PROGRESS IN CARDIOVASCULAR DISEASES 55 (2013) 345– 356 Available online at www.sciencedirect.com www.onlinepcd.com Pathophysiological Basis of Syncope and Neurological Conditions that Mimic Syncope J. Gert van Dijka,⁎, Wouter Wielingb aDepartment of Neurology, Leiden University Medical Center, Leiden, The Netherlands bDepartment of Internal Medicine, Academic Medical Center, University of Amsterdam, The Netherlands ARTICLE INFO ABSTRACT Keywords: The definition of syncope has clinical and pathophysiological parts. The clinical part is that Syncope syncope is a form of transient loss of consciousness (TLOC), while the pathophysiological Transient loss of consciousness element is that syncope differs from other forms of TLOC by virtue of the basis of true Pathophysiology syncope – specifically cerebral hypoperfusion. As such, the signs and symptoms of syncope Hypoperfusion rely on three steps, starting with the cause of syncope and including the response of the systemic circulation and neurological effects. The causes of syncope all result in low blood pressure through low peripheral resistance and/or low cardiac output. The next step is the cerebral circulation, which is a large-volume and low-resistance system, characterized by relatively high diastolic flow. The cerebral circulation is usually protected against swings in arterial pressure by cerebral autoregulation, but in abrupt syncope, autoregulation acts too slowly to have much effect. In syncope, diastolic flow velocity is more impaired than systolic flow velocity, probably because closing vascular forces then opposes flow. The third step concerns neurological signs and symptoms; the cerebral cortex first responds by disruption of normal activity, followed by a complete cessation of activity when hypoperfusion deepens. The latter is likely when there is asystole or marked bradycardia. The neurological signs and symptoms suggest different principles: a loss of normal cortical activity, abnormal cortical activity and activity due to disinhibition of brainstem activity. © 2013 Elsevier Inc. All rights reserved. The importance of pathophysiology in understanding synco- Consequently, while it may seem counterproductive to use a pe is emphasized by its inclusion in the definition as the one pathophysiological criterion to define a clinical entity, it is item that sets syncope apart from all other forms of transient essential to do so in this case for at least two reasons. The first loss of consciousness (TLOC). In essence, syncope is TLOC due is that there is no practical way to define clinical criteria that to transient global cerebral hypoperfusion, characterized by encompass all expressions of syncope and also exclude rapid onset, short duration and spontaneous complete epileptic seizures and psychogenic TLOC. For example, the 1 recovery (Fig 1). following items can be present or absent in syncope: pallor, Except for cerebral hypoperfusion, the clinical features nausea, opening of the eyes, incontinence and myoclonic associated with syncope are shared by all three major TLOC jerks. The second is that without a criterion specific to groups: syncope, epileptic seizures and psychogenic TLOC. syncope it becomes impossible to distinguish it from other Statement of Conflict of Interest: see page 354. ⁎ Address reprint requests to J. Gert van Dijk, MD, PhD, Professor of Clinical Neurophysiology, Department of Neurology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands. E-mail address: [email protected] (J.G. van Dijk). 0033-0620/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pcad.2012.10.016 346 PROGRESS IN CARDIOVASCULAR DISEASES 55 (2013) 345– 356 Abbreviations and Acronyms forms of TLOC and briefly touches upon the pathophysiology of epileptic sei- thereby develop ap- zures and psychogenic TLOC. CBF = cerebral blood flow propriate treatment EEG = electroencephalogram options.2 Pathophysiological Key factors in cerebral perfusion ESC = European Society of knowledge helps cli- Cardiology nicians understand The human brain is an expensive organ; even at rest it requires 15 MAP = mean arterial pressure the nature of signs to 20% of cardiac output, although at 1400 grams it constitutes and symptoms in syn- only about 2% of an adult's mass.3 In children of around two years PNES = psychogenic non- 4 epileptic seizures cope, which in turn of age, no less than 50% of cardiac output subserves the brain. It is helps them infer the also a ‘spoiled’ organ with an extremely small metabolic reserve PPS = psychogenic cause of a particular capacity. In fact, loss of consciousness starts only about eight pseudosyncope spell. For instance, seconds after the heart stops.5 The arterial system still pumps SFS = slow-flat-slow syncope beginning some blood through the body after the heart has stopped, so this while supine suggests short period does not reflect the pure metabolic reserve of the TCD = trans-cranial Doppler that gravity does not brain. Early experiments abolished that arterial pump effect by ultrasound play a role. Inasmuch occluding all neck arteries instantly with a cuff around the neck. TLOC = transient loss of as a prime task of Unconsciousness then started six to seven seconds after cuff 6 consciousness blood pressure regula- inflation. This latter finding vividly illustrates how little reserve tion is countering the capacity the brain has, and also suggests that the arterial pump TSLB = time since last beat effects of gravity in does not appreciably prevent loss of consciousness after cardiac the upright position, standstill. In the end, apart from cardiac output, cerebral perfusion supine syncope is not likely to be due to a primary failure of depends on the baroreflex system to maintain systemic blood blood pressure regulation. Instead, a low cardiac output, for pressure, and cerebral autoregulation maintains cerebral blood instance as a result of arrhythmia, is much more likely to be flow in the face of changes in arterial pressure. the basis for supine syncope, as it causes the circulation to come to a halt regardless of body position. The baroreflex system This paper focuses on the pathophysiology of the systemic and cerebral circulation and the neurological The baroreflex sensors are located in the carotid sinus and in consequences of cerebral hypoperfusion in syncope, and the aorta; those in the carotid sinus are located where the Fig 1 – Forms of transient loss of consciousness (TLOC). Traumatic TLOC concerns concussions that usually do not pose diagnostic confusion. The three major groups that do cause confusion are syncope, epileptic seizures and psychogenic TLOC. The ‘rare and mimics’ group is not discussed in this paper. For further discussion, see Refs. 1 and.24 PROGRESS IN CARDIOVASCULAR DISEASES 55 (2013) 345– 356 347 common carotid artery splits into the internal and external but this simplification ignores several factors that can play a role carotid arteries. As the arterial system has no valves, in syncope (Fig 2). A more detailed view holds that cerebral blood hydrostatic factors affect actual blood pressure depending flow (CBF) firstly depends on a pressure difference between on the height of the artery in question. In the upright position, arterial pressure and venous pressures; without that, there is no a distance of 30 cm between the aorta and the brain at eye flow. The second consideration is whether blood vessels are level means that arterial pressure at eye level is 22 mmHg less closed by forces opposing the pressure in their lumen that keeps than at the level of the heart and upper arm where blood them open: the closing forces are vessel wall tension and tissue pressure is conventionally measured. In the supine position pressure.3,10 All elements in this equation can affect the result. the upper arm, heart and brain are at the same height. If blood Tissue pressure, which for the brain means intracranial pres- pressure at the heart stays the same, lying down will sure, is normally very low. The exception occurs when the therefore increase arterial pressure at brain level by about volume of the content of the skull increases, through brain 22 mmHg. This simple effect partly explains the beneficial swelling or bleeding. As the rigid skull prohibits any significant effects of lying down when blood pressure is low; another changes of the volume of its contents, intracranial pressure will effect is that the change in posture often allows blood increase quickly. This increase of pressure diminishes cerebral pressure at heart level to increase. blood flow. When pressure rises sufficiently high that it exceeds The baroreflex arc involves afferent fibers running from the the arterial pressure, cerebral blood flow stops entirely. This carotid sinus baroreceptors through the glossopharyngeal nerve, latter termination of flow is the major mechanism in brain and from the aortic arch through the vagal nerve, to the nucleus death. A temporary increase in intracanial pressure probably tractus solitarii in the medulla oblongata, where integration with also explains the temporary self-limiting loss of consciousness other incoming inputs takes place. The efferent signals course that can occur in subarachnoid hemorrhage (luckily, other through sympathetic nerves running to peripheral blood vessels features in its presentation make diagnostic confusion with and to the heart, and parasympathetic (vagal) nerve branches to syncope very unlikely). the heart. The fibers to the heart control heart