Movement Disorders Vol. 21, No. 12, 2006, pp. 2122–2126 © 2006 Movement Disorder Society Cerebral Autoregulation Is Preserved in Multiple System Atrophy: A Transcranial Doppler Study Anne Pavy-Le Traon, MD, PhD,1,2* Richard L. Hughson, PhD,3 Claire Thalamas, MD,4 Monique Galitsky, MD,4 Nelly Fabre, MD,5 Olivier Rascol, MD, PhD,4,6 and Jean-Michel Senard, MD, PhD2,6 1 Laboratory of Autonomic Nervous System and Neurosonology, Vascular Neurology Department, Hopital Rangueil, Toulouse, France 2 INSERM, U 586, Toulouse, France 3 Cardiorespiratory and Vascular Dynamics Laboratory, University of Waterloo, Ontario, Canada 4 Clinical Investigation Centre, Hopital Purpan, Toulouse, France 5 Neurology Department, Hopital Rangueil, Toulouse, France 6 Department of Clinical Pharmacology, Faculty of Medicine, University Hospital, Toulouse, France Abstract: Patients with multiple system atrophy (MSA) present large changes in blood pressure (BP) due to autonomic disturbances. We analyzed how this change may influence dynamic cerebral autoregulation (DCA). Simultaneous recordings of arterial BP (Finapres) and middle cerebral artery (MCA) blood flow velocity (BFV) (transcranial Doppler) were performed in 10 patients with MSA (61 ⫾ 12 yr of age) and 12 healthy volunteers (61 ⫾ 11 yr of age): cerebral BFV response to oscillations in mean BP was studied in the supine position by cross-spectral analysis of mean BP and mean MCA BFV. The DCA was also studied during the decrease in BP the first seconds when standing up from a sitting position by the as- sessment of the cerebrovascular resistance index (CR; mean BP/mean MCA BFV ratio). The MCA BFV/BP cross-spectral analysis showed a phase for the mid-frequency band (0.07– 0.2 Hz) significantly larger in MSA, suggesting more active autoregulation in response to larger changes in BP. Changes in CR reflecting the rate of autoregulation, when standing did not differ between the two groups. These data suggest that dynamic cerebral autoregulation is preserved in MSA. © 2006 Movement Disorder Society Key words: cerebral autoregulation; multiple system atrophy; transcranial Doppler; autonomic failure; orthostatic hypotension; cross-spectral analysis Multiple system atrophy (MSA) is a sporadic, adultonset neurodegenerative disease characterized by autonomic dysfunction, Parkinsonism, and ataxia in any combination.1,2 Autonomic dysfunction is characterized by deficient baroreflex regulation with orthostatic hypotension and supine hypertension. However, patients with chronic orthostatic hypotension may be remarkably tolerant of low orthostatic blood pressure developing no or few symptoms.1 This finding may be related to an expansion of the auto- regulated range of lower blood pressures.3 Cerebral autoregulation is a fast-acting mechanism that acts through arteriolar caliber changes that control cerebrovascular resistance. The influence of autonomic nervous system on cerebral blood flow (CBF) regulation is not well known. Some studies dealt with cerebral autoregulation in patients with autonomic failure but were not focused only on patients with MSA.3–5 The objective of this study was to analyze how the autonomic disturbances observed in MSA may influence cerebral autoregulation. Complementary approaches to study dynamic cerebral autoregulation by transcranial Doppler were used. *Correspondence to: Anne Pavy-Le Traon, Laboratory of Autonomic Nervous System and Neurosonology, Vascular Neurology Department, Hopital Rangueil, TSA 50032, 31059 Toulouse Cedex 9, France. E-mail: pavy.a@chu-toulouse.fr Received 31 October 2005; Revised 13 June 2006; Accepted 18 June 2006 Published online 6 October 2006 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.21130 SUBJECTS AND METHODS Subjects A total of 10 patients with probable MSA (6 women, 4 men; mean age, 61 ⫾ 12 years) were recruited accord- 2122 CEREBRAL AUTOREGULATION IN MSA ing to the consensus statement on the diagnosis of multiple system atrophy.2 The main clinical early features were Parkinsonism with poor or unsustained levodopa response, cerebellar or pyramidal signs, autonomic disorders (genitourinary dysfunction and orthostatic hypotension).1,2,6 The mean duration of disease was 4.8 ⫾ 2 years. Seven patients had the MSA/P(parkinsonian) type, and three patients had the MSA/C (cerebellar) type of disease. All patients except 1 underwent treatment by levodopa. All these patients were able to stand up and presented an orthostatic hypotension.7 Only 5 patients had a treatment against orthostatic hypotension: heptaminol (n ⫽ 2), midodrine (n ⫽ 1), fludrocortisone (n ⫽ 1), or midodrine and fludrocortisone (n ⫽ 1). Midodrine and heptaminol were stopped the day before the cerebral autoregulation assessment. Twelve healthy age-matched controls participated in this study (7 women, 5 men; mean age, 61 ⫾ 11 years). Exclusion criteria were history of coronary heart disease, heart rhythm disorders, renal insufficiency, alcoholism, diabetes, and hyper- or hypotension (control group). Carotid duplex and transcranial Doppler were performed to check the absence of carotid artery and middle cerebral artery (MCA) stenosis. Cardiovascular autonomic testing8 was performed in the two groups to confirm the autonomic failure (MSA group) and to check its absence (control group). The protocol of the study was approved by the local Ethics Committee. All subjects gave their written informed consent to participate. 2123 Autoregulation Assessment Dynamic autoregulation was assessed by methods based on continuous and simultaneous recordings of arterial BP and cerebral blood flow velocity (BFV) in two conditions: (1) the analysis of the CBF response to oscillations in mean BP was studied at rest in supine position by cross-spectral analysis of the mean BP and the mean MCA BFV. The cross-spectral analysis is a transfer function that provides an estimate of the relationship between the input variable, the mean BP, and the output variable, the mean MCA BFV, reflecting the cerebral autoregulation. (2) The dynamics of CBF autoregulation was also studied during the rapid decrease in BP induced during the first seconds when standing up rapidly from the sitting position. Ten minutes of baseline data were collected in the supine position during which the MCA BFV/BP crossspectral analysis was performed. Then, the subjects were asked to stay in a sitting position for 2 minutes, after which they stood up rapidly and kept the upright position for 2 minutes. The initial changes of mean BP and mean MCA BFV in the upright position were analyzed. Data Analysis The digitized signals from Finapres (BP curve and HR), TCD (outline of the Doppler spectra) and capnogragh (PCO2 values) were sampled every 0.5 sec and simultaneously recorded on a PC computer. These signals were processed with the PDL software (Notocord Systems, France). MCA BFV/BP Cross-Spectral Analysis Experimental Procedure Signals Recording Blood pressure (BP) and heart rate (HR) were continuously monitored with a noninvasive finger cuff (Finapres 2300, Ohmeda, France) with the arm of the subject at the level of the heart. Systolic, diastolic, and mean arterial BP and HR were also measured automatically every minute on the brachial artery with an automated sphygmomanometer (Dinamap, Critikon, Inc., Tampa, FL) to validate Finapres measurements. Relative CBF changes were assessed using transcranial Doppler (TCD) recordings of the MCA through the temporal window, with a 2 MHz probe maintained by a headset (Diadop 500, Diatecnic, France). Instantaneous values of end-tidal PCO2 were recorded by sampling exhaled CO2 using a nasal sensor (Datex Normocap, Helsinki, Finland). The cross-spectral analysis describes the relative power (gain) and timing (phase) over a range of frequencies between the mean MCA BFV and the mean BP (Finapres). The gain power and the phase were analyzed in three frequency bands: Low-frequency range, 0.01 to 0.07 Hz (LF); medium frequency range, 0.07 to 0.20 Hz (MF); high frequency range, 0.20 to 0.40 Hz (HF). The gain is an indicator of what magnitude of change in BFV is caused by a change in BP: smaller gain indicates more effective regulation. The phase indicates the shift in degrees (or radians) required to align the input signal (BP) with the output signal. A decrease in phase corresponds to less-effective autoregulation; that is, the input signal is more directly transferred into an output response. We looked at the gain and phase in the midfrequency band (0.07– 0.2 Hz), because previous studies showed that the cerebral autoregulation assessment is mainly reflected by the gain and phase in this band.9 Movement Disorders, Vol. 21, No. 12, 2006 2124 A. PAVY-LE TRAON ET AL. TABLE 1. MCA mean blood flow velocity/mean blood pressure cross-spectral analysis data MSA group (mean⫾SD) Control group (mean⫾SD) P value (Mann-Whitney) 0.635 ⫾ 0.595 1.002 ⫾ 0.851 1.281 ⫾ 0.766 0.660 ⫾ 0.610 0.876 ⫾ 0.429 0.150 ⫾ 0.241 0.626 ⫾ 0.381 0.820 ⫾ 0.227 0.901 ⫾ 0.204 0.706 ⫾ 0.515 0.519 ⫾ 0.209 ⫺0.015 ⫾ 0.170 0.94 – NS 0.72 – NS 0.075 – NS 0.131 – NS 0.019 0.1552 – NS LF gain MF gain HF gain LF phase (radian) MF phase (radian) HF phase (radian) Data are shown for gain and phase in the different frequency bands in multiple system atrophy patients and in controls, compared using a nonparametric test (Mann–Whitney). MCA, middle cerebral artery; LF, low frequency; MF, mid-frequency; HF, high frequency; NS, not significant. Dynamic Autoregulation During Active Standing The time course of cerebrovascular resistance (CR) after standing up from the sitting position was determined by using an index (mean BP [mm Hg]/mean MCA velocity [cm/sec]). The following data were analyzed (mean ⫾ SD): maximum decrease in mean BP, mean BFV, and CR; time to obtain the maximum decrease in CR (T1) and to obtain the recovery value after the initial decrease (T2); rate of autoregulation, defined as normalized changes in CR per second during the BP decrease; and end tidal PCO2 changes during the decrease in CR. Statistical Analysis The results in the two groups were studied using nonparametric tests (Mann–Whitney). Differences were considered as statistically significant when P ⬍ 0.05. Active standing-up from the sitting position induced slight but usual changes in BP. Only two healthy volunteers did not have a initial decrease in mean BP when standing. The magnitude of the initial relative decrease in mean BP was slightly larger in MSA (⫺21 ⫾ 9%) than in controls (⫺12 ⫾ 9%; P ⫽ 0.05). Recovery to basal values was rapidly observed in controls and not in MSA patients (Fig. 2). Standing-up also induced changes in MCA BFV characterized by a slight decrease in MCA BFV followed by recovery to baseline values. The magnitude of this decrease did not differ significantly between the two groups (⫺11 ⫾ 9% in controls; ⫺12 ⫾ 7% in MSA; P ⫽ 0.66). The decrease in CR after RESULTS Resting Supine Conditions Measurements of BP in the supine position showed a trend to higher mean BP (Finapres) in the MSA group (MBP, 90.9 ⫾ 20 mm Hg versus 73.4 ⫾ 9 mm Hg in the control group; P ⫽ 0.056). The mean BFV did not differ significantly between the two groups (MBFV, 55 ⫾ 10 cm/sec in the MSA group versus 52 ⫾ 5 cm/sec in the control group; not significant). End-tidal PCO2 did not differ in the two groups. Cerebral Autoregulation Studied by Cross-Spectral Analysis As shown on Table 1, only the phase for the midfrequency band was significantly larger in the MSA group. The other parameters did not differ significantly in the two groups. Patients showed larger interindividual variability. Dynamics of Cerebral Autoregulation During Active Standing An example of the recorded parameters is shown in a healthy volunteer (Fig. 1A) and in a patient (Fig. 1B). Movement Disorders, Vol. 21, No. 12, 2006 FIG. 1. Changes induced by rapidly standing up from sitting position for mean arterial blood pressure (A), heart rate (B), mean middle cerebral artery blood flow velocity (C), and cerebrovascular resistance index (D) in a healthy volunteer (A) and in a multiple system atrophy patient (B). CEREBRAL AUTOREGULATION IN MSA 2125 FIG. 2. Changes (mean ⫾ SD) in mean blood pressure (BP) (A), middle cerebral artery (MCA) mean blood flow velocity (B), and cerebrovascular resistance index (C) from sitting (left) to upright immediately (middle) and after 30 seconds (right) in controls and multiple system atrophy (MSA) patients. Mean BP differed between the groups in the recovery period (*P ⬍ 0.05). standing (Fig. 2) tended to be larger in the MSA group (⫺20 ⫾ 11% versus ⫺12 ⫾ 13%; P ⫽ 0.15). The normalized changes in CR/sec reflecting the rate of autoregulation did not differ between the two groups (P ⫽ 0.52). The time to maximum decrease of CR (T1) and the time to full recovery of CR after the initial drop (T2) were also similar in the two groups: T1, 12.4 ⫾ 3.4 seconds in MSA and 11.6 ⫾ 3.5 seconds in controls (P ⫽ 0.65)/T2, 13 ⫾ 4.4 seconds in MSA and 14.7 ⫾ 4 seconds in controls (P ⫽ 0.38). End-tidal PCO2 decreased slightly during active standing, but this change did not differ significantly in the two groups (⫺6.5% in the control group, ⫺9% in the MSA group). DISCUSSION Our results did not show alteration of the dynamics of cerebral autoregulation in patients with MSA, compared to age-matched controls. This finding may contribute to the rather good clinical tolerance observed in patients with chronic orthostatic hypotension. The resting values showed that mean BFV did not differ significantly in the two groups. The trend to higher BP in MSA group was probably related by the dysautonomia also characterized by supine hypertension, and the treatment may have favored it in two patients on fludrocortisone during the test. Two kinds of methods exist for evaluating cerebral autoregulation: the original static methods that study the capacity to maintain constant CBF after prolonged and steady changes in arterial BP. Newer methods of dynamic testing allowed the assessment of transient changes in CBF (or velocity) in response to changes in BP induced by different maneuvers (Valsalva, deflation of thigh cuffs, positional changes) or to spontaneous oscillations in mean BP.9,10 The two techniques of dynamic testing we used showed concordant results, suggesting a preserved cerebral autoregulation in MSA patients: at rest, in response to spontaneous oscillations in mean BP at rest (MCA BFV/BP cross-spectral analysis), and during the initial transient decrease in BP when standing up from the sitting position. Cross-Spectral Analysis Previous studies in healthy volunteers with CO2 changes11 and in patients with autoregulation impairment (arteriovenous malformations, carotid occlusive disease)9,12 showed the cerebral autoregulation assessment is mainly reflected by the gain and phase in the midfrequency band (0.07– 0.2 Hz). Our data showed a significant increase in the MF phase in MSA patients, which may suggest more active autoregulation in response to larger BP changes. Blaber and colleagues5 used crossspectral analysis in patients with autonomic failure compared to controls. The authors concluded there was an altered but yet present autoregulatory response with autonomic failure. Patients characteristics in that study may explain some of the differences compared with the results obtained in our study. Blaber and associates performed their study on 11 patients with different diseases (pure autonomic failure, n ⫽ 7; MSA, n ⫽ 2; and insulin dependent diabetes mellitus, n ⫽ 2), which may influence differently cerebral autoregulation. In particular, some studies showed cerebral autoregulation disorders in diabetes probably related to micro- and macroangiopathy.13,14 Stand Test Standing up rapidly after staying in a sitting position induced a slight but significant decrease in BP and MCA BFV. Most of the autoregulatory response develops within a few seconds of the variation of the cerebral perfusion pressure.10 With this method, we did not find significant differences in the autoregulatory response in the two groups. This method can be easily used15 but has some limitations: the decrease in BP was constant in MSA patients, but variable, often less marked and reproducible in healthy patients. Therefore, this method is less suitable to study the dynamics of autoregulation than other methods that induce a steeper drop in BP such as the use of the sudden deflation of thigh cuffs10,16 or by standing up after 2 minutes in squatting position17; but Movement Disorders, Vol. 21, No. 12, 2006 2126 A. PAVY-LE TRAON ET AL. this kind of testing may be painful or cannot be used in MSA patients with motor and balance disorders. Our results are in line with several studies that showed a preserved dynamic autoregulation in MSA using other techniques to induce BP changes. Briebach and coworkers4 studied the MCA BFV during a 60-degree head-up tilt (HUT) test in 4 patients suffering from Shy–Drager syndrome (now classified in MSA). They found a lower percentage change in mean BFV than in mean BP and suggested a preserved cerebral autoregulation. Hetzel and colleagues18 evaluated the interaction between cerebral blood flow velocity (TCD) and BP during a 70degree HUT test and a Valsalva maneuver in 9 patients with MSA compared to 14 controls. During the HUT test, BP dropped markedly but the decrease in CBF velocity was small and did not differ significantly from controls. The investigators looked at the cerebrovascular resistance changes and concluded that cerebral autoregulation was rather well preserved. Limits The methods we used have the advantages of being nonpharmacological and noninvasive. They have, however, some limitations. First, the evaluation of relative changes in CBF using measurements of MCA velocities by TCD relies on the assumption that the diameter of the MCA does not vary between successive measurements. Although the design of our experiment did not permit us to control for this variable, previous studies have demonstrated that the changes in the diameter of the MCA in response to BP drops within the range of those we observed are negligible.10,16 This study was performed in a small number of patients, with larger interindividual variability in the MSA group. However, all data obtained with different ways of testing are concordant. In conclusion, the data obtained with two noninvasive methods using TCD are coherent and suggest that dynamic cerebral autoregulation is preserved in MSA patients, despite large variations in BP. The BP/MCA BFV cross-spectral analysis performed in the supine position provides new perspectives to study cerebral autoregulation in particular in disabled patients. Acknowledgments: This work was supported by a grant INSERM-Merck and sponsored by the University Hospital of Toulouse for regulatory and ethical submission. The authors Movement Disorders, Vol. 21, No. 12, 2006 thank the staff of the Clinical Investigation Centre of Toulouse for their assistance regarding the subjects recruitment. REFERENCES 1. Low PA, Bannister R. Multiple system atrophy and pure autonomic failure. In: Low PA, editor. Clinical Autonomic Disorders. Philadelphia: Lippincott-Raven Publishers; 1997. p 555–585. 2. Gilman S, Low P, Quinn N, et al. Consensus statement on the diagnosis of multiple system atrophy. J Neurol Sci 1999;163:94 – 98. 3. Brooks DJ, Redmond S, Mathias CJ, Bannister R, Symon L. The effect of orthostatic hypotension on cerebral blood flow and middle cerebral artery velocity in autonomic failure with observations on the action of ephedrine. J Neurol Neurosurg Psychiatry 1989;52: 962–966. 4. Briebach T, Laubenberger J, Fischer PA. Transcranial Doppler sonographic studies of cerebral autoregulation in Shy-Drager syndrome. J Neurol 1989;236:349 –350. 5. Blaber AP, Bondar R, Stein F, et al. Transfer function analysis of cerebral autoregulation dynamics in autonomic failure patients. Stroke 1997;28:1686 –1692. 6. Quinn N. How to diagnose multiple system atrophy. Mov Disord 2005;(Suppl. 12):5–10. 7. Consensus statement on the definition of orthostatic hypotension, pure autonomic failure, and multiple system atrophy. The Consensus Committee of the American Autonomic Society and the American Academy of Neurology. Neurology 1996;46:1470. 8. Ewing DJ, Martyn CN, Young RJ, Clark BF. The value of cardiovascular autonomic function tests: 10 years experience in diabetes. Diabetes Care 1995;8:491– 498. 9. Panerai RB. Assessment of cerebral pressure autoregulation in humans – a review of measurement methods. Physiol Meas 1998; 19:305–338. 10. Aaslid R, Lindegaard KF, Sorteberg W, Normes H. Cerebral autoregulation dynamics in humans. Stroke 1989;1:45–52. 11. Edwards MR, Shoemaker JK, Hughson RL Dynamic modulation of cerebrovascular resistance as an index of autoregulation under tilt and controlled PET(CO(2)). Am J Physiol Regul Integr Comp Physiol 2002;283:653– 662. 12. Diehl RR, Linden D, Lucke D, Berlit P. Phase relationship between cerebral blood flow velocity and blood pressure. A clinical test of autoregulation. Stroke 1995;26:1801–1804. 13. Pallas F, Larson DF. Cerebral blood flow in the diabetic patient. Perfusion 1996;11:363–370. 14. Mankovsky BN, Piolot R, Mankovsky OL, Ziegler D. Impairment of cerebral autoregulation in diabetic patients with cardiovascular autonomic neuropathy and orthostatic hypotension. Diabet Med 2003;20:119 –126. 15. Lipstiz LA, Mukai S, Hamner J, Gagnon M, Babikian V. Dynamic regulation of middle cerebral artery blood flow velocity in aging and hypertension. Stroke 2000;31:1897–1903. 16. Newell DW, Aaslid R, Lam A, Mayberg TS, Winn HR Comparison of flow and velocity during dynamic autoregulation testing in humans. Stroke 1994;25:793–797. 17. Pavy-Le Traon A, Costes-Salon MC, Galinier M, Fourcade J, Larrue V. Dynamics of cerebral blood flow autoregulation in hypertensive patients. J Neurol Sci 2002;195:139 –144. 18. Hetzel A, Reinhard M, Guschlbauer B, Braune S. Challenging cerebral autoregulation in patients with preganglionic autonomic failure. Clin Auton Res 2003;13:27–35.