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Context: Hypoglycemia-associated autonomic failure (HAAF), defined as blunting of counterregulatory hormone and symptom responses to recurrent hypoglycemia, remains a therapeutic challenge in diabetes treatment. The opioid system may play a role in HAAF pathogenesis since activation of opioid receptors induces HAAF. Blockade of opioid receptors with intravenous naloxone ameliorates HAAF experimentally yet is not feasible therapeutically., Objective: To investigate the effects of opioid receptor blockade with intranasal naloxone on experimentally induced HAAF., Design: Randomized, double-blinded, placebo-controlled crossover study., Setting: Academic research center., Participants: Healthy nondiabetic volunteers., Interventions: Paired 2-day studies, 5 to 10 weeks apart, each consisting of 3 consecutive hypoglycemic episodes (hyperinsulinemic hypoglycemic clamps, glucose nadir: 54 mg/dL): 2 on day 1 with administration of intranasal naloxone vs placebo, followed by the third episode on day 2., Main Outcome Measures: Differences in counterregulatory hormones responses and hypoglycemia symptoms between first and third hypoglycemic episodes in naloxone vs placebo studies., Results: Out of 17 participants, 9 developed HAAF, confirming variable interindividual susceptibility. Among participants susceptible to HAAF, naloxone maintained some hormonal and symptomatic responses to hypoglycemia and prevented the associated requirement for increased glucose infusion. Unexpectedly, naloxone reduced plasma epinephrine and GH responses to the first hypoglycemic episode but prevented further reduction with subsequent hypoglycemia., Conclusion: This is the first study to report that intranasal naloxone, a widely used opioid receptor antagonist, may ameliorate some features of HAAF. Further investigation is warranted into mechanisms of variable interindividual susceptibility to HAAF and the effects of intranasal naloxone in people with diabetes at risk for HAAF., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Background and Purpose: Pure autonomic failure (PAF) presents primarily as cardiovascular autonomic failure and may phenoconvert to other neurodegenerative disorders. However, the involvement of other autonomic functions has been poorly evaluated. This study aims to characterize genitourinary and bowel dysfunction and explore their relationship with cardiovascular autonomic dysfunction., Methods: Pure autonomic failure patients underwent cardiovascular autonomic testing and an assessment of pelvic autonomic dysfunction using urinary, sexual symptoms questionnaires and a bladder diary. Demographic, clinical features and related medical comorbidities were assessed., Results: Twenty-five patients (10 males) with PAF were included (mean age 71 ± 8 years; disease duration 13 ± 8 years). 96% (24/25) reported lower urinary tract symptoms, of which overactive bladder symptoms were most commonly reported (n = 23; 92%; median overactive subscore 8, interquartile range [IQR] 3-11), followed by voiding difficulties (n = 19; 76%; median low stream subscore 2, IQR 1-3) using the Urinary Symptom Profile; however, only four (16%) required clean intermittent self-catheterization. Sexual dysfunction was common (n = 21; 84%) using the Arizona Sexual Experience Scale. Mild faecal incontinence and constipation were reported. 86% (19/22) had nocturnal polyuria (NP) and the median NP index was 47% (IQR 38%-51%; normal range <33%). 77% (10/13) had voiding dysfunction and 31% (4/13) had post-void residual urine >100 mL. There were no significant correlations between the need for catheterization and the degree of NP with age, disease duration and cardiovascular autonomic parameters (p > 0.05)., Conclusions: Nocturnal polyuria, genitourinary and bowel symptoms are commonly seen in PAF. The pathophysiology of NP in PAF is most likely multifactorial and may occur independent of cardiovascular autonomic failure., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Autonomic failure is frequently encountered in synucleinopathies such as multiple system atrophy (MSA), Parkinson's disease (PD), Lewy body disease, and pure autonomic failure (PAF). Cardiovascular autonomic failure affects quality of life and can be life threatening due to the risk of falls and the increased incidence of myocardial infarction, stroke, and heart failure. In PD and PAF, pathogenic involvement is mainly post-ganglionic, while in MSA, the involvement is mainly pre-ganglionic. Cardiovascular tests exploring the autonomic nervous system (ANS) are based on the analysis of continuous, non-invasive recordings of heart rate and digital blood pressure (BP). They assess facets of sympathetic and parasympathetic activities and provide indications on the integrity of the baroreflex arc. The tilt test is widely used in clinical practice. It can be combined with catecholamine level measurement and analysis of baroreflex activity and cardiac variability for a detailed analysis of cardiovascular damage. MIBG myocardial scintigraphy is the most sensitive test for early detection of autonomic dysfunction. It provides a useful measure of post-ganglionic sympathetic fiber integrity and function and is therefore an effective tool for distinguishing PD from other parkinsonian syndromes such as MSA. Autonomic cardiovascular investigations differentiate between certain parkinsonian syndromes that would otherwise be difficult to segregate, particularly in the early stages of the disease. Exploring autonomic failure by gathering information about residual sympathetic tone, low plasma norepinephrine levels, and supine hypertension can guide therapeutic management of orthostatic hypotension (OH)., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Pure autonomic failure (PAF) is a neurodegenerative disease affecting the sympathetic component of the autonomic nervous system and presenting as orthostatic hypotension (OH). It is a rare, sporadic disease of adults. Although OH is the primary symptom, the autonomic dysfunction may be more generalised, leading to genitourinary and intestinal dysfunction and sweating disorders. Autonomic symptoms in PAF may be similar to those observed in other autonomic neuropathies that need to be ruled out. PAF belongs to the group of α synucleinopathies and is characterised by predominant peripheral deposition of α-synuclein in autonomic ganglia and nerves. However, in a significant number of cases, PAF may convert into another synucleinopathy with central nervous system involvement with varying prognosis: Parkinson's disease (PD), multiple system atrophy (MSA), or dementia with Lewy bodies (DLB). The clinical features, the main differential diagnoses, the risk factors for "phenoconversion" to another synucleinopathy as well as an overview of treatment will be discussed., (Copyright © 2023. Published by Elsevier Masson SAS.)

Purpose: Pure autonomic failure (PAF) is a rare disease characterized by neurogenic orthostatic hypotension (nOH), no known secondary cause, and lack of a neurodegenerative movement or cognitive disorder. Clinically diagnosed PAF can evolve ("phenoconvert") to a central Lewy body disease [LBD, e.g., Parkinson's disease (PD) or dementia with Lewy bodies (DLB)] or to the non-LBD synucleinopathy multiple system atrophy (MSA). Since cardiac 18 F-dopamine-derived radioactivity usually is low in LBDs and usually is normal in MSA, we hypothesized that patients with PAF with low cardiac 18 F-dopamine-derived radioactivity would be more likely to phenoconvert to a central LBD than to MSA., Methods: We reviewed data from all the patients seen at the National Institutes of Health Clinical Center from 1994 to 2023 with a clinical diagnosis of PAF and data about 18 F-dopamine positron emission tomography (PET)., Results: Nineteen patients (15 with low 18 F-dopamine-derived radioactivity, 4 with normal radioactivity) met the above criteria and had follow-up data. Nine (47%) phenoconverted to a central synucleinopathy over a mean of 6.6 years (range 1.5-18.8 years). All 6 patients with low cardiac 18 F-dopamine-derived radioactivity who phenoconverted during follow-up developed a central LBD, whereas none of 4 patients with consistently normal 18 F-dopamine PET phenoconverted to a central LBD (p = 0.0048), 3 evolving to probable MSA and 1 upon autopsy having neither a LBD nor MSA., Conclusion: Cardiac 18 F-dopamine PET can predict the type of phenoconversion of PAF. This capability could refine eligibility criteria for entry into disease-modification trials aimed at preventing evolution of PAF to symptomatic central LBDs., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Aim: This study explores the burden of caring for an individual with neurogenic orthostatic hypotension (nOH) and an underlying neurodegenerative disease (Parkinson's disease, multiple system atrophy, pure autonomic failure or dementia with Lewy bodies). Materials & methods: A survey including several validated instruments was conducted with informal caregivers of individuals with Parkinson's disease, multiple system atrophy, pure autonomic failure or dementia with Lewy bodies. Results: Caregivers of patients with nOH (n = 60) reported greater burden across all outcomes compared with those without nOH (n = 60). Receiving pharmacological treatment for nOH was the variable most consistently associated with significantly better caregiver health-related quality-of-life (p < 0.05). Conclusion: This study demonstrates the burden of nOH on informal caregivers and highlights the potential benefit of pharmacological treatment not only for patients but also indirectly, their caregivers.

Over the past century, generations of neuroscientists, pathologists, and clinicians have elucidated the underlying causes of autonomic failure found in neurodegenerative, inherited, and antibody-mediated autoimmune disorders, each with pathognomonic clinicopathologic features. Autonomic failure affects central autonomic nervous system components in the α-synucleinopathy, multiple system atrophy, characterized clinically by levodopa-unresponsive parkinsonism or cerebellar ataxia, and pathologically by argyrophilic glial cytoplasmic inclusions (GCIs). Two other central neurodegenerative disorders, pure autonomic failure characterized clinically by deficits in norepinephrine synthesis and release from peripheral sympathetic nerve terminals; and Parkinson's disease, with early and widespread autonomic deficits independent of the loss of striatal dopamine terminals, both express Lewy pathology. The rare congenital disorder, hereditary sensory, and autonomic neuropathy type III (or Riley-Day, familial dysautonomia) causes life-threatening autonomic failure due to a genetic mutation that results in loss of functioning baroreceptors, effectively separating afferent mechanosensing neurons from the brain. Autoimmune autonomic ganglionopathy caused by autoantibodies targeting ganglionic α3-acetylcholine receptors instead presents with subacute isolated autonomic failure affecting sympathetic, parasympathetic, and enteric nervous system function in various combinations. This chapter is an overview of these major autonomic disorders with an emphasis on their historical background, neuropathological features, etiopathogenesis, diagnosis, and treatment., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Pure autonomic failure (PAF) is a rare disease in which chronic neurogenic orthostatic hypotension (nOH) dominates the clinical picture. Longitudinal studies have reported that PAF can phenoconvert to a central synucleinopathy with motor or cognitive involvement-i.e., to Parkinson disease (PD), dementia with Lewy bodies (DLB), or multiple system atrophy (MSA). These studies have classified patients clinically as having PAF based on nOH without an identified secondary cause or clinical evidence of motor or cognitive impairment due to central neurodegeneration. This approach lumps together two nOH syndromes that are pathologically and neurochemically distinct. One is characterized by intraneuronal cytoplasmic alpha-synuclein aggregates (i.e., Lewy bodies) and degeneration of postganglionic sympathetic neurons, as in PD and DLB; the other is not, as in MSA. Clinical and postmortem data show that the form of PAF that involves sympathetic intraneuronal synucleinopathy and noradrenergic deficiency can phenoconvert to PD or DLB-but not to MSA. Conversely, PAF without these features leaves open the possibility of premotor MSA., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Pure autonomic failure is a neurodegenerative disorder affecting the autonomic nervous system which clinically presents with orthostatic hypotension. It is a diagnosis of exclusion after detailed clinical examinations and relevant investigations. Here, we discuss a case of 68 years old male who had complaints of multiple episodes of loss of consciousness on standing from a sitting position for the last 3 years. The diagnosis was considered by clinical examinations revealing autonomic dysfunctions with normal appropriate investigations. The patient was treated successfully with midodrine, fludrocortisone, and other non-pharmacological interventions. We focused on doing various autonomic dysfunction tests in the evaluation of a patient with recurrent orthostatic hypotension. We suspect that pure autonomic failure might not have been considered in the differential diagnosis of recurrent orthostatic hypotension and suggest that it is to be kept as a differential in such a scenario. Midodrine has an effective role in syncope due to sympathetic vasoconstrictor failure.

Background Supine hypertension affects a majority of patients with autonomic failure; it is associated with end-organ damage and can worsen daytime orthostatic hypotension by inducing pressure diuresis and volume loss during the night. Because sympathetic activation prevents blood pressure (BP) from falling in healthy subjects exposed to heat, we hypothesized that passive heat had a BP-lowering effect in patients with autonomic failure and could be used to treat their supine hypertension. Methods and Results In Protocol 1 (n=22), the acute effects of local heat (40-42°C applied with a heating pad placed over the abdomen for 2 hours) versus sham control were assessed in a randomized crossover fashion. Heat acutely decreased systolic BP by -19±4 mm Hg (versus 3±4 with sham, P <0.001) owing to decreases in stroke volume (-18±5% versus -4±4%, P =0.013 ) and cardiac output (-15±5% versus -2±4%, P =0.013). In Protocol 2 (proof-of-concept overnight study; n=12), we compared the effects of local heat (38°C applied with a water-perfused heating pad placed under the torso from 10 pm to 6 am) versus placebo pill. Heat decreased nighttime systolic BP (maximal change -28±6 versus -2±6 mm Hg, P <0.001). BP returned to baseline by 8 am. The nocturnal systolic BP decrease correlated with a decrease in urinary volume ( r =0.57, P =0.072) and an improvement in the morning upright systolic BP ( r =-0.76, P =0.007). Conclusions Local heat therapy effectively lowered overnight BP in patients with autonomic failure and supine hypertension and offers a novel approach to treat this condition. Future studies are needed to assess the long-term safety and efficacy in improving nighttime fluid loss and daytime orthostatic hypotension. Registration URL: https://www.clinicaltrials.gov; Unique identifiers: NCT02417415 and NCT03042988.

Neurogenic orthostatic hypotension (OH) is a disabling disorder caused by impairment of the normal autonomic compensatory mechanisms that maintain upright blood pressure. Nonpharmacologic treatment is always the first step in the management of this condition, but a considerable number of patients will require pharmacologic therapies. Denervation hypersensitivity and impairment of baroreflex buffering makes these patients sensitive to small doses of pressor agents. Understanding the underlying pathophysiology can help in selecting between treatment options. In general, patients with low "sympathetic reserve", i.e., those with peripheral noradrenergic degeneration (pure autonomic failure, Parkinson's disease) and low plasma norepinephrine, tend to respond better to "norepinephrine replacers" (midodrine and droxidopa). On the other hand, patients with relatively preserved "sympathetic reserve", i.e., those with impaired central autonomic pathways but spared peripheral noradrenergic fibers (multiple system atrophy) and normal or slightly reduced plasma norepinephrine, tend to respond better to "norepinephrine enhancers" (pyridostigmine, atomoxetine, and yohimbine). There is, however, a spectrum of responses within these extremes, and treatment should be individualized. Other nonspecific treatments include fludrocortisone and octreotide. The presence of associated clinical conditions, such as supine hypertension, heart failure, postprandial hypotension, PD, MSA, and diabetes need to be considered in the pharmacologic management of these patients., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Pure autonomic failure (PAF) is a neurodegenerative disorder of the autonomic nervous system clinically characterized by orthostatic hypotension. The disorder has also been known as Bradbury-Eggleston syndrome, named for the authors of the 1925 seminal description. Patients typically present in midlife or later with orthostatic hypotension or syncope. Autonomic failure may also manifest as genitourinary, bowel, and thermoregulatory dysfunction. With widespread involvement, patients may present to a variety of different specialties and require multidisciplinary treatment approaches. Pathologically, PAF is characterized by predominantly peripheral deposition of α-synuclein. However, patients with PAF may progress into other synucleinopathies with central nervous system involvement., (Copyright © 2019 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Pure autonomic failure (PAF) is a progressive syndrome of neurogenic orthostatic hypotension, widespread anhidrosis, urinary retention, and constipation without other neurologic manifestations. It is generally considered a peripheral ganglionic synucleinopathy. Natural history studies have described risk factors for the conversion of PAF to Parkinson's disease, multiple system atrophy, or dementia with Lewy bodies, yet the early stages of PAF are not well characterized. We present a patient with unilateral anhidrosis, contralateral facial flushing and hyperhidrosis consistent with Harlequin syndrome that, over 6 years, progressed to PAF, suggesting that PAF may present with focal autonomic impairment prior to generalized autonomic failure., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Rapid eye movement sleep behavior disorder is characterized by dream enactment and complex motor behaviors during rapid eye movement sleep and rapid eye movement sleep atonia loss (rapid eye movement sleep without atonia) during polysomnography. Rapid eye movement sleep behavior disorder may be idiopathic or symptomatic and in both settings is highly associated with synucleinopathy neurodegeneration, especially Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and pure autonomic failure. Rapid eye movement sleep behavior disorder frequently manifests years to decades prior to overt motor, cognitive, or autonomic impairments as the presenting manifestation of synucleinopathy, along with other subtler prodromal "soft" signs of hyposmia, constipation, and orthostatic hypotension. Between 35% and 91.9% of patients initially diagnosed with idiopathic rapid eye movement sleep behavior disorder at a sleep center later develop a defined neurodegenerative disease. Less is known about the long-term prognosis of community-dwelling younger patients, especially women, and rapid eye movement sleep behavior disorder associated with antidepressant medications. Patients with rapid eye movement sleep behavior disorder are frequently prone to sleep-related injuries and should be treated to prevent injury with either melatonin 3-12 mg or clonazepam 0.5-2.0 mg to limit injury potential. Further evidence-based studies about rapid eye movement sleep behavior disorder are greatly needed, both to enable accurate prognostic prediction of end synucleinopathy phenotypes for individual patients and to support the application of symptomatic and neuroprotective therapies. Rapid eye movement sleep behavior disorder as a prodromal synucleinopathy represents a defined time point at which neuroprotective therapies could potentially be applied for the prevention of Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and pure autonomic failure. © 2017 International Parkinson and Movement Disorder Society., (© 2017 International Parkinson and Movement Disorder Society.)

We describe the case of a man whose initial clinical presentation included sensorineural hearing loss and orthostatic hypotension. The patient was diagnosed with superficial siderosis associated with peripheral autonomic failure and tetraventricular hydrocephalus.

The long-term safety of droxidopa for the treatment of symptomatic neurogenic orthostatic hypotension in patients with Parkinson disease, pure autonomic failure, multiple system atrophy, or nondiabetic autonomic neuropathy was evaluated in a phase 3, multinational, open-label study in patients who previously participated in a double-blind, placebo-controlled clinical trial of droxidopa. A total of 350 patients received droxidopa 100 to 600 mg three times daily. Mean duration of droxidopa exposure was 363 days (range, 2-1133 days). Rates of serious adverse events (AEs), cardiac-related AEs, and supine hypertension were 24%, 5%, and 5%, respectively. Most AEs, including those of a cardiovascular nature, were not attributed by investigators to droxidopa. In this large cohort of patients with neurogenic orthostatic hypotension, droxidopa was well tolerated during long-term use., (Copyright © 2016 The Author. Published by Elsevier Inc. All rights reserved.)

Primary autonomic failure is characterized by disabling orthostatic hypotension, but at least half of these patients have paradoxical supine hypertension. Renin-angiotensin mechanisms were not initially thought to contribute to this hypertension because plasma renin activity is often undetectable in autonomic failure. Plasma aldosterone levels are normal, however, and we recently showed that plasma angiotensin II is elevated and acts at AT1 (angiotensin type 1) receptors to contribute to hypertension in these patients. Because aldosterone and angiotensin II can also bind mineralocorticoid receptors to elevate blood pressure, we hypothesized that mineralocorticoid receptor activation plays a role in the hypertension of autonomic failure. To test this hypothesis, we determined the acute effects of the mineralocorticoid receptor antagonist eplerenone (50 mg, oral) versus placebo on supine blood pressure in a randomized, double-blind, crossover study. Medications were given at 8:00 pm with blood pressure recorded every 2 hours for 12 hours. Ten primary autonomic failure patients with supine hypertension completed this study (7 pure autonomic failure, 2 multiple system atrophy, 1 parkinson's disease; 7 male; 70±2 years of age). Eplerenone maximally reduced supine systolic blood pressure by 32±6 mm Hg at 8 hours after administration (versus 8±10 mm Hg placebo, P=0.016), with no effect on nocturia (12-hour urine volume: 985±134 mL placebo versus 931±94 mL eplerenone, P=0.492; nocturnal weight loss: -1.19±0.15 kg placebo versus -1.18±0.15 kg eplerenone, P=0.766). These findings suggest that inappropriate mineralocorticoid receptor activation contributes to the hypertension of autonomic failure, likely independent of canonical mineralocorticoid effects, and provides rationale for use of eplerenone in these patients., (© 2015 American Heart Association, Inc.)

Patients with autonomic failure are characterized by orthostatic hypotension, supine hypertension, high blood pressure variability, blunted heart rate variability, and often have a "non-dipping" or "reverse dipping" pattern on 24-h ambulatory blood pressure monitoring. These alterations may lead to cardiovascular and cerebrovascular changes, similar to the target organ damage found in hypertension. Often patients with autonomic failure are on treatment with anti-hypotensive drugs, which may worsen supine hypertension. The aim of this review is to summarize the evidence for cardiac, vascular, renal, and cerebrovascular damage in patients with autonomic failure.

The clinical presentation of autonomic failure is orthostatic hypotension. Severely affected patients require pharmacological treatment to prevent presyncopal symptoms or frank syncope. We previously reported in a proof of concept study that pediatric doses of the norepinephrine transporter blockade, atomoxetine, increases blood pressure in autonomic failure patients with residual sympathetic activity compared with placebo. Given that the sympathetic nervous system is maximally activated in the upright position, we hypothesized that atomoxetine would be superior to midodrine, a direct vasoconstrictor, in improving upright blood pressure and orthostatic hypotension-related symptoms. To test this hypothesis, we compared the effect of acute atomoxetine versus midodrine on upright systolic blood pressure and orthostatic symptom scores in 65 patients with severe autonomic failure. There were no differences in seated systolic blood pressure (means difference=0.3 mm Hg; 95% confidence [CI], -7.3 to 7.9; P=0.94). In contrast, atomoxetine produced a greater pressor response in upright systolic blood pressure (means difference=7.5 mm Hg; 95% CI, 0.6 to 15; P=0.03) compared with midodrine. Furthermore, atomoxetine (means difference=0.4; 95% CI, 0.1 to 0.8; P=0.02), but not midodrine (means difference=0.5; 95% CI, -0.1 to 1.0; P=0.08), improved orthostatic hypotension-related symptoms as compared with placebo. The results of our study suggest that atomoxetine could be a superior therapeutic option than midodrine for the treatment of orthostatic hypotension in autonomic failure., (© 2014 American Heart Association, Inc.)

Patients with autonomic failure experience orthostatic hypotension (OH) often leading to syncope. Arrhythmias may cause severe syncope, characterized by an increased risk of mortality. We report two cases of patients with primary autonomic neuropathy suffering from both severe OH and arrhythmic syncope.

Objective: To determine whether droxidopa, an oral norepinephrine precursor, improves symptomatic neurogenic orthostatic hypotension (nOH)., Methods: Patients with symptomatic nOH due to Parkinson disease, multiple system atrophy, pure autonomic failure, or nondiabetic autonomic neuropathy underwent open-label droxidopa dose optimization (100-600 mg 3 times daily), followed, in responders, by 7-day washout and then a 7-day double-blind trial of droxidopa vs placebo. Outcome measures included patient self-ratings on the Orthostatic Hypotension Questionnaire (OHQ), a validated, nOH-specific tool that assesses symptom severity and symptom impact on daily activities., Results: From randomization to endpoint (n = 162), improvement in mean OHQ composite score favored droxidopa over placebo by 0.90 units (p = 0.003). Improvement in OHQ symptom subscore favored droxidopa by 0.73 units (p = 0.010), with maximum change in "dizziness/lightheadedness." Improvement in symptom-impact subscore favored droxidopa by 1.06 units (p = 0.003), with maximum change for "standing a long time." Mean standing systolic blood pressure (BP) increased by 11.2 vs 3.9 mm Hg (p < 0.001), and mean supine systolic BP by 7.6 vs 0.8 mm Hg (p < 0.001). At endpoint, supine systolic BP >180 mm Hg was observed in 4.9% of droxidopa and 2.5% of placebo recipients. Adverse events reported in ≥ 3% of double-blind droxidopa recipients were headache (7.4%) and dizziness (3.7%). No patients discontinued double-blind treatment because of adverse events., Conclusions: In patients with symptomatic nOH, droxidopa improved symptoms and symptom impact on daily activities, with an associated increase in standing systolic BP, and was generally well tolerated., Classification of Evidence: This study provides Class I evidence that in patients with symptomatic nOH who respond to open-label droxidopa, droxidopa improves subjective and objective manifestation of nOH at 7 days., (© 2014 American Academy of Neurology.)

The report presents a case of a 46-year-old male patient, previously treated because of dysphagia, pyrosis, vertigo while standing up and impotency. Manometric and pH-metric analysis showed presence of gastroesophageal reflux disease (GERD) caused by transient relaxation of lower esophageal sphincter (TRLES). Heart-rate variability showed decreased sympathetic function. Electromyoneurography showed a neurological lesion in muscles of upper extremities. The patient received midodrine and clonazepam which resolved this condition. These findings suggest that a neurological disorder can be a cause of GERD.

In pure autonomic failure (PAF) - a rare form of primary dysautonomia - some patients show cerebrovascular lesions usually found in hypertensive subjects. In an autonomic laboratory records of patients with a definitive diagnosis of PAF having had cerebral imaging (cMRI, cCT) were analysed retrospectively. Tilt table data (supine/tilted), 24 hour blood pressure recordings (day/night) and serum catecholamine levels were correlated with cerebrovascular lesions and also compared to published normal values. 50 PAF patients (23 female, 27 male) were identified, mean age 67 years (sd 9.5). Out of these 35 (70%) had pathologic cerebral scans showing white matter lesions (WML) in 30, lacunar strokes in 5 and hemispheric stroke and microbleeds each in 1. Age and supine systolic blood pressure were significantly elevated in patients with pathologic scans (70 compared to 61 years [p=0.007], and 170 compared to 154 mmHg [p=0.045]). Out of 28 patients with WML and ambulatory blood pressure recordings available 24 were non-dippers. The data show that the frequency of WML is lower in PAF patients aged 60 to 80 years compared to age matched community based samples. Although PAF usually results in hypotension, a frequent complication is supine hypertension. Although the overall frequency of WML seems to be reduced in PAF, a number of patients with elevated supine systolic blood pressure (>160 mmHg) develop WML and some of these suffer stroke., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Pure autonomic failure (PAF) is a progressive autonomic neurodegenerative disorder. Cold induced sweating occurred in syndromes with mutations in CRLF1 and CLCF1 genes and in a case of cervical dissection. A patient with PAF developed sweating induced by cool ambient temperatures. He had severe orthostatic hypotension, abnormal cardiovagal reflexes, and paradoxical sweating in the upper trunk at a room temperature of 18°C. Skin biopsy showed involvement of somatic epidermal unmyelinated nerve fibers. Quantitative sensory testing showed abnormal thresholds to all thermal modalities. Possible mechanisms include cold induced noradrenaline release in remaining autonomic innervation and a supersensitive sudomotor response., (Copyright © 2013 Elsevier B.V. All rights reserved.)

A syncope evaluation should start by identifying potentially life-threatening causes, including valvular heart disease, cardiomyopathies, and arrhythmias. Most patients who present with syncope, however, have the more benign vasovagal (reflex) syncope. A busy syncope practice often also sees patients with neurogenic orthostatic hypotension presenting with syncope or severe recurrent presyncope. Recognition of these potential confounders of syncope might be difficult without adequate knowledge of their presentation, and this can adversely affect optimal management. This article reviews the presentation of the vasovagal syncope confounder and the putative pathophysiology of orthostatic hypotension, and suggests options for nonpharmacologic and pharmacologic management., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Cardiovascular autonomic failure is the second most common dysautonomic feature of α-synucleinopathies and has significant impact on daily activities and quality of life. Here we provide a systematic review of cardiovascular autonomic failure in α-synucleinopathies, emphasizing its impact on cognitive functions and disease outcomes. Articles spanning the period between January 1985 and April 2012 were identified from the PubMed database using a keyword-based search. Epidemiological studies highlight the negative prognostic effect of cardiovascular autonomic failure on cardiovascular and cerebrovascular outcomes and overall mortality in all α-synucleinopathies. Altered cerebral perfusion, vascular pressure stress, and related disruption of the blood-brain barrier may also contribute to the white matter hyperintensities and cognitive dysfunction frequently found in patients affected by neurocardiovascular instability. These findings support the hypothesis that cardiovascular autonomic failure may play a negative prognostic role in α-synucleinopathies and suggest that precocious screening and therapeutic management of cardiovascular autonomic failure may positively impact disease course., (© 2012 The Author(s) European Journal of Neurology © 2012 EFNS.)

Autoimmune autonomic ganglionopathy is a syndrome of panautonomic failure caused by antibodies to ganglionic acetylcholine receptors. The clinical syndrome is characterized by significant postural hypotension, diffuse cholinergic and adrenergic impairment, gastrointestinal dysmotility, urinary retention, and pupillary dysfunction. While acute to subacute onset of disease is commonly seen, chronic, slowly progressive variants have been described. Serological testing for ganglionic acetylcholine receptor antibodies helps confirm the diagnosis. These antibodies cause a similar phenotype of autonomic failure in animal models indicating that an antibody-mediated functional impairment of ganglionic transmission is the underlying etiology. Decrease in antibody levels correlates with clinical improvement. Patients may respond to immunomodulatory therapies such as prednisone, intravenous immunoglobulin, plasma exchange, and oral immunosuppressants. A combination treatment is often required as well as symptomatic therapy., (© 2013 Elsevier B.V. All rights reserved.)

A 1925 report by Bradbury and Eggleston first described patients with extreme orthostatic hypotension and a low, steady heart rate. Evidence accumulated over the next two decades that patients with orthostatic hypotension include those with pure autonomic failure (PAF), characterized by isolated peripheral autonomic dysfunction and decreased norepinephrine synthesis; multiple system atrophy (MSA) with symptoms of a central Parkinson-like syndrome and normal resting plasma norepinephrine; and Parkinson's disease (PD), with lesions in postganglionic noradrenergic neurons and signs of autonomic dysfunction. All three disorders are classified as α-synucleinopathies. Insoluble deposits of α-synuclein are found in glia in MSA, whereas they take the form of neuronal cytoplasmic inclusions called Lewy bodies in PAF and PD. The exact relationship between α-synuclein deposits and the pathology remains undetermined. PAF occurs sporadically, and progresses slowly with a relatively good prognosis. However, it has been proposed that some cases of PAF may develop a central neurodegenerative disorder. Differentiation between PAF, MSA, and PD with autonomic failure can be facilitated by a number of biochemical and functional tests and by imaging studies. Cardiac sympathetic innervation is generally intact in MSA but decreased or absent in Parkinson's disease with autonomic failure and PAF. Treatment of PAF is directed at relieving symptoms with nonpharmacological interventions and with medications producing volume expansion and vasoconstriction. Future studies should focus on determining the factors that lead to central rather than solely peripheral neurodegeneration., (© 2013 Elsevier B.V. All rights reserved.)

A cardinal manifestation of chronic autonomic failure is neurogenic orthostatic hypotension (OH), which often is associated with supine hypertension, posing a therapeutic dilemma. We report here success in a first step toward development of a "prosthetic baroreceptor system" to maintain blood pressure during orthostasis without worsening supine hypertension. In all of four patients with neurogenic OH, titrated i.v. NE infusion kept directly recorded intra-arterial pressure at or above baseline during progressive head-up tilt. We conclude that titrated i.v. NE infusion temporarily eliminates OH.

The clinical picture of autonomic failure is characterized by severe and disabling orthostatic hypotension. These disorders can develop as a result of damage of central neural pathways or peripheral autonomic nerves, caused either by a primary autonomic neurodegenerative disorder or secondary to systemic illness. Treatment should be focused on decreasing pre-syncopal symptoms instead of achieving blood pressure goals. Non-pharmacologic strategies such as physical counter-maneuvers, dietary changes (i.e. high salt diet, rapid water drinking or compression garments) are the first line therapy. Affected patients should be screened for co-morbid conditions such as post-prandial hypotension and supine hypertension that can worsen orthostatic hypotension if not treated. If symptoms are not controlled with these conservative measures the next step is to start pharmacological agents; these interventions should be aimed at increasing intravascular volume either by promoting water and salt retention (fludrocortisone) or by increasing red blood cell mass when anemia is present (recombinant erythropoietin). When pressor agents are needed, direct pressor agents (midodrine) or agents that potentiate sympathetic activity (atomoxetine, yohimbine, pyridostigmine) can be used. It is preferable to use short-acting pressor agents that can be taken on as needed basis in preparation for upright activities., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The sympathetic nervous system regulates thermogenesis and energy homeostasis in humans. When activated it increases energy expenditure, particularly resting energy expenditure. Most human studies used acute infusion of β-blockers as a model to eliminate sympathetic stimulation and to examine the contribution of the sympathetic nervous system to energy metabolism and balance. Clinically, however, it is also important to assess the effect of chronic sympathetic attenuation on energy metabolism. In this context, we hypothesized that resting energy expenditure is decreased in patients with autonomic failure who, by definition, have low sympathetic tone. We measured 24-hour energy expenditure using whole-room indirect calorimeter in 10 adults with chronic autonomic failure (6 women; age, 64.9±9.1 years; body mass index, 25.2±4.4 kg/m(2)) and 15 sedentary healthy controls of similar age and body composition (8 women; age, 63.1±4.0 years; body mass index, 24.4±3.9 kg/m(2)). In 4 patients, we eliminated residual sympathetic activity with the ganglionic blocker trimethaphan. We found that, after adjusting for body composition, resting energy expenditure did not differ between patients with autonomic failure and healthy controls. However, resting energy expenditure significantly decreased when residual sympathetic activity was eliminated. Our findings suggest that sympathetic tonic support of resting energy expenditure is preserved, at least in part, in pathophysiological models of chronic sympathetic attenuation.

The pure autonomic failure is a rare entity, with only a few cases reported in the literature. The authors describe a case with compensatory excessive sweating of the right hemithorax as an initial manifestation of a pure autonomic failure, and the authors review the clinical characteristics of this disease. A 69-year-old man presented excessive sweating of the right hemithorax. Physical examination revealed orthostatic hypotension. No other neurological features were present. The autonomic study showed a low heart rate response to the Valsalva maneuver and reduced supine plasma norepinephrine levels. A pure autonomic failure was diagnosed. Treatment did not improve patient's symptoms. Anhidrosis with asymmetrical compensatory hyperhidrosis can be the only symptom of a pure autonomic failure. The authors highlight an unusual form of presentation of a rare disease, difficult to diagnose if it is not taken into consideration.

Objective: To compare odor identification function in patients with peripheral or central autonomic neurodegeneration and in patients with intact autonomic neurons but undetectable norepinephrine., Methods: Olfactory function was evaluated with the University of Pennsylvania Smell Identification Test (UPSIT) in 12 patients with pure autonomic failure, 10 patients with multiple system atrophy, and 4 patients with dopamine β-hydroxylase deficiency. Blood pressure and catecholamine data were also compared., Results: Odor identification was significantly impaired in patients with pure autonomic failure relative to patients with multiple system atrophy or dopamine β-hydroxylase deficiency. Out of 40 odors, the patients correctly identified mean (95% confidence interval) 19.2 (14.1 to 24.2), 34.4 (32.2 to 36.6), and 31.7 (29.4 to 34.1) (p < 0.001). The difference between patients with pure autonomic failure and those with multiple system atrophy or dopamine β-hydroxylase deficiency persisted after adjustment for age (p = 0.001). Patients with pure autonomic failure also had a greater orthostatic fall in blood pressure and lower plasma norepinephrine levels than patients with multiple system atrophy., Conclusions: Olfactory function was relatively intact in patients with dopamine β-hydroxylase deficiency, who have intact noradrenergic neurons but lack norepinephrine. Odor identification was impaired in pure autonomic failure but not in multiple system atrophy, suggesting that 1) peripheral noradrenergic innervation is important for olfactory identification but norepinephrine is not essential and 2) UPSIT may be useful in the differential diagnosis between these disorders.

Orthostatic hypotension affects patients with autonomic failure producing considerable disability because of presyncopal symptoms. Severely affected patients may have residual sympathetic tone that can be engaged to increase blood pressure (BP) with the α-2 adrenergic antagonist yohimbine. This medication activates sympathetic outflow centrally and unrestrains norepinephrine release from noradrenergic neurons. Alternatively, the acetylcholinesterase inhibitor, pyridostigmine, can increase sympathetic tone by improving ganglionic cholinergic neurotransmission. Our purpose was to compare these complementary approaches and to explore whether the combination would lead to synergistic increases in BP. We compared the effects of 60 mg of pyridostigmine and 5.4 mg of yohimbine in a single-blind, randomized, placebo-controlled, crossover fashion. In a subset of patients we tested the combination of pyridostigmine and yohimbine. Our primary outcome was the change in standing diastolic BP 60 minutes after drug administration from baseline. We studied a total of 31 patients with severe autonomic failure. Yohimbine significantly improved standing diastolic BP as compared with placebo (11±3 mm Hg [95% CI: 6 to 16 mm Hg]; P<0.001). On the contrary, pyridostigmine did not increase the standing diastolic BP (0.6±3 mm Hg [95% CI: -5 to 5 mm Hg]; P=0.823). Only yohimbine showed a significant improvement in presyncopal symptoms. Sixteen patients received the combination of pyridostigmine and yohimbine, but no evidence of synergistic pressor effect was found. Engaging residual sympathetic tone with yohimbine is a more effective approach to improve orthostatic hypotension as compared with pyridostigmine in patients with severe orthostatic hypotension.

There are three diseases classified as primary autonomic failure (PAF), multiple system atrophy, Parkinson's disease, pure autonomic failure. Compensatory mechanisms preventing from decrease in blood pressure are inefficient in PAF. Among half of the patients with PAF occur orthostatic hypotension (OH) and supine hypertension (SH), which are the cause of deterioration of life quality. The treatment is based on modification of lifestyle and pharmacotherapy. Drugs used in OH may exacerbate SH and vice versa.

We present a case report of severe autonomic failure in a 43-year-old well-controlled HIV patient. Clinical and pharmacological autonomic function testing supported the diagnosis of peripheral autonomic failure. Simple physiological manoeuvres substantially improved symptoms.

Objective: Chronic autonomic failure (CAF), as in Parkinson disease (PD), multiple system atrophy (MSA), and pure autonomic failure (PAF), typically entails baroreflex failure, neurogenic orthostatic hypotension (NOH), and supine hypertension. The combination might predispose to cardiac ectopy, which in turn might predispose to syncope and falls during manipulations decreasing venous return to the heart. This study assessed whether CAF is associated with an increased prevalence of cardiac ectopy., Methods: Recordings lasting > or = 15 min of the electrocardiogram, beat-to-beat heart rate, and continuous blood pressure were reviewed from a total of 97 CAF patients (34 PD + NOH, 48 MSA, 15 PAF) and 82 control subjects (41 PD without NOH, 33 non-parkinsonian patients, 8 healthy volunteers). Cardiac ectopy was considered present if there were at least two premature beats or an arrhythmia., Results: Atrial ectopy was found in 74% of patients with PD + NOH, 68% with MSA, and 63% with PAF, prevalences 2-3 times those in PD without NOH (28%, p < 0.0001) or other controls (24%, p < 0.0001). Atrial ectopy was related to subject age (p < 0.0001), supine systolic pressure (p < 0.0001), and the orthostatic fall in systolic pressure (p = 0.0007) and inversely with baroreflex-cardiovagal gain (p = 0.005) and the orthostatic increment in plasma norepinephrine (p = 0.0004). In two PD + NOH patients, atrial ectopy was associated with documented sustained hypotension after the Valsalva maneuver; and in an MSA patient, acute atrial flutter/fibrillation was associated with sudden loss of consciousness., Interpretation: CAF patients have a relatively high frequency of atrial ectopy, which might interact with baroreflex failure to increase morbidity from orthostatic hypotension.

Leg crossing increases arterial pressure and combats symptomatic orthostatic hypotension in patients with sympathetic failure. This study compared the central and cerebrovascular effects of leg crossing in patients with sympathetic failure and healthy controls. We addressed the relationship between MCA Vmean (middle cerebral artery blood velocity; using transcranial Doppler ultrasound), frontal lobe oxygenation [O2Hb (oxyhaemoglobin)] and MAP (mean arterial pressure), CO (cardiac output) and TPR (total peripheral resistance) in six patients (aged 37-67 years; three women) and age- and gender-matched controls during leg crossing. In the patients, leg crossing increased MAP from 58 (42-79) to 72 (52-89) compared with 84 (70-95) to 90 (74-94) mmHg in the controls. MCA Vmean increased from 55 (38-77) to 63 (45-80) and from 56 (46-77) to 64 (46-80) cm/s respectively (P<0.05), with a larger rise in O2Hb [1.12 (0.52-3.27)] in the patients compared with the controls [0.83 (-0.11 to 2.04) micromol/l]. In the control subjects, CO increased 11% (P<0.05) with no change in TPR. By contrast, in the patients, CO increased 9% (P<0.05), but also TPR increased by 13% (P<0.05). In conclusion, leg crossing improves cerebral perfusion and oxygenation both in patients with sympathetic failure and in healthy subjects. However, in healthy subjects, cerebral perfusion and oxygenation were improved by a rise in CO without significant changes in TPR or MAP, whereas in patients with sympathetic failure, cerebral perfusion and oxygenation were improved through a rise in MAP due to increments in both CO and TPR.

Background: Olfactory dysfunction and autonomic failure are gaining recognition as nonmotor manifestations of Parkinson disease (PD). This observational study assessed whether in PD anosmia and autonomic failure are related to each other or to neuroimaging evidence of striatal dopamine deficiency., Methods: Olfactory function was assessed by the University of Pennsylvania Smell Identification Test (UPSIT) in 23 patients with sporadic PD. Baroreflex-cardiovagal gain was quantified from the relationship between cardiac interbeat interval and systolic pressure during the Valsalva maneuver and baroreflex-sympathoneural function by responses of systolic pressure to the Valsalva maneuver and of hemodynamics and plasma norepinephrine (NE) and dihydroxyphenylglycol (DHPG) levels to orthostasis. 6-[(18)F]Fluorodopamine PET and plasma and skeletal muscle microdialysate NE and DHPG were used to indicate cardiac and extracardiac noradrenergic innervation and brain 6-[(18)F]fluorodopa PET to indicate striatal dopaminergic innervation. Parkinsonism was assessed by UPDRS scores., Results: Compared to patients with PD and normal to moderately decreased sense of smell, patients with anosmic PD had lower mean baroreflex-cardiovagal gain (p = 0.04), larger falls in systolic pressure during the Valsalva maneuver and orthostasis (p = 0.04, p = 0.02), smaller orthostatic increments in plasma NE and DHPG (p = 0.003, p = 0.03), lower cardiac septal:hepatic and renal cortical:hepatic ratios of 6-[(18)F]fluorodopamine-derived radioactivity (p = 0.01, p = 0.06), and lower microdialysate NE and DHPG (p = 0.01; p = 0.006). Neither clinical severity of parkinsonism nor the putamen:occipital cortex ratio of 6-[(18)F]fluorodopa-derived radioactivity was related to the UPSIT category., Conclusions: In Parkinson disease, anosmia is associated with baroreflex failure and cardiac and organ-selective extracardiac noradrenergic denervation, independently of parkinsonism or striatal dopaminergic denervation.

Supine hypertension is difficult to manage in patients with pure autonomic failure (PAF), because treatment can worsen orthostatic hypotension. Supine hypertension in PAF has been associated with left ventricular hypertrophy, but end organ damage in the kidney has not been assessed. We reviewed hemodynamic and laboratory data of 64 male patients with PAF who were 69+/-11 (mean+/-SD) years old. Systolic blood pressure fell by 67+/-40 mm Hg within 10 minutes of standing, with an inappropriately low 13+/-11-bpm increase in heart rate. Plasma norepinephrine levels were below normal (0.62+/-0.32 nmol/L supine and 1.28+/-1.25 nmol/L standing). A control data set of 75 men (67+/-12 years) was obtained from a deidentified version of the Vanderbilt University Medical Center electronic medical chart database. Compared with controls, PAF patients had lower hemoglobin (8.3+/-0.9 versus 9.3+/-0.8 mmol/L; P<0.001), packed cell volume (0.40+/-0.04 versus 0.45+/-0.04; P<0.001), and red blood cell count (4.4+/-0.5 x 10(12) versus 5.0+/-0.5 x 10(12) cells/L; P<0.001). Serum creatinine and blood urea nitrogen levels were elevated in patients. Forty-eight percent of patients with PAF had supine hypertension (supine systolic blood pressure: > or = 150 mm Hg). Serum creatinine was higher in patients with supine hypertension (133+/-44 versus 106+/-27 micromol/L; P=0.021) and estimated glomerular filtration rate was lower (57+/-22 versus 70+/-20 mL/min per 1.73 m2; P=0.022) compared with patients who did not have supine hypertension. These findings may indicate that renal function is diminished in PAF in association with supine hypertension.

Background: Pure autonomic failure (PAF) and Parkinson disease (PD) both are Lewy body diseases, and both entail substantia nigra dopaminergic, locus ceruleus noradrenergic, and cardiac sympathetic denervation. Multiple system atrophy (MSA) is a non-Lewy body disease in which alpha-synuclein accumulates in glial cells, with central catecholamine deficiency but preserved cardiac sympathetic innervation in most patients. PD is associated with more severe and consistent olfactory dysfunction than in MSA; whether PAF entails olfactory dysfunction has been unknown. In this study we assessed olfactory function in PAF in comparison with the two other synucleinopathies and whether olfactory dysfunction correlates with neuroimaging evidence of cardiac noradrenergic or nigrostriatal dopaminergic denervation., Method: The University of Pennsylvania Smell Identification Test (UPSIT) was administered to 8 patients with PAF, 23 with PD, and 20 with MSA. 6-[(18)F]Fluorodopamine positron emission tomographic (PET) scanning was used to indicate cardiac noradrenergic innervation and the putamen:occipital cortex (PUT:OCC) and substantia nigra (SN):OCC ratios of 6-[(18)F]fluorodopa-derived radioactivity to indicate nigrostriatal dopaminergic innervation., Results: The PAF group had a low mean UPSIT score (22+/-3), similar to that in PD (20+/-2) and lower than in MSA (31+/-2, p=0.004). Individual UPSIT scores correlated positively with cardiac 6-[(18)F]fluorodopamine-derived radioactivity (r=0.63 in the septum, p<0.0001; r=0.64 in the free wall, p<0.0001) but not with PUT:OCC or SN:OCC ratios of 6-[(18)F]fluorodopa-derived radioactivity., Discussion: In synucleinopathies, olfactory dysfunction is related to Lewy body pathology and cardiac sympathetic denervation, independently of parkinsonism or striatal dopamine deficiency.

A 73-year-old man with severe orthostatic hypotension was scheduled for open cholecystectomy. His blood pressure was 126/80 mmHg in the supine position and 50/30 mmHg in the upright posture. Preoperative autonomic function tests suggested that postsynaptic fibers of the sympathetic nervous system were impaired, and the disorder was probably due to pure autonomic failure. Anesthesia was induced with thiamylal and vecuronium, and maintained with sevoflurane (3%) and fentanyl (100 microg). Epidural anesthesia was used in the latter half of the operation. Meticulous use of vasoactive drugs such as dopamine and phenylephrine as well as adequate maintenance of systemic blood volume by infusion of a crystalloid solution enabled his hemodynamic condition to become stable during anesthesia.