Faculty Bibliography

OBJECTIVE: The susceptibility to suffer neurally mediated syncope and loss of consciousness varies markedly. In addition to vasodilatation and bradycardia, hyperventilation precedes loss of consciousness. The resultant hypocapnia causes cerebral vasoconstriction and peripheral vasodilatation. We postulate that more pronounced cerebral and peripheral vascular responses to reductions in arterial CO(2) levels underlie greater susceptibility to neurally mediated syncope. METHODS: We compared vascular responses to CO(2) among 31 patients with histories of recurrent neurally mediated syncope and low orthostatic tolerance and 14 age- and sex-matched control subjects with no history of syncope and normal orthostatic tolerance. Vascular responses to CO(2) were calculated after all subjects had fully recovered and their blood pressures and heart rates were stable. We measured blood flow velocity in the middle cerebral artery (transcranial Doppler) and in the left brachial artery (brachial Doppler), and end-tidal CO(2) during voluntary hyperventilation and hypoventilation (end-tidal CO(2) from 21-45mm Hg), and determined the slopes of the relations. RESULTS: Hypocapnia produced a significantly greater reduction in cerebral blood flow velocity and in forearm vascular resistance in patients with neurally mediated syncope than in control subjects. Opposite changes occurred in response to hypercapnia. In all subjects, the changes in cerebral blood flow velocity and forearm vasodilatation were inversely related with orthostatic tolerance. INTERPRETATION: Susceptibility to neurally mediated syncope can be explained, at least in part, by enhanced cerebral vasoconstriction and peripheral vasodilatation in response to hypocapnia. This may have therapeutic implications. Ann Neurol 2007

Neurogenic orthostatic hypotension results from failure to release norepinephrine, the neurotransmitter of sympathetic postganglionic neurons, appropriately upon standing. In double blind, cross over, placebo controlled trials, administration of droxidopa, a synthetic amino acid that is decarboxylated to norepinephrine by the enzyme L: -aromatic amino acid decarboxylase increases standing blood pressure, ameliorates symptoms of orthostatic hypotension and improves standing ability in patients with neurogenic orthostatic hypotension due to degenerative autonomic disorders. The pressor effect results from conversion of droxidopa to norepinephrine outside the central nervous system both in neural and non-neural tissue. This mechanism of action makes droxidopa effective in patients with central and peripheral autonomic disorders

Orthostatic intolerance with orthostatic hypotension and syncope are disabling features of patients with disorders of autonomic cardiovascular control. The hallmark of both central and peripheral autonomic disorders is the failure of the sympathetic postganglionic neurons to release norepinephrine appropriately upon standing. Impaired norepinephrine release is permanent in patients with autonomic failure, and upon standing, blood pressure always falls. On the other hand, in patients with neurally mediated syncopal syndromes (also known as vasovagal, vasodepressor, or reflex syncope) impaired norepinephrine release occurs episodically, typically in response to a trigger. Between syncopal episodes, patients with neurally mediated syncope usually have normal blood pressure and orthostatic tolerance. Orthostatic intolerance without a fall in blood pressure, but with a pronounced increase in heart rate, occurs in the postural tachycardia syndrome, a puzzling disorder with several possible causes characterized by excessive sympathetic activation in response to physiologic stimuli. The distinction between these disorders is important because their prognosis and management is different. Autonomic failure can be severely disabling, while neurally mediated syncopal syndromes and the postural tachycardia syndrome are always benign. Patient education is key to managing these disorders. Several simple measures should be implemented to improve orthostatic tolerance prior to pharmacologic intervention

Autonomic failure is a frequent feature of two types of neurodegenerative disorders-multiple system atrophy and the Lewy body syndromes, which include Parkinson's disease, pure autonomic failure, and dementia with Lewy bodies. These disorders are known collectively as synucleinopathies because accumulations of the protein alpha-synuclein are found intracellularly in the brains of affected patients. Other neurodegenerative disorders, including the amyloidopathies or tauopathies (eg, Alzheimer's disease, progressive supranuclear palsy, frontotemporal dementia, sporadic and inherited ataxias, and prion diseases), only rarely entail clinically significant autonomic failure

Muscle sympathetic nerve activity (MSNA) is modulated on a beat-to-beat basis by the baroreflex. Vestibular input from the otolith organs also modulates MSNA, but characteristics of the vestibulo-sympathetic reflex (VSR) are largely unknown. The purpose of this study was to elicit the VSR with electrical stimulation to estimate its latency in generating MSNA. The vestibular nerves of seven subjects were stimulated across the mastoids with short trains of high frequency, constant current pulses. Pulse trains were delivered every fourth heartbeat at delays of 300-700 ms after the R wave of the electrocardiogram. Vestibular nerve stimulation given 500 ms after the R wave significantly increased baroreflex-driven MSNA, as well as the diastolic blood pressure threshold at which bursts of MSNA occurred. These changes were specific to beats in which vestibular stimulation was applied. Electrical stimulation across the shoulders provided a control condition. When trans-shoulder trials were subtracted from trials with vestibular nerve stimulation, eliminating the background baroreflex-driven sympathetic activity, there was a sharp increase in MSNA beginning 660 ms after the vestibular nerve stimulus and lasting for about 60 ms. The increase in the MSNA produced by vestibular nerve stimulation, and the associated increase in the diastolic blood pressure threshold at which the baroreflex-driven bursts occurred, provide evidence for the presence of a short-latency VSR in humans that is likely to be important for the maintenance of blood pressure during rapid changes in head and body position with respect to gravity