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Purpose of Review: Multiple system atrophy (MSA) is a rapidly progressive synucleinopathy characterized by autonomic failure, parkinsonism, and cerebellar ataxia. Here, we provide an update on α-synuclein's role in MSA pathophysiology and review the new Movement Disorders Society (MDS) diagnostic criteria and the utility of α-synuclein-based biomarkers. We also highlight ongoing efforts toward clinical trial readiness and review potential disease-modifying therapies undergoing clinical trials., Recent Findings: A role of urinary tract infections in triggering α-synuclein aggregation and contribution of genes implicated in oligodendroglial development have been suggested in the MSA pathophysiology. The clinically probable MSA category of the new diagnostic criteria shows improved accuracy in early disease stages. Predictors of phenoconversion from pure autonomic failure to MSA are now better defined. Alpha-synuclein strains in CSF and serum, phosphorylated α-synuclein deposits in the skin, and brain α-synuclein pathology visualized using PET ligand [18F]ACI-12589 are emerging as valuable diagnostic tools. Clinical trials in MSA investigate drugs targeting α-synuclein aggregation or preventing α-synuclein expression, along with stem cell and gene therapies to halt disease progression., Summary: New MSA diagnostic criteria and α-synuclein-based biomarkers may enhance diagnostic accuracy while promising therapies are in development to address disease progression., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Objectives: Multiple system atrophy (MSA) is a progressive neurodegenerative disorder caused by the abnormal accumulation of α-synuclein in the nervous system. Clinical features include autonomic and motor dysfunction, which overlap with those of Parkinson disease (PD), particularly at early disease stages. There is an unmet need for accurate diagnostic and prognostic biomarkers for MSA and, specifically, a critical need to distinguish MSA from other synucleinopathies, particularly PD. The purpose of the study was to develop a unique cutaneous pathologic signature of phosphorylated α-synuclein that could distinguish patients with MSA from patients with PD and healthy controls., Methods: We studied 31 patients with MSA and 54 patients with PD diagnosed according to current clinical consensus criteria. We also included 24 matched controls. All participants underwent neurologic examinations, autonomic testing, and skin biopsies at 3 locations. The density of intraepidermal, sudomotor, and pilomotor nerve fibers was measured. The deposition of phosphorylated α-synuclein was quantified. Results were compared with clinical rating assessments and autonomic function test results., Results: Patients with PD had reduced nerve fiber densities compared with patients with MSA ( p < 0.05, all fiber types). All patients with MSA and 51/54 with PD had evidence of phosphorylated α-synuclein in at least one skin biopsy. No phosphorylated α-synuclein was detected in controls. Patients with MSA had greater phosphorylated α-synuclein deposition ( p < 0.0001) and more widespread peripheral distribution ( p < 0.0001) than patients with PD. These results provided >90% sensitivity and specificity in distinguishing between the 2 disorders., Discussion: α-synuclein is present in the peripheral autonomic nerves of patients with MSA and when combined with synuclein distribution accurately distinguishes MSA from PD., Classification of Evidence: This study provides Class II evidence that measurement of phosphorylated α-synuclein in skin biopsies can differentiate patients with MSA from those with PD., (© 2023 American Academy of Neurology.)

Purpose of Review: This article reviews the management of orthostatic hypotension with emphasis on neurogenic orthostatic hypotension., Recent Findings: Establishing whether the cause of orthostatic hypotension is a pathologic lesion in sympathetic neurons (ie, neurogenic orthostatic hypotension) or secondary to other medical causes (ie, non-neurogenic orthostatic hypotension) can be achieved by measuring blood pressure and heart rate at the bedside. Whereas fludrocortisone has been extensively used as first-line treatment in the past, it is associated with adverse events including renal and cardiac failure and increased risk of all-cause hospitalization. Distinguishing whether neurogenic orthostatic hypotension is caused by central or peripheral dysfunction has therapeutic implications. Patients with peripheral sympathetic denervation respond better to norepinephrine agonists/precursors such as droxidopa, whereas patients with central autonomic dysfunction respond better to norepinephrine reuptake inhibitors., Summary: Management of orthostatic hypotension is aimed at improving quality of life and reducing symptoms rather than at normalizing blood pressure. Nonpharmacologic measures are the key to success. Pharmacologic options include volume expansion with fludrocortisone and sympathetic enhancement with midodrine, droxidopa, and norepinephrine reuptake inhibitors. Neurogenic supine hypertension complicates management of orthostatic hypotension and is primarily ameliorated by avoiding the supine position and sleeping with the head of the bed elevated.

Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by a combination of autonomic failure, cerebellar ataxia, and parkinsonism. Laryngeal stridor is an additional feature for MSA diagnosis, showing a high diagnostic positive predictive value, and its early occurrence might contribute to shorten survival. A consensus definition of stridor in MSA is lacking, and disagreement persists about its diagnosis, prognosis, and treatment. An International Consensus Conference among experts with methodological support was convened in Bologna in 2017 to define stridor in MSA and to reach consensus statements for the diagnosis, prognosis, and treatment. Stridor was defined as a strained, high-pitched, harsh respiratory sound, mainly inspiratory, occurring only during sleep or during both sleep and wakefulness, and caused by laryngeal dysfunction leading to narrowing of the rima glottidis. According to the consensus, stridor may be recognized clinically by the physician if present at the time of examination, with the help of a witness, or by listening to an audio recording. Laryngoscopy is suggested to exclude mechanical lesions or functional vocal cord abnormalities related to different neurologic conditions. If the suspicion of stridor needs confirmation, drug-induced sleep endoscopy or video polysomnography may be useful. The impact of stridor on survival and quality of life remains uncertain. Continuous positive airway pressure and tracheostomy are both suggested as symptomatic treatment of stridor, but whether they improve survival is uncertain. Several research gaps emerged involving diagnosis, prognosis, and treatment. Unmet needs for research were identified., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: To test whether the plasma levels of norepinephrine (NE) in patients with neurogenic orthostatic hypotension (nOH) predict their pressor response to droxidopa., Methods: This was an observational study, which included patients with nOH. All patients had standardized autonomic function testing including determination of venous plasma catecholamine levels drawn through an indwelling catheter while resting supine. This was followed by a droxidopa titration with 100 mg increments in successive days until relief of symptoms, side effects, or the maximum dose of 600 mg was reached. No response was defined as an increase of <10 mm Hg in systolic blood pressure (BP) after 3-minute standing 1 hour after droxidopa administration. Nonlinear regression models were used to determine the relationship between BP response and plasma NE levels., Results: We studied 20 patients with nOH due to Parkinson disease, pure autonomic failure, multiple system atrophy, or autoimmune autonomic neuropathies. Their supine plasma NE levels ranged from 44 to 850 pg/mL. Lower supine plasma NE levels were associated with greater pressor effect 1 hour after dose (R 2 = 0.49) and higher standing BP (R 2 = 0.45). Patients with no pressor response to droxidopa had higher NE levels (382 ± 100 vs 115 ± 20 pg/mL, p = 0.0014). A supine NE level of <219.5 pg/mL had 83% sensitivity and 93% specificity to predict a pressor response (area under the curve = 0.95, p = 0.0023)., Conclusions: In patients with nOH, lower supine resting plasma NE levels are associated with a greater pressor effect of droxidopa treatment. This finding should help identify patients with nOH most likely to respond to standard doses of droxidopa., Classification of Evidence: This study provides Class I evidence that lower supine plasma NE levels accurately identify patients with nOH more likely to have a greater pressor effect from droxidopa., (© 2018 American Academy of Neurology.)

Multiple system atrophy (MSA) is a rare neurodegenerative disorder with substantial knowledge gaps despite recent gains in basic and clinical research. In order to make further advances, concerted international collaboration is vital. In 2014, an international meeting involving leaders in the field and MSA advocacy groups was convened in Las Vegas, Nevada, to identify critical research areas where consensus and progress was needed to improve understanding, diagnosis, and treatment of the disease. Eight topic areas were defined: pathogenesis, preclinical modeling, target identification, endophenotyping, clinical measures, imaging biomarkers, nonimaging biomarkers, treatments/trial designs, and patient advocacy. For each topic area, an expert served as a working group chair and each working group developed priority-ranked research recommendations with associated timelines and pathways to reach the intended goals. In this report, each groups' recommendations are provided., (Copyright © 2017 American Academy of Neurology.)

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.)

Objective: The purpose of this study was to determine whether carbidopa (Lodosyn), an inhibitor of dopa-decarboxylase that blocks the synthesis of dopamine outside the brain, is an effective antiemetic in patients with familial dysautonomia (FD) and hyperdopaminergic nausea/retching/vomiting attacks., Methods: We enrolled 12 patients with FD in an open-label titration and treatment study to assess the safety of carbidopa. We then conducted a randomized, double-blind, placebo-controlled, crossover study to evaluate its antiemetic efficacy., Results: Previous fundoplication surgery in each patient studied prevented vomiting, but all of the subjects experienced severe cyclical nausea and uncontrollable retching that was refractory to standard treatments. Carbidopa at an average daily dose of 480 mg (range 325-600 mg/day) was well tolerated. In the double-blind phase, patients experienced significantly less nausea and retching while on carbidopa than on placebo (p < 0.03 and p < 0.02, respectively). Twenty-four-hour urinary dopamine excretion was significantly lower while on carbidopa (147 ± 32 µg/gCr) than while on placebo (222 ± 41µg/gCr, p < 0.05)., Conclusions: Carbidopa is a safe and effective antiemetic in patients with FD, likely by reducing the formation of dopamine outside the brain., Classification of Evidence: This study provides Class II evidence that carbidopa is effective in reducing nausea/retching/vomiting in patients with FD.

Background: To define the clinical neuro-ophthalmic abnormalities of patients with familial dysautonomia (FD)., Methods: Sixteen patients (32 eyes) with the clinical and molecular diagnoses of FD underwent thorough neuro-ophthalmic clinical evaluation., Results: Visual acuity ranged from 0.05 to 1.0 decimal units and was reduced in 15 of 16 patients. Mild to moderate corneal opacities were found in most patients but were visually significant in only 2 eyes. Red-green color vision was impaired in almost all cases. Depression of the central visual fields was present on automated visual fields in all patients, even in those with normal visual acuity. Temporal optic nerve pallor was present in all cases and was associated with retinal nerve fiber layer loss in the papillomacular region. Various ocular motility abnormalities also were observed., Conclusion: Patients with FD have a specific type of optic neuropathy with predominant loss of papillomacular nerve fibers, a pattern similar to other hereditary optic neuropathies caused by mutations either in nuclear or in mitochondrial DNA, affecting mitochondrial protein function. Defects of eye movements, particularly saccades, also appear to be a feature of patients with FD.

Background: Familial dysautonomia (FD) is due to a genetic deficiency of the protein IKAP, which affects development of peripheral neurons. Patients with FD display complex abnormalities of the baroreflex of unknown cause., Methods: To test the hypothesis that the autonomic phenotype of FD is due to selective impairment of afferent baroreceptor input, we examined the autonomic and neuroendocrine responses triggered by stimuli that either engage (postural changes) or bypass (cognitive/emotional) afferent baroreflex pathways in 50 patients with FD and compared them to those of normal subjects and to those of patients with pure autonomic failure (PAF), a disorder with selective impairment of efferent autonomic neurons., Results: During upright tilt, in patients with FD and in patients with PAF blood pressure fell markedly but the heart rate increased in PAF and decreased in FD. Plasma norepinephrine levels failed to increase in both groups. Vasopressin levels increased appropriately in patients with PAF but failed to increase in patients with FD. Head-down tilt increased blood pressure in both groups but increased heart rate only in patients with FD. Mental stress evoked a marked increase in blood pressure and heart rate in patients with FD but little change in those with PAF., Conclusion: The failure to modulate sympathetic activity and to release vasopressin by baroreflex-mediated stimuli together with marked sympathetic activation during cognitive tasks indicate selective failure of baroreceptor afference. These findings indicate that IKAP is critical for the development of afferent baroreflex pathways and has therapeutic implications in the management of these patients.

Objective: To test the hypothesis that panic disorder (PD) patients have a heightened or deregulated autonomic nervous system at rest and during autonomic challenge compared with healthy controls (HC); and to test a second hypothesis that severity of illness differentiates patients'; sympathovagal balance both at rest and during orthostatic challenge., Methods: Spectral analysis of heart rate (HR) and blood pressure was performed on 30 PD and 10 HC participants during an orthostatic challenge (head-up tilt)., Results: PD patients presented higher HR (p < .001), lower heart rate variability (HRV) (p < .015), higher mean diastolic blood pressure (p < .006), higher low-frequency component of HR (p < .001), and a higher ratio of low-frequency to high-frequency component of HR (LF/HF) (p < .022) than HC at baseline. During tilt, PD patients responded with higher HR (p < .039), lower HRV (p < .043), increased mean diastolic blood pressure (p < .028), and a mild increase in LF/HF, whereas controls responded with a five-fold increase in LF/HF (p < .022). Patients with higher illness severity ratings (Clinical Global Impression Scale) showed higher HR (p < .002), lower HRV (p < .026), and a lower total power of systolic blood pressure (p < .02) compared with less ill patients., Conclusion: These findings demonstrate a consistently higher or deregulated autonomic arousal in PD patients at rest and during orthostatic challenge compared with HC. These data also reveal a possible association between the level of anxiety illness severity and sympathovagal balance, which may imply greater cardiac risk.

To clarify whether the R3 component of the electrically elicited blink reflex is a nociceptive response we studied two patients with congenital insensitivity to pain due to the impaired development of Adelta and C nerve fibers (hereditary sensory and autonomic neuropathy types III and IV). We postulated that if the R3 component is a nociceptive reflex, it should be absent in these patients. The R3 responses were elicited in both sides in both the patients at all intensities, strongly suggesting that the R3 component of the blink reflex is not a nociceptive response.

Background: A consensus conference on multiple system atrophy (MSA) in 1998 established criteria for diagnosis that have been accepted widely. Since then, clinical, laboratory, neuropathologic, and imaging studies have advanced the field, requiring a fresh evaluation of diagnostic criteria. We held a second consensus conference in 2007 and present the results here., Methods: Experts in the clinical, neuropathologic, and imaging aspects of MSA were invited to participate in a 2-day consensus conference. Participants were divided into five groups, consisting of specialists in the parkinsonian, cerebellar, autonomic, neuropathologic, and imaging aspects of the disorder. Each group independently wrote diagnostic criteria for its area of expertise in advance of the meeting. These criteria were discussed and reconciled during the meeting using consensus methodology., Results: The new criteria retain the diagnostic categories of MSA with predominant parkinsonism and MSA with predominant cerebellar ataxia to designate the predominant motor features and also retain the designations of definite, probable, and possible MSA. Definite MSA requires neuropathologic demonstration of CNS alpha-synuclein-positive glial cytoplasmic inclusions with neurodegenerative changes in striatonigral or olivopontocerebellar structures. Probable MSA requires a sporadic, progressive adult-onset disorder including rigorously defined autonomic failure and poorly levodopa-responsive parkinsonism or cerebellar ataxia. Possible MSA requires a sporadic, progressive adult-onset disease including parkinsonism or cerebellar ataxia and at least one feature suggesting autonomic dysfunction plus one other feature that may be a clinical or a neuroimaging abnormality., Conclusions: These new criteria have simplified the previous criteria, have incorporated current knowledge, and are expected to enhance future assessments of the disease.

The authors report a 46-year-old woman with antibodies to the nicotinic acetylcholine receptor (NiAchR) of the autonomic ganglia. She presented with severe orthostatic intolerance refractory to treatment with midodrine, fludrocortisone, erythropoietin, vasopressin, salt, and fluid loading. Addition of L-threo-3,4-dihidroxyphenylserine (L-DOPS) substantially improved blood pressure and orthostatic tolerance. L-DOPS may benefit patients with severe orthostatic intolerance and be particularly effective in patients with ganglionic NiAchR antibodies.

The authors report the clinical and postmortem neuropathologic findings of two patients, one with Parkinson disease (PD) and one with dementia with Lewy bodies (DLB), both of whom initially sought treatment for isolated autonomic failure. These cases suggest that neurodegeneration in PD and DLB may begin outside the CNS in autonomic postganglionic neurons, a finding with potential diagnostic and therapeutic implications.

Background: In patients with neurogenic orthostatic hypotension (NOH), the availability of the sympathetic neurotransmitter norepinephrine (NE) in the synaptic cleft is insufficient to maintain blood pressure while in the standing posture., Methods and Results: We determined the effect of oral administration of the synthetic amino acid L-threo-3,4-dihydroxyphenylserine (L-DOPS), which is decarboxylated to NE by the enzyme L-aromatic amino acid decarboxylase (L-AADC) in neural and nonneural tissue, on blood pressure and orthostatic tolerance in 19 patients with severe NOH (8 with pure autonomic failure and 11 with multiple-system atrophy). A single-blind dose-titration study determined the most appropriate dose for each patient. Patients were then enrolled in a double-blind, placebo-controlled, crossover trial. L-DOPS significantly raised mean blood pressure both supine (from 101+/-4 to 141+/-5 mm Hg) and standing (from 60+/-4 to 100+/-6 mm Hg) for several hours and improved orthostatic tolerance in all patients. After L-DOPS, blood pressure increases were closely associated with increases in plasma NE levels. Oral administration of carbidopa, which inhibits L-AADC outside the blood-brain barrier, blunted both the increase in plasma NE and the pressor response to L-DOPS in all patients, Conclusions: Acute administration of L-DOPS increases blood pressure and improves orthostatic tolerance in patients with NOH. The pressor effect results from conversion of L-DOPS to NE outside the central nervous system.

Background: Syncope is caused by a severe but reversible reduction in blood flow to the brain stem neurons responsible for supporting consciousness (reticular activating system). Neurally mediated syncope, also referred to as vasovagal or reflex syncope, is the most frequent cause of loss of consciousness in apparently normal subjects., Review Summary: Neurally mediated syncope is believed to be a reflex response with afferent, central, and efferent pathways. Characteristic autonomic changes in neurally mediated syncope are an increase in parasympathetic efferent activity causing bradycardia and a reduction in sympathetic vasoconstrictor outflow causing vasodilatation. Premonitory symptoms, such as nausea, diaphoresis, abdominal discomfort, and blurred vision, are caused by autonomic activation and are distinguishing features of neurally mediated syncope. Neurally mediated syncope frequently has a characteristic trigger, although this may not be apparent. Testing orthostatic tolerance during passive head-up tilt is the best available diagnostic procedure to evaluate patients with syncope in whom a cardiac cause has been excluded. In many cases, once the diagnosis of neurally mediated syncope is confirmed, it may suffice to reassure the patient and teach him to avoid known triggers and to recognize and act upon early warning symptoms. Because subjects with neurally mediated syncope may potentially be sodium depleted, increasing salt intake can be beneficial in improving their orthostatic intolerance., Conclusions: Neurally mediated syncope is the most common form of syncope in healthy adults. The best diagnostic tools are the clinical history and passive head-up tilt. The best treatment strategies are the avoidance of triggering factors as well as intravascular volume expansion.

Background: Primary palmar hyperhidrosis is characterized by excessive sweating due to increased sympathetic cholinergic sudomotor nerve traffic to the palmar surface of the hands. Clinical studies suggest that intradermal injections of botulinum toxin are effective in the treatment of palmar hyperhidrosis., Objectives: To establish the effectiveness of intradermal botulinum toxin in reducing hyperhidrosis, to determine the most effective dose of toxin, and to examine its effect on muscle strength., Methods: In a prospective, single blind, randomized trial, 24 patients with severe palmar hyperhidrosis received either a low (50 U) or a high dose (100 U) of botulinum toxin type A (Botox, Allergan) injected intradermally in 20 sites in each palm., Results: Following injection with either dose, iodine starch test revealed a significant decrease in sweating within the first month. Six months after injection, the anhidrotic effect was still evident in two thirds of the patients in both groups. Handgrip strength was not affected with either dose but finger pinch strength, 2 weeks after the injection, decreased 23 +/- 27% with 50 U (p < 0.05) and 40 +/- 21% with 100 U (p < 0.001). Pinch strength improved gradually but 6 months after treatment it was still 7-11% lower than at baseline., Conclusions: Both 50 and 100 U of botulinum toxin type A, injected intradermally in each hand, decreased sweating in patients with primary hyperhidrosis for at least 2 months in all the patients, and 6 months in most patients. Weakness in the intrinsic muscles of the hand was observed.

Although the precise definition of multiple system atrophy has been difficult, a recent consensus in diagnostic criteria for multiple system atrophy has been achieved. This should lead to progress in defining the underlying pathophysiology of the neuroendocrine, autonomic and motor deficits characteristic of multiple system atrophy. Hopefully, these developments will lead to effective treatment.

Syncope is a transient loss of consciousness and postural tone caused by a global reduction of blood flow to the brain. Abnormalities in autonomic cardiovascular control can impair blood supply to the brain and produce syncope in two different disorders: autonomic failure and neurally mediated syncope. In autonomic failure, sympathetic efferent activity is chronically impaired so that vasoconstriction is deficient, upon standing blood pressure always falls (i.e., orthostatic hypotension), and syncope or presyncope occurs. Conversely, in neurally mediated syncope, the failure of sympathetic efferent vasoconstrictor traffic (and hypotension) occurs episodically and in response to a trigger. Between syncopal episodes, patients with neurally mediated syncope have normal blood pressure and orthostatic tolerance. This article reviews the characteristics of autonomic failure and describes in more detail the pathophysiology, diagnosis, and treatment of neurally mediated syncope.

Neurally mediated syncope is the most frequent cause of syncope in patients who do not have structural heart disease. Neurally mediated syncope is believed to be a reflex triggered by excessive afferent discharge from mechanoreceptors located in the arterial tree or viscera, particularly the left ventricle of the heart. In response to these signals, a CNS-mediated sudden rise in parasympathetic efferent activity occurs, causing relative or absolute bradycardia and sympathoinhibition with arterial vasodilation and hypotension. Although our understanding of the pathophysiology of this syndrome is still incomplete, it is well established that sympathetic nerve activity and norepinephrine release fall inappropriately during neurally mediated syncope, whereas appropriate increases in plasma concentrations of epinephrine, angiotensin II, vasopressin, and endothelin-1 occur. Recent studies from our laboratory suggest that synthesis of the vasodilator nitric oxide increases during neurally mediated syncope. This suggests that nitric oxide-mediated arterial vasodilation could contribute to the profound hypotension characteristic of this syndrome. The diagnosis of neurally mediated syncope can be made with acceptable levels of specificity and sensitivity by the upright tilt test. Explaining the mechanisms responsible for arterial vasodilation in neurally mediated syncope may lead to effective treatment.

To investigate whether activation of afferent and central baroreceptor pathways could differentiate between pure autonomic failure (PAF) and multiple system atrophy with autonomic failure (MSA), we determined the effect of upright tilt on circulating levels of vasopressin in patients with PAF and patients with MSA. We also studied 14 normal subjects, nine of whom developed acute hypotension due to vasovagal syncope. In patients with PAF and in normal subjects with vasovagal syncope, upright tilt induced marked hypotension and a pronounced increase in the plasma concentration of vasopressin (1.1 +/- 0.3 to 38.0 +/- 8.0 pmol/l in PAF and 1.0 +/- 0.2 to 27.4 +/- 7.2 pmol/l in vasovagal syncope, p less than 0.005 for both). In patients with MSA, upright tilt also elicited profound hypotension but circulating levels of vasopressin increased little (0.5 +/- 0.1 to 1.5 +/- 0.3 pmol/l, p less than 0.05). During upright tilt, the plasma concentration of norepinephrine significantly increased in normal subjects but did not increase in patients with autonomic failure. Our results indicate that afferent and central baroreceptor pathways involved in vasopressin release are normal in patients with PAF but are impaired in patients with MSA. Thus, measurement of baroreceptor-mediated vasopressin release appears to provide a clear marker to differentiate between patients with PAF and patients with MSA.

To investigate whether excessive circulating levels of atrial natriuretic factor (ANF) are responsible for orthostatic hypotension and nocturnal polyuria in patients with autonomic failure, we determined the circadian variation in the plasma concentration of ANF as well as the response of this peptide to changes in posture and extracellular fluid volume in patients with autonomic failure. We found that the plasma concentration of ANF was significantly lower in patients with autonomic failure than in controls. Patients with autonomic failure had a significantly higher urinary sodium excretion during the night (8 PM to 8 AM) than during the day (8 AM to 8 PM), and the plasma concentration of ANF significantly decreased during the night in these patients, indicating that high circulating levels of ANF were not the cause of the nocturnal natriuresis. Furthermore, circulating levels of ANF responded appropriately to reductions in right atrial pressure induced by head-up tilt and extracellular fluid volume changes induced by mineralocorticoid administration. These results indicate that exaggerated circulating levels of ANF are not responsible for the orthostatic hypotension or nocturnal natriuresis in patients with autonomic failure, and that appropriate regulation of ANF occurs in patients with autonomic failure.

The therapeutic efficacy of midodrine, an alpha-adrenergic agonist that does not cross the blood-brain barrier, was investigated in a double-blind crossover trial in seven patients with orthostatic hypotension due to autonomic failure. We identified two groups of patients: those in whom upright mean arterial pressure significantly increased (group I, n = 3) and those in whom upright mean arterial pressure decreased (group II, n = 4) during midodrine treatment. Body weight changed in a parallel manner with upright blood pressure, increasing in patients of group I and decreasing in patients of group II (p less than 0.05). Autonomic cardiovascular reflexes were significantly more impaired in patients of group II than in patients of group I. We conclude that midodrine is effective in the treatment of orthostatic hypotension only in those patients with significant preservation of autonomic reflexes. Conversely, in patients with markedly impaired baroreceptor mechanisms, treatment with midodrine may produce extracellular fluid volume depletion and exacerbate orthostatic hypotension.

Dopamine release into the extracellular space was measured with in vivo electrochemical detection in the ipsilateral and contralateral striata in Mongolian gerbils that suffered a stroke after acute unilateral carotid artery ligations. A sevenfold increase in the dopamine signal occurred within 15 minutes of carotid ligation in the ischemic side, while the unlesioned side had no significant change. Increased extracellular levels of dopamine persisted throughout the 3-hour recording period. Pretreatment with alpha-methyl-p-tyrosine 6 hours prior to recording significantly attenuated the signal increase. This study is the first direct demonstration of the marked, continuous dopamine release that occurs during acute cerebral ischemia.