The cardiovascular effects of metoclopramide in multiple system atrophy and pure autonomic failure

Metoclopramide (MCP), a central and peripheral dopaminergic blocker with cholinergic activity, has been proposed to treat orthostatic hypotension (OH) on the basis that it could antagonize the vasodilator and natriuretic effects of dopamine. The authors evaluated cardiovascular responses to MCP in 11 subjects with OH: 6 with multiple system atrophy (MSA) and 5 with pure autonomic failure (PAF), along with 6 healthy control subjects. Supine blood pressure (BP), heart rate (HR), and breathing were continuously monitored before, during, and after MCP infusion. The pre-MCP head-up tilt test was tolerated at 65° for 10 minutes in all subjects except in one with PAF, who tolerated 30° for only 5 minutes. Tilting confirmed the OH in patients with MSA (change in mean arterial pressure [ΔMAP]=−31±13 mm Hg) and PAF (ΔMAP=−34±8 mm Hg). Infusion of MCP was given in four 5-mg doses every 5 minutes, with the subject in a supine position. Infusion of MCP induced the following effects: (1) A transient hypotensive effect occurred after each infusion in both patients and control subjects, the fall in MAP being counteracted by an increase in HR in control subjects but not in patients; this acute MAP fall was more severe in patients. (2) A progressive reduction of MAP occurred during the test, which never returned to preinfusion levels in patients; this effect was so pronounced in two PAF patients as to prevent them from receiving the last dose. Post-MCP tilting was tolerated in control subjects but in only in 5 MSA patients and 4 PAF patients. In those patients who tolerated the test, the MAP fall was similar to, or worse than, that before MCP (MSA: ΔMAP=−28±16 mm Hg; PAF: ΔMAP=−38±16 mm Hg). The cardiovascular effect of MCP in normal subjects was a transient hypotension counterbalanced by reflex tachycardia. The lack of an HR increase and the progressive fall in supine BP in MSA and PAF patients, together with worsening orthostatic tolerance after MCP infusion, are effects that should strongly discourage the use of this drug in the treatment of OH.     

Hemodynamic effects of clonidine in two contrasting models of autonomic failure: multiple system atrophy and pure autonomic failure.

We assessed the effects of clonidine on blood pressure (BP) and heart rate (HR) in multiple system atrophy (MSA), where the autonomic nervous system lesion site is preganglionic, and in pure autonomic failure (PAF), where it is postganglionic. In normal subjects, intravenous infusion of the selective alpha2-adrenoceptor agonist clonidine reduces BP and plasma noradrenaline (NA) levels by means of central alpha2-adrenoceptor action, as well as inducing growth hormone (GH) release. Clonidine-induced GH release is impaired in MSA but spared in PAF. However, the hemodynamic effects of clonidine have not been studied extensively in these disorders. We examined intravenous clonidine test results (performed in our autonomic laboratories using the London Autonomic Units protocol) in 58 patients: 39 with probable MSA and 19 with PAF. Systolic BP (SBP), diastolic BP (DBP), HR, and NA levels were measured supine at baseline and for up to 60 minutes after clonidine. Clonidine resulted in a significant BP fall in MSA patients, which occurred earlier (within 15 minutes of clonidine) and to a greater extent than seen in PAF patients. MSA and PAF patients showed reduction in HR after clonidine administration, although this finding was significantly greater in MSA than in PAF patients. NA levels decreased significantly after clonidine administration in both groups. Although basal NA levels were lower in PAF than in MSA patients, there was no difference in NA reduction relative to baseline between groups. MSA patients showed significant negative correlation between basal NA levels and BP response to clonidine. Clonidine infusion reduces BP and HR in both MSA and PAF groups but to a greater extent in MSA patients. The greater vasodepressor action of clonidine in MSA patients suggests that there is partial preservation of brainstem sympathetic outflow pathways in MSA and may reflect its action at sites in the brainstem and spinal cord that were in part functionally preserved in MSA. Despite similar degrees of NA reduction after clonidine administration, the vasodepressor effect of clonidine was attenuated in PAF compared with MSA patients. This attenuation in PAF patients may reflect greater peripheral alpha2-adrenoceptor denervation supersensitivity due to the postganglionic lesion site. These BP differences, thus, may reflect the underlying lesion site in MSA and PAF, and the hemodynamic data after clonidine infusion may help differentiate these conditions.     

Cardiovascular and renin responses to head-up tilt tests in parkinsonism

Objectives - We investigated cardiovascular and renin responses to head-up tilt tests in patients with Parkinson's disease (PD), multiple system atrophy (MSA), and in controls to determine variables for the assignment of parkinsonism to the potential underlying neurologic condition. Patients and methods - Sequential changes in sympathetic-mediated circulatory variables such as heart rate, blood pressure, and plasma renin concentration during head-up tilt tests were studied in 14 patients with PD and 11 patients with MSA. Twelve subjects with normal autonomic functions were studied as controls. Results - Head-up tilt resulted in significant differences in blood pressure and heart rate responses between PD, MSA, and controls. The baseline plasma renin concentration was significantly lower in MSA than in controls. Twenty min head-up tilt revealed significant differences in plasma renin concentration between PD, MSA, and controls. Conclusion - We conclude that investigating sequential changes in mean arterial blood pressure, heart rate, and plasma renin concentration during head-up tilt test can potentially support differential diagnosis of PD and MSA.     

Symptoms associated with orthostatic hypotension in pure autonomic failure and multiple system atrophy

The symptoms caused by or relating to orthostatic hypotension (over 20 mmHg systolic blood pressure) were evaluated using a questionnaire in 72 patients with primary chronic autonomic failure, 32 of whom had pure autonomic failure (PAF, and 40 multiple system atrophy (MSA). The most common posturally related symptoms were dizziness (84% PAF, 83% MSA), syncope (91% PAF, 45% MSA), visual disturbances (75% PAF, 53% MSA) and suboccipital/paracervical ‘coat-hanger’ neck pain (8 l% PAF, 53% MSA). Chest pain occurred mainly in patients with PAF (44% PAF, 13% MSA). Improvement occurred with sitting or lying flat. Non-specific symptoms (weakness, lethargy and fatigue) were common in both groups (91% PAF, 85% MSA); six patients (one PAF, five MSA) had these symptoms only. Postural symptoms (mainly dizziness and neck pain) were worse in the morning and with warm temperature, straining, exertion, arm movements and food ingestion; they were more common in PAF. Compensatory autonomic symptoms, such as palpitations and sweating, did not occur in either group. In conclusion, orthostatic hypotension caused symptoms of cerebral hypoperfusion (syncope, dizziness and visual disturbances); neck pain, presumably due to muscle hypoperfusion, also occurred frequently. These symptoms were exacerbated by various factors in daily life and were relieved by returning to the horizontal. Non-specific symptoms (such as fatigue) also were common. In MSA, despite substantial orthostatic hypotension, fewer patients had syncope, visual disturbance and neck pain; the reasons for this are unclear. Lack of these features does not exclude the need to assess and investigate orthostatic hypotension and possible autonomic failure. Received: 12 December 1998 Received in revised form: 18 February 1999 Accepted: 17 March 1999     

Cardiac autonomic responses to progressive head-up tilt in individuals with paraplegia

Abstract. Beat-to-beat fluctuations in heart rate are partially controlled by the autonomic nervous system and may be altered by a spinal cord injury. The purpose of the present investigation was to examine the role of the autonomic nervous system in modulating the heart rate response to head-up tilt (HUT) in subjects with low lesion paraplegia. Nineteen subjects with paraplegia and nine age-, height-, and weight-matched control subjects consented to participate. A three lead ECG was used to acquire heart rate (HR), cardiac sympathetic [low frequency component of R-R interval variability (LFRRI)], vagal [high frequency component of R-R interval variability (HFRRI)] and sympatho-vagal balance (LF/HF). A finger photoplethysmograph was used to assess beat-to-beat blood pressure for the estimation of sympathetic vasomotor tone [low frequency component of peak systolic blood pressure variability (LFSBP)]. The results showed a significant main effect for tilt angle for the HR response to HUT, which was comparable between the groups. LFRRI was significantly increased (P < 0.001) and HFRRI was significantly reduced (P < 0.001) across tilt angle in the control group, whereas subjects with paraplegia demonstrated no significant change in LFRRI, but significantly reduced HFRRI (P < 0.001) across tilt angle. There was a significant interaction effect for LF/HF (P < 0.05). LFSBP was significantly reduced in the group with paraplegia compared to controls (P < 0.05). These findings suggest that although cardiac autonomic control is intact, there is a blunted sympathetic response to HUT in subjects with low lesion paraplegia, which may implicate an altered baroreceptor response to acute orthostatic provocation.     

l-threo-dihydroxyphenylserine (l-threo-DOPS; droxidopa) in the management of neurogenic orthostatic hypotension: A multi-national, multi-center, dose-ranging study in multiple system atrophy and pure autonomic failure

This study was designed to determine the efficacy and tolerability of increasing doses ofl-threo-dihydroxyphenylserine (l-threo-DOPS) in treating symptomatic orthostatic hypotension associated with multiple system atrophy (MSA) and pure autonomic failure (PAF). Following a one-week run-in, patients (26 MSA; 6 PAF) with symptomatic orthostatic hypotension received increasing doses ofl-threo-DOPS (100, 200 and 300 mg, twice daily) in an open, dose-ranging study. Incremental dose adjustment (after weeks two and four of outpatient treatment) was based on clinical need until blood pressure (BP), and symptoms improved. Final dosage was maintained for six weeks. Withl-threo-DOPS, systolic BP decrease was reduced during orthostatic challenge (–22±28 mm Hg reduction from a baseline decrease of 54.3±27.7 mm Hg, p=0.0001, n=32; supine systolic BP at final visit was 118.9±28.2 mm Hg). By the end of the study, 25 patients (78%) improved, and in 14 patients (44%) orthostatic hypotension was no longer observed. Decreased orthostatic systolic BP decrease occurred in 22% (7/32), 24% (6/25) and 61% (11/18) of patients treated with 100, 200, and 300 mgl-threo-DOPS twice daily, respectively. An improvement occurred in symptoms associated with orthostatic hypotension, such as light-headedness, dizziness (p=0.0125), and blurred vision (p=0.0290).l-threo-DOPS was well tolerated, with the 2 serious adverse events reported being a possible complication of the disease under study, and with no reports of supine hypertension. I conclusion,l-threo-DOPS (100, 200, and 300 mg, twice daily) was well tolerated. The dosage of 300 mg twice dailyl-threo-DOPS seemed to offer the most effective control of symptomatic orthostatic hypotension in MSA and PAF.The study was supported by Sumitomo Pharmaceuticals Europe, London, U.K.     

Skin vasomotor reflex responses in two contrasting groups of autonomic failure

Background & Aim A variety of stimuli such as deep inspiration, isometric exercise and mental arithmetic, result in a transient vasoconstriction,mediated by sympathetic efferent nerves, in the skin of the fingers and toes of healthy controls (Skin Vasomotor Reflex: SkVR). Multiple system atrophy (MSA) and pure autonomic failure (PAF) provide contrasting models of autonomic failure. In MSA the lesion is central and preganglionic, whilst in PAF the lesion site is peripheral and postganglionic. We evaluated the SkVR in response to various stimuli in MSA and PAF, to determine differences in skin vasomotor involvement between these two patient groups. Methods 25 subjects (10 MSA, 7 PAF, 8 healthy controls) were studied. Baseline recordings of skin blood flow were obtained with a laser Doppler probe on the left index finger pulp and forearm. The subject then underwent a variety of stimuli with rest periods in between to reestablish baseline SkBF. These stimuli were: single deep inspiration (inspiratory gasp); mental arithmetic; bilateral leg elevation and cutaneous cold. Results Healthy control subjects demonstrated marked SkVRs on the finger pulp to each of the stimuli of a magnitude similar to those seen in previous studies, but no SkVRs on the forearm. In MSA SkVRs to inspiratory gasp on the finger pulp were reduced relative to controls. In PAF SkVRs were reduced relative to controls or MSA. The magnitude of SkVR response to gasp and cutaneous cold in PAF was significantly less than in healthy controls. In addition, the magnitude of the response in PAF was significantly less than in MSA for inspiratory gasp. Conclusions PAF showed a decreased SkVR response to all 4 stimuli, the response being significantly less than controls (for inspiratory gasp and cutaneous cold) or MSA (cutaneous cold inspiratory gasp). The decreased responses in PAF may reflect the extensive postganglionic sympathetic denervation seen in this group. The measurement of SkVR may therefore provide a non-invasive aid to the differentiation of MSA and PAF.     

Differential effect of L-threo-3,4-dihydroxyphenylserine in pure autonomic failure and multiple system atrophy with autonomic failure

Summary Treatment with L-threo-3,4-dihydroxyphenylserine (L-threo-dops), a synthetic precursor of norepinephrine, significantly increased upright blood pressure in patients with multiple system atrophy but had no effect on the upright blood pressure of patients with pure autonomic failure. These results suggest that the site of action of L-threo-dops is central and that its pressor effect requires intact peripheral sympathetic neurons.     

Differences in overshoot of blood pressure after head-up tilt in two groups with chronic autonomic failure: pure autonomic failure and multiple system atrophy

On head down tilt to the supine horizontal position (tilt reversal) after head up tilt (HUT), patients with orthostatic hypotension may show an increase in blood pressure (BP) relative to baseline readings. We assessed this BP overshoot in 8 patients with pure autonomic failure (PAF, 64+/-13 years) and 8 patients with multiple system atrophy (MSA, 66+/-10 years). BP was intermittently measured during pre-tilt supine, HUT (60 degrees , 10 min), and post-tilt supine periods. In addition, beat-to-beat BP was measured continuously using the Portapres model 2 device to calculate stroke volume (SV), cardiac output (CO) and total peripheral resistance (TPR). There was systolic BP overshoot of > or = 15 mmHg after tilt reversal in 5 out of 8 PAF, but in only one of 8 MSA. A mean increase of systolic BP in PAF was significantly higher than that in MSA (p<0.01). TPR increased over baseline level after tilt reversal, although there was no significant difference. SV and CO levels during the post-tilt supine period were similar to baseline levels. In conclusion, BP overshoot was prominent in the PAF group but not in the MSA group. The phenomenon of BP overshoot while supine, especially in PAF, may have implications for long term cardiac and vascular damage in such patients.     

Clinical and physiological characteristics of autonomic failure with Parkinson's disease

We analyzed the clinical and physiological features of autonomic failure with Parkinson's disease (AF-PD) in seven patients and compared them with those of autonomic failure with multiple system atrophy (AF-MSA). In AF-PD, parkinsonism was more gradually progressive than in AF-MSA, and symptoms were responsive to L-dopa. All seven patients with AF-PD had orthostatic hypotension, postprandial hypotension, and constipation, but no urinary retention. Of these, three had hypohidrosis and five had frequent urination; five patients had subnormal plasma norepinephrine (NE) concentrations. Supersensitivity to NE infusion was observed in all patients. Head-up tilting (HUT) test resulted in no increase of plasma NE concentrations in both groups, but a significant increase of the plasma arginine vasopressin (AVP) concentrations in the patients with AF-PD. Urodynamic studies revealed that urinary bladder function was relatively well preserved in AF-PD in contrast to AF-MSA. In conclusion, there exists some clinical and physiological differences in autonomic features between AF-PD and AF-MSA, and postganglionic involvement predominates in AF-PD.     

Cerebral blood flow and oxygenation during head-up tilt in patients with multiple system atrophy and healthy control subjects

To assess cerebral hemodynamics in patients with multiple system atrophy (MSA), cerebral blood flow and oxygenation were evaluated in 7 MSA patients and 9 healthy controls during a head-up tilt test (HUT) by means of transcranial Doppler ultrasonography and near-infrared spectrophotometry. In the MSA patients examined, the perfusion pressure reduction during HUT was marked, but severe reduction in blood flow velocity was prevented because of a decrease in cerebrovascular resistance. The MSA patients showed no severe reduction in cerebral oxygenation during HUT. These findings indicate that our MSA patients exhibited a compensatory cerebral vasodilatation response to orthostatic hypotension.     

Pyridostigmine in autonomic failure: can we treat postural hypotension and bladder dysfunction with one drug?

In a 66-year-old man with autonomic failure, pyridostigmine (180 mg/day orally) improved both postural hypotension and underactive detrusor bladder dysfunction. Acetylcholinesterase inhibition may be useful in the management of orthostatic hypotension and bladder dysfunction in autonomic failure patients.     

Amezinium metilsulfate,a sympathomimetic agent,may increase the risk of urinary retention in multiple system atrophy

In 5 patients with multiple system atrophy, administration of 15 mg/day of amezinium metilsulfate, an adrenergic agent, during 6 months for the treatment of postural hypotension exacerbated post-micturition residuals as compared to that before treatment (178 ml versus 113 ml for a change of 37 %, p < 0.05). Amezinium metilsulfate most probably stimulates both α1B-receptors in the vascular wall and α1A/D-receptors in the proximal urethra. Correspondence to Ryuji Sakakibara, MD     

Neuroendocrine and behavioural responses to CO2 inhalation in central versus peripheral autonomic failure

Abstract Multiple system atrophy (MSA) and pure autonomic failure (PAF) represent distinct pathological models of autonomic failure in humans. We have investigated the neuroendocrine, behavioural and autonomic cardiovascular responses to the 35% CO₂ challenge. Nine patients with MSA, nine with PAF and five control subjects received a single breath of 35% CO₂. Peripheral autonomic failure (i.e., PAF) was associated with significantly lower resting noradrenaline levels. All groups demonstrated a significant pressor response to CO₂. In controls, the mean pressor response was +60.2 mm Hg, which was significantly smaller in both the PAF (+26.8 mm Hg, P < 0.01) and MSA (+18.3 mm Hg, P < 0.001) patients. In addition, the onset of the response was significantly delayed in both MSA (140.2 s) and PAF (154.2 s) patients compared with controls (32.4 s, P = 0.04 and P = 0.03, respectively). Noradrenaline levels increased only in controls. Central autonomic impairment (i.e., MSA) was associated with lower cortisol release (+8.8% in MSA compared with +35.2% in control and +23.7% in PAF) and fewer somatic symptoms of emotional arousal. Both MSA and PAF exhibit marked sympathetic autonomic impairment, however, residual (albeit differing) sympathetic pathways can still maintain a partial cardiovascular response. A central autonomic lesion, however, also appears to be associated with blunting of both cortisol and emotional responses to this stress paradigm.     

Computed tomography,magnetic resonance imaging and positron emission tomography with [18F] fluorodeoxyglucose in multiple system atrophy and pure autonomic failure

We studied 45 patients who had autonomic failure with computed tomography, magnetic resonance imaging and positron emission tomography with [¹⁸F]fluorodeoxyglucose to characterize the neuroimaging features of multiple system atrophy and pure autonomic failure and determine the utility of these techniques in distinguishing multiple system atrophy from pure autonomic failure. There were 30 patients with multiple system atrophy and 15 with pure autonomic failure. In the multiple system atrophy group, eight patients had mainly cerebellar signs, seven extrapyramidal and 15 had combinations of cerebellar and extrapyramidal signs. Cerebellar atrophy on computerized tomography and magnetic resonance imaging, signal hypointensity in the posterolateral putamen on magnetic resonance imaging and a generalized reduction in glucose utilization rate with positron emission tomography with [¹⁸F]fluorodeoxyglucose, were the main findings and were seen only in the patients with multiple system atrophy. Decreased glucose utilization (hypometabolism) was most prominent in the cerebellum, brainstem, striatum and frontal and motor cortices. These results indicate clear differences, using neuroimaging studies, between multiple system atrophy and pure autonomic failure.     

MIBG scintigraphy for differentiating Parkinson's disease with autonomic dysfunction from Parkinsonism‐predominant multiple system atrophy

Parkinson's disease (PD) with autonomic dysfunction is difficult to differentiate from Parkinsonism‐predominant multiple system atrophy (MSA‐p). This study aimed to analyze the validity of MIBG scintigraphy for PD with autonomic dysfunction and MSA‐p. Thirty‐nine patients (PD: 27 patients, MSA‐p type: 12) and 12 age‐matched controls were prospectively enrolled and underwent MIBG scintigraphy and autonomic function test (AFT). We separately calculated early and delayed heart‐to‐mediastinal (H/M) ratio and washout rates (WRs). AFT was composed of sympathetic skin reflex and parasympathetic tests based on heart rate variability. Abnormal AFT was observed in 17 (63%) of PD and 10 (83%) of MSA‐p. On comparing PD with abnormal AFT with MSA‐p, either the early or delayed H/M ratio in PD was not different from that in MSA‐p (P > 0.05). Only the WR could differentiate PD with abnormal AFT from MSA‐p (47.07 ± 57.48 vs. 31.39 ± 31.52, respectively) (P = 0.026). According to the results, WR may be more useful than the early and delayed H/M ratio to distinguish MSA‐p from PD with abnormal AFT. Furthermore, the MIBG uptake did not reflect the disease duration or severity. © 2009 Movement Disorder Society     

Reduced morning cortisol secretion in patients with multiple system atrophy

To determine whether daytime or nighttime cortisol secretion is aberrant in patients with multiple system atrophy (MSA), the plasma cortisol concentrations in 20 patients with MSA were measured at 4-hr intervals for one day. Ten age-matched healthy individuals and 20 patients with cerebral infarction but without hypothalamic lesions were used as controls. The results showed that morning (8a.m.) cortisol concentrations in patients with MSA were significantly lower than those in the control subjects. This phenomenon is highly associated with dysfunction in the autonomic nervous system in MSA.This study was supported in part by the Tsubaki Memorial Neuroscience Research Foundation and Mishima Hospital Research Foundation.     

Cerebral autoregulation is preserved in multiple system atrophy: A transcranial Doppler study.

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 assessment 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.     

Oculomotor function in multiple system atrophy: Clinical and laboratory features in 30 patients

We reviewed the clinical and laboratory oculomotor features in 30 patients with probable multiple system atrophy (MSA), 22 with MSA‐P and 8 with MSA‐C. Six patients were also examined post mortem, MSA being confirmed in four and excluded in two (Parkinson's disease and progressive supranuclear palsy). Clinical examination showed the following abnormalities; excessive square wave jerks—21 of 30 patients; mild vertical supranuclear gaze palsy—8 of 30; gaze‐evoked nystagmus—12 of 30 patients, three of whom had no extraocular evidence of cerebellar dysfunction; positioning downbeat nystagmus—10 of 25; mild or moderate saccadic hypometria—22 of 30; impaired (“broken up”) smooth pursuit—28 of 30; reduced VOR suppression—16 of 24. Electro‐oculography and caloric testing did not add significant extra information. In patients presenting with an akinetic‐rigid syndrome it can be difficult to differentiate idiopathic Parkinson's disease from MSA‐P and other causes of atypical parkinsonism. Our findings suggest that the presence of excessive square wave jerks, mild – moderate hypometria of saccades, impaired VOR suppression, spontaneous nystagmus or positioning downbeat nystagmus may be oculomotor “red flags” or clues to the presence of MSA. Further, the presence of clinically slow saccades, or moderate‐to‐severe gaze restriction, suggests a diagnosis other than MSA. © 2008 Movement Disorder Society