Central Autonomic Failure Research Articles

Abstract 058: Factors Contributing To Postprandial Hypotension In Neurogenic Orthostatic Hypotension

Postprandial hypotension (PPH) is defined as a sudden and substantial decrease (>20 mmHg or >10 mmHg) in blood pressure (BP) within two hours post meal intake; This condition is highly prevalent in neurogenic orthostatic hypotension (nOH) and is associated with pre-syncopal symptoms and postprandial syncope. We studied factors contributing to PPH in nOH. Patients were admitted at the Vanderbilt clinical research center and placed on a sodium-controlled diet. Autonomic function testing, including continuous recording of BP and heart rate (HR) during head up tilt, sinus arrhythmia, and Valsalva Maneuver, was performed. Subjects took a high-carbohydrate meal (~500 Kcal). Hemodynamic parameters were monitored every 5 mins for 30 minutes before and up to 120 minutes afterwards. Results: We recruited 13 patients with peripheral autonomic failure (Parkinson’s Disease), 62% males, 73±9.08 y.o. and 13 with central autonomic failure (Multiple System Atrophy), 69% males, 62±8.23 y.o. All subjects had a substantial SBP (-42.9 ±27.90 mmHg) and DBP (-20.8 ±15.2 mmHg) decrease within 3 mins of standing, without compensatory HR increase (11.64 ± 5.97 bpm). The orthostatic increase in HR adjusted by decrease in SBP was abnormal (0.4±0.43, normal>0.5), sinus arrhythmia ratio was abnormal (1.05±0.04, normal>1.2). Pressor response in Valsalva Maneuver showed impaired sympathetic vasoconstriction. Postprandial hemodynamic changes were analyzed with area under the curve (AUC) and at 30-min timepoint post meal, which was the nadir. PD had a larger DBP increase (907±214.83 mmHg vs.1209±277.68 mmHg MSA, P=0.016), MSA had a higher HR increase (1102±236 mmHg vs. 1318±199.82 mmHg, P=0.029). No difference was found in AUC SBP, however at 30-min post-meal, SBP was lower in PD (-25±24.19 mmHg vs. -3.3±15.05 mmHg MSA, P=0.026). Only supine SBP predicted the postprandial decrease in SBP at 30 min (r=-0.5, P=0.04). Conclusion: PPH is more severe in peripheral autonomic failure; supine BP was associated with PPH.

Abstract P408: Treatment Of Orthostatic Hypotension With Pyridostigmine: Relevance To Supine Hypertension

Supine hypertension, a common comorbidity in patients with orthostatic hypotension (OH), creates a management challenge because the treatment of one condition can worsen the other. Treatment of OH with the acetylcholinesterase inhibitor pyridostigmine has the advantage of preferentially increasing upright blood pressure (BP) by facilitating autonomic ganglia neurotransmission. We did a retrospective analysis of 37 patients with neurogenic OH (65±2 yr, 21 men) to study the efficacy of pyridostigmine 60 mg (defined as the increase in upright systolic BP [SBP] 1-hr postdrug) and determine clinical predictors of efficacy. Pyridostigmine increased upright SBP by 4 (-6 to 11 mmHg, median, IQR). Pyridostigmine efficacy was inversely correlated with the severity of OH (the SBP drop on standing, r 2 =0.4, p=0.022) and with the magnitude of autonomic impairment, the ratio of the increase in heart rate on standing divided by the drop in SBP, (r 2 =0.32, p=0.044) only in patients with central autonomic failure and intact efferent sympathetic pathways (multiple system atrophy, MSA; n=13), but not in patients with pure autonomic failure (PAF; n=24). Pyridostigmine efficacy was negatively correlated to supine BP (r 2 =0.20, p=0.006; Figure). In conclusion, pyridostigmine was less effective in patients with severe autonomic impairment and those with supine hypertension, who are most likely to benefit from the preferential increase in upright BP produced by the drug. PAF patients had severe OH (-74±6 vs. -56±8 mmHg in MSA), and our results may not reflect patients with milder OH.

Effects of Atomoxetine for the Treatment of Neurogenic Orthostatic Hypotension in Patients With Alpha-synucleinopathies: A Systematic Review of Randomized Controlled Trials and a Focus-Group Discussion.

Neurogenic orthostatic hypotension (nOH) is one of the most important nonmotor symptoms in patients with α-synucleinopathies. Atomoxetine is a selective norepinephrine transporter blocker that is a treatment option for nOH. This systematic review and expert focus-group study was designed to obtain evidence from published data and clinical experiences of Korean movement-disorder specialists about the efficacy and safety of atomoxetine for the pharmacological treatment of nOH in patients with α-synucleinopathies. The study comprised a systematic review and a focus-group discussion with clinicians. For the systematic review, multiple comprehensive databases including MEDLINE, Embase, Cochrane Library, CINAHL, PsycInfo, and KoreaMed were searched to retrieve articles that assessed the outcomes of atomoxetine therapy. A focus-group discussion was additionally performed to solicit opinions from experts with experience in managing nOH. The literature review process yielded only four randomized controlled trials on atomoxetine matching the inclusion criteria. Atomoxetine effectively increased systolic blood pressure and improved OH-related symptoms as monotherapy or in combination with other drugs. Its effects were pronounced in cases with central autonomic failure, including multiple-system atrophy (MSA). Atomoxetine might be a safe monotherapy regarding the risk of supine hypertension. Atomoxetine is an effective and safe option for short-term nOH management, which could be more evident in patients with central autonomic dysfunction such as MSA. However, there is a paucity of evidence in the literature, and data from the focus-group discussion were inadequate, and so further investigation is warranted.

Autonomic Dysfunction in the Synucleinopathies.

Autonomic dysfunction is a characteristic feature in the synucleinopathies. Differences in cellular deposition and neuronal populations affected by α-synuclein aggregation influence the manifestations and severity of autonomic failure in the different synucleinopathy disorders. The Lewy body disorders (Parkinson's disease, dementia with Lewy bodies, and pure autonomic failure) have predominantly peripheral involvement, whereas multiple system atrophy chiefly manifests as central autonomic failure. Clinical and laboratory features may be useful in distinguishing the different synucleinopathies based on the pattern and severity of autonomic failure. Treatment recommendations are aimed at the underlying pathophysiology and utilize non-pharmacologic and pharmacologic approaches. This review will focus on pathophysiology, clinical manifestations, and management recommendations for autonomic failure including neurogenic orthostatic hypotension, thermoregulatory dysfunction, genitourinary dysfunction, and gastrointestinal dysfunction in the synucleinopathies.

The Treatment of Primary Orthostatic Hypotension

To review the efficacy and safety of pharmacological and nonpharmacological strategies used to treat primary orthostatic hypotension (OH). A literature review using PubMed and MEDLINE databases searching hypotension, non-pharmacological therapy, midodrine, droxidopa, pyridostigmine, fludrocortisone, atomoxetine, pseudoephedrine, and octreotide was performed. Randomized or observational studies, cohorts, case series, or case reports written in English between January 1970 and November 2016 that assessed primary OH treatment in adult patients were evaluated. Based on the chosen criteria, it was found that OH patients make up approximately 15% of all syncope patients, predominantly as a result of cardiovascular or neurological insults, or offending medication. Nonpharmacological strategies are the primary treatment, such as discontinuing offending medications, switching medication administration to bedtime, avoiding large carbohydrate-rich meals, limiting alcohol, maintaining adequate hydration, adding salt to diet, and so on. If these fail, pharmacotherapy can help ameliorate symptoms, including midodrine, droxidopa, fludrocortisone, pyridostigmine, atomoxetine, sympathomimetic agents, and octreotide. Midodrine and droxidopa possess the most evidence with respect to increasing blood pressure and alleviating symptoms. Pyridostigmine and fludrocortisone can be used in patients who fail to respond to these agents. Emerging evidence with low-dose atomoxetine is promising, especially in those with central autonomic failure, and may prove to be a viable alternative treatment option. Data surrounding other therapies such as sympathomimetic agents or octreotide are minimal. Medication management of primary OH should be guided by patient-specific factors, such as tolerability, adverse effects, and drug-drug and drug-disease interactions.

Angiotensin II contributes to sympathetically‐mediated hypertension in autonomic failure (875.4)

Angiotensin (Ang) II contributes to hypertension by direct vasoconstriction, and indirectly by promoting sympathetic activation. The importance of the latter to blood pressure regulation remains controversial, particularly in clinical populations. As a novel approach to test the hypothesis that Ang II promotes sympathetically‐mediated hypertension, we compared depressor responses to the Ang II AT1 receptor antagonist losartan in central autonomic failure (AF) patients in whom supine hypertension is driven by residual sympathetic tone to peripheral AF patients with noradrenergic denervation and sympathetic‐independent hypertension. Single dose losartan (50 mg, PO) was administered at bedtime to 10 peripheral and 7 central AF patients, with supine blood pressure measured q2 hours for 12 hours in a randomized, double‐blind, placebo‐controlled study. There were no differences in plasma Ang II levels between groups (42±3 central vs. 43±5 pg/ml peripheral AF; p=0.734); however, peak depressor responses to losartan were significantly greater in central (‐43±10 mmHg) compared to peripheral AF patients (‐19±8 mmHg; p<0.05). These findings suggest that Ang II contributes to residual sympathetic tone in central autonomic failure, and through this mechanism to hypertension. Overall, these patients provide a unique model to assess the importance of Ang II‐sympathetic interactions in human hypertension.Grant Funding Source: Supported by AHA grant 11POST7330010 and NIH grants HL056693, 5U54NS065736 and UL1TR000445.

Autonomic dysfunction in adult-onset alexander disease

Alexander disease (AxD) is an astrogliopathy, resulting from a mutation in the glial fibrillary astrocytic protein gene. Different clinical subtypes have been described, including infantile, juvenile, and adult onset, based upon the age at which symptoms begin. Patients with the adult-onset form, develop a progressive, spastic paraparesis, palatal myoclonus, ataxia, and bulbar weakness. Autonomic nervous system (ANS) dysfunction has been reported as a potential manifestation of adult-onset AxD, but has not been well characterized. We report a case of adult-onset AxD with symptomatic orthostatic hypotension (OH) and heat intolerance that underwent formal autonomic testing. In addition, a comprehensive literature search was conducted to review the frequency and pattern of autonomic dysfunction in this patient population. A 51-year-old patient was diagnosed with AxD at the age of 47, following an 8-year history of vertigo, intermittent diplopia, and sleep disturbance. The patient developed symptoms of OH, erectile dysfunction, and heat intolerance soon after his diagnosis. Autonomic testing demonstrated OH on tilt-table testing (47mmHg decrease in BP with 18 BPM heart rate increment) with absent late phase II and IV responses during the Valsalva maneuver, severe cardiovagal impairment, and preserved postganglionic sympathetic sudomotor function. These findings were interpreted as being consistent with central autonomic failure. The most common autonomic symptoms reported in other AxD cases include constipation, urinary incontinence, and sphincter dysfunction. To our knowledge, this is the first report of formal autonomic testing in AxD. Signs and symptoms of ANS impairment can occur in patients with AxD, and can include orthostatic hypotension and bowel/bladder dysfunction. Autonomic testing in our patient suggests impairment in central autonomic pathways.

Norepinephrine transporter function and human cardiovascular disease

Approximately 80-90% of the norepinephrine released in the brain or in peripheral tissues is taken up again through the neuronal norepinephrine transporter (NET). Pharmacological studies with NET inhibitors showed that NET has opposing effects on cardiovascular sympathetic regulation in the brain and in the periphery. Furthermore, NET is involved in the distribution of sympathetic activity between vasculature, heart, and kidney. Genetic NET dysfunction is a rare cause of the postural tachycardia syndrome. The condition is characterized by excessive adrenergic stimulation of the heart, particularly with standing. Conversely, NET inhibition may be beneficial in hypoadrenergic states, such as central autonomic failure or neurally mediated syncope, which results from acute sympathetic withdrawal. Biochemical studies suggested reduced NET function in some patients with essential hypertension. Furthermore, cardiac NET function appears to be reduced in common heart diseases, such as congestive heart failure, ischemic heart disease, and stress-induced cardiomyopathy. Whether NET dysfunction is a consequence or cause of progressive heart disease in human subjects requires further study. However, studies with the nonselective NET inhibitor sibutramine suggest that reduced NET function could have an adverse effect on the cardiovascular system. Given the widespread use of medications inhibiting NET, the issue deserves more attention.

Norepinephrine Transporter Blockade With Atomoxetine Induces Hypertension in Patients With Impaired Autonomic Function

Atomoxetine, a selective norepinephrine transporter blocker, could increase blood pressure by elevating norepinephrine concentration in peripheral sympathetic neurons. This effect may be masked in healthy subjects by central sympatholytic mechanisms. To test this hypothesis we studied the pressor effect of 18 mg of atomoxetine (pediatric dose) in 21 patients with damage of the central (10 subjects) and peripheral (11 subjects) autonomic nervous system. Atomoxetine was administered in a randomized, crossover, placebo-controlled fashion, and blood pressure and heart rate were measured at baseline and for 60 minutes after drug intake. Atomoxetine acutely increased seated and standing systolic blood pressure in patients with central autonomic failure by 54+/-26 (mean+/-standard deviation; P=0.004) and 45+/-23 mm Hg (P=0.016), respectively, as compared with placebo. At the end of the observation period the mean seated systolic blood pressure in the atomoxetine group was in the hypertensive range (149+/-26, range 113 to 209 mm Hg). However, in patients with peripheral autonomic failure, atomoxetine did not elicit a pressor response; seated and standing systolic blood pressure increased by 4+/-18 mm Hg (P=0.695) and 0.6+/-8 mm Hg (P=0.546) with atomoxetine as compared with placebo. In conclusion, atomoxetine induces a dramatic increase in blood pressure in patients with central autonomic failure even at very low doses. These findings suggest that a functional central sympatholytic pathway is essential to avoid hypertension in patients treated with this drug. Caution should be exercised when this medication is used in patients with milder form of autonomic impairment.

Contribution of nitric oxide to exercise-induced hypotension in human sympathetic denervation.

The cardiovascular, catecholamine, and nitrate/nitrite (NO) responses to bicycle exercise were measured in 14 normal subjects (controls) and two groups with sympathetic denervation; 14 with peripheral autonomic failure (pure autonomic failure [PAF]); and 13 with central autonomic failure (multiple system atrophy [MSA]). With exercise, blood pressure increased in control subjects by 40 +/- 7/24 +/- 5 mm Hg (p < 0.001) and fell in PAF by 24 +/- 8/24 +/- 5 mm Hg (p < 0.02 and p < 0.007) and MSA by 31 +/- 7/11 +/- 3 mm Hg (p < 0.005 and p < 0.04). With exercise, the increase in heart rate was greater in control subjects (60 +/- 3 to 111 +/- 4/min; p < 0.0001) than in PAF (69 +/- 3 to 86 +/- 4/min; p < 0.0001) and MSA (70 +/- 4 to 90 +/- 4; p < 0.001). Resting plasma noradrenaline levels were similar in controls (291 +/- 51 pg ml(-1)) and MSA (257 +/- 49 pg ml(-1)), but lower in PAF (82 +/- 14 pg ml(-1)). With exercise, plasma noradrenaline increased in controls but was unchanged in PAF and MSA. Resting NOx was similar in controls (50 +/- 5 nmol/L; range, 23.3-87.6 nmol/L) and PAF patients (59+/-8 nmol/l; range, 19.3-116.4 nmol/L), but was higher in MSA patients (87 +/-14 nmol/L; p <0.025, range 15.4-157.2 nmol/L). With exercise, NOx was unchanged in control subjects and increased by 10% and 17% in PAF and MSA, respectively; these changes were not statistically significant. This study suggests that circulating changes in NOx levels do not exert a major role in exercise-induced hypotension in subjects with sympathetic denervation.

Distinction of idiopathic Parkinson's disease from multiple-system atrophy by stimulation of growth-hormone release with clonidine

Idiopathic Parkinson's disease is a common neurodegenerative disease that is difficult to distinguish from other parkinsonian syndromes such as multiple-system atrophy (MSA). In MSA, autonomic dysfunction is common and is associated with either parkinsonian or cerebellar features, or both. Differentiation of idiopathic Parkinson's disease from MSA is important because prognosis, complications, and response to therapy vary according to disorder. Our aim was to find out whether clonidine/growth hormone (GH) testing distinguishes idiopathic Parkinson's disease from MSA. Clonidine is a centrally active alpha 2-adrenoceptor agonist that raises concentrations of GH in serum in healthy people and those with pure autonomic failure (with peripheral lesions), but not in those with MSA (with a central autonomic deficit). We investigated the effects of clonidine on 14 people with idiopathic Parkinson's disease (without autonomic deficits). 31 people with MSA of the three different clinical forms (parkinsonian, cerebellar, and mixed), 19 people with pure autonomic failure, and 27 healthy participants. In nine people with parkinsonian MSA (MSA-P), the GH response to levodopa was also assessed. Clonidine raised serum GH concentrations in patients with idiopathic Parkinson's disease (median increase 8.98 [IQR 6.6-16.6] mU/L), normal participants (13.2 [7.0-18.6] mU/L), and patients with pure autonomic failure (12.5 [5.6-18.2] mU/L). In those with MSA who had central autonomic failure, GH concentrations were unchanged (MSA-P; 0.41 [-0.30 to 2.09] mU/L and cerebellar MSA [MSA-C] 1.67 [0-4.49] mU/L). The GH response to clonidine in idiopathic Parkinson's disease was significantly different from that in MSA-P (p < 0.0002). In MSA-P, the dopamine precursor levodopa raised GH concentrations (from mean 2.7 [SE 1.0] mU/L to mean 18.2 [6.0] mU/L, p < 0.05) and GH-releasing hormone (GHRH) concentrations (from mean 20.6 [3.25] ng/L to mean 68.0 [10.6] ng/L, p < 0.05), excluding dysfunction of pituitary somatotrophs or GHRH neurons as a cause for the absent GH response to clonidine in MSA. The GH responses to clonidine clearly differentiated idiopathic Parkinson's disease from MSA-C and MSA-P. Together with the levodopa studies they indicated a specific alpha 2-adrenoceptor-hypothalamic deficit in MSA. The clonidine-GH test may provide further insight into central neurotransmitter and alpha 2-adrenoceptor-hypothalamic abnormalities in MSA.

Bovril and moclobemide: a novel therapeutic strategy for central autonomic failure

The consumption of tyramine-containing foods is contraindicated in patients on classic monoamine oxidase (MAO) inhibitors. We report successful therapeutic use of moclobemide (a MAO-A selective inhibitor) plus controlled amounts of Bovril (a tyramine-rich yeast-extract available as a food) in a patient with pure central autonomic failure who was rendered bed-bound by severe postural hypotension. Standing blood pressure is now at least 90/45 mm Hg. The selectivity of moclobemide allows about a tenth of ingested tyramine to reach nerve endings and thus the modest hypertensive effect of this combination re-established day-to-day function by restoring normotension.