MSA.
The selection of autonomic function tests was done with two goals in mind. We selected tests that we hypothesized, based on preliminary data and autonomic pathophysiology, should discriminate between MSA and PD. Second, we chose tests that were currently available at clinical autonomic laboratories, that are well-validated and reproducible, with a coefficient of variability <20%. MSA differs from PD in the involvement of hypothalamic regions responsible for thermoregulation,39, 40
in addition to involvement of preganglionic neurons,41
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, 9
and serves as a reliable diagnostic test to differentiate PD_AF from MSA. The QSART values in MSA are significantly higher than that of PD, indicating that the denervated postganglionic axon undergoes some secondary changes. Of note is that the values are typically <2 indicating that there are areas of anhidrosis on TST that maintain a sweat response to QSART, supporting 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_AF patients where autonomic failure dominates the clinical phenotype is problematic to the clinician since they could closely mimic MSA. When MSA is compared with PD_AF subset alone, COMPASS_Select, UMSARS, and CASS 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_AF and central-preganglionic in MSA) and %-anhidrosis are significantly different in MSA. Additionally by combining QSART and TST, intact QSART in anhidrotic areas is typical of MSA and confirms a preganglionic site of the lesion.
Plasma norepinephrine measured in both the supine and standing positions has been reported to differentiate a preganglionic from postganglionic disorder.42, 43
Supine norepinephrine is reduced in widespread postganglionic disorder such as PAF and normal in a preganglionic disorder of MSA.42, 43
In contrast, the latter condition is associated with a failure of norepinephrine to approximately double, because of widespread preganglionic failure disorder.42, 43
The poor discriminatory value of norepinephrine or its intracellular metabolite, DHPG, 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.23, 30
The domains that are significantly different between MSA and PD are those on BP control (syncope, orthostatic intolerance, vasomotor) and dysfunctional secretomotor, bladder, and sleep. The high correlation of COMPASS_select with CASS supports the notion that these autonomic symptoms are due to autonomic failure in MSA (and PD). Its high correlation with UMSARS 1 and 2 emphasize that autonomic dysfunction affect activities of daily living and that autonomic dysfunction parallels neurologic deficits. The high discriminatory value of COMPASS_Change over 12 months emphasize that change in autonomic function over time is greater, being almost 3-fold that of PD.
One potential limitation of the study is the reduced number of patients at follow-up compared to the number recruited. We have therefore not been able to test part 2 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 inability to return for autonomic evaluation are death and incapacity. We minimized the problem by the use of UMSARS 1 and COMPASS_Change, 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 since 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
one 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 have 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.