Syncope: an Overview of Diagnosis and Treatment DAVID G BENDITT

Home , Coma, Orthostatic syncope, Reflex syncope, Stupor, Syncope (medicine)

ARTÍCULO DE REVISIÓN REV URUG CARDIOL 2011; 26: 55-70

Syncope:David G Benditt an overview of diagnosis and treatment Syncope: an overview of diagnosis and treatment DAVID G BENDITT. MD, FACC, FHRS, FESC, FRCPC 1

INTRODUCTION LOSS OF CONSCIOUSNESS Syncope is a syndrome in which a relatively Consciousness and ‘loss of consciousness’ sudden-onset, brief loss of consciousness re- (LOC) are complex concepts, but most physi- sults from a temporary self-terminating pe- cians have a working understanding of what riod of total cerebral hypoperfusion (1-4).In is meant (8). Essentially, LOC implies not only this regard, it is important to note that other loss of awareness and appropriate responsi- conditions (e.g., epilepsy, concussions, meta- veness to external stimuli, but also loss of bolic disturbances and intoxications) may al- postural tone. Occasionally, however, so cause a temporary loss of consciousness (T- symptoms may suggest that ‘syncope’ is im- LOC) but nonetheless are not ‘syncope’ (3-5). minent, but the full clinical picture does not Each of these differ from syncope either by evolve at that time; such cases are often ter- the need for medical intervention to reverse med ‘near-syncope’. In such instances, the pa- the process (e.g., hypoglycemia) or by the un- tient may experience near loss of vision derlying mechanism of the loss of conscious- (‘grey-out’ due principally to transient loss of ness (e.g., electrical disturbance in epilepsy, blood supply to the retina), diminution of hea- trauma in head injury, etc.) or both. Other ring, and feeling ‘out-of-touch’ with their su- conditions may also mimic syncope. These are rroundings and/or confused. On the other often termed ‘syncope mimics’ or ‘pseudosy- hand, many times patients complain of less ncope’, but differ from syncope inasmuch as well defined symptoms such as “dizziness” or they do not cause true loss of consciousness “lightheadedness”. These latter complaints (e.g., conversion reactions, malingering, and (especially in the elderly) may be due to an ill- cataplexy). defined functional cerebral dysfunction trig- In itself, ‘syncope’ is not a complete diag- gered by transient hypotension (perhaps not nosis. Identifying the cause is important, sin- severe enough to cause TLOC), but in most ce syncope may be a marker of increased mor- cases it is believed that such symptoms are tality risk in some cases, but even more often not related to either ‘syncope’ or ‘near- may lead to physical injury resulting from syncope’, and should not be reported as such. falls or accidents, diminished quality-of-life, and possible restriction from employment or avocation. The goal should be to determine EPIDEMIOLOGY AND SOCIAL COST OF SYNCOPE the cause of syncope with sufficient confiden- Syncope is known to be a relatively common ce to provide a reasonable assessment of prog- cause of emergency department evaluation nosis, recurrence risk, and treatment options. and hospital admission, but precise estimates The initial step is always the documentation of frequency are hard to establish, since in of a comprehensive and detailed medical his- many reports the precision with which synco- tory (3-7). pe has been differentiated from TLOC is unclear. Given this limitation, various reports estimate that syncope accounts for 1% to 3%

1. Professor of Medicine, Co-Director Cardiac Arrhythmia Center, University of Minnesota Medical School. From the Cardiac Arrhythmia Center, Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, MMC 508, 420 Delaware Street SE, Minneapolis, MN 55455, USA. Correspondence: David G Benditt MD. Mail Code 508, 420 Delaware St SE. Minneapolis, MN, 55455 Email [email protected]

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Figure 1. Classification of the principal causes of syncope. See text for details.

of emergency department visits and 1% to 6% Recent estimates place the proportion of of hospital admissions (1,2). emergency room visits due to syncope at An early report from the Framingham fo- about 1% in Italy, France, and the United llow-up study (9) found that only 3,2% of adults States (1,2). In the US, this translated into admitted to one or more syncope spells. By >1.127 million visits in 2006 based on ‘pri- contrast, in a more recent report from the sa- mary diagnoses’ recorded in the 2006 Natio- me study (10) noted that 10% of 7814 subjects nal Hospital Ambulatory Care survey, and admitted to at least one syncope spell over a >411,000 hospital admissions when syncope 17-year sampling time. In another extensive and collapse were listed among discharge community-based study of American adults diagnoses. aged 45 years and older, Chen et al (2006) (11) The direct cost of diagnosing and treating reported that 19% of adults admitted to at syncope is substantial. In the USA, an esti- least one syncope spell. Studies from Calgary mate of direct cost may be obtained from the (Canada), and Amsterdam (The Netherlands), Medicare database. In the year 2000 (20) the reported similar results for estimates of com- estimated total annual charges for syncope- munity lifetime cumulative incidence. Ganze- related admissions were $5.4 billion, with a boom et al (12) surveyed medical students and mean charge of $12,000 per hospitalization. found that 39% had fainted at least once. The Data in 2005-2006 from the United Kingdom Calgary group (13) reported that by age 60 provide estimates of £70 million per annum years 31% of males and 42% of females had (14,15). On the other hand, determining ‘total fainted, very similar to the proportions repor- cost’ is difficult since the indirect costs related ted by Amsterdam study (12,13). Thus, females to loss of earning by patients or family mem- were more likely to faint than males, or are at bers are much harder to measure. least more likely to volunteer the information. Taken together, the studies consistently suggest that 40% of people faint at least once in CLASSIFICATION OF THE CAUSES OF SYNCOPE their lives with females perhaps being somew- Syncope has many possible causes, and it is hat more susceptible. Further, within three essential to approach the diagnostic possibili- years of the initial episode, about 35% of pa- ties in an organized manner (Figure 1). Ho- tients experience recurrences. wever, even after a thorough assessment, it

56 SYNCOPE: AN OVERVIEW OF DIAGNOSIS AND TREATMENT DAVID G BENDITT

TABLE 1. THE PRINCIPAL NEURALLY-MEDIATED REFLEX sively warm closed-in environments, or extre- SYNCOPE SYNDROMES me emotions. Common places for these events · Vasovagal (‘common’) faint are churches, restaurants and long queues. · Post-exercise variant Warning symptoms may occur, and include · Carotid Sinus Syndrome feeling: hot or cold, sweaty, tachycardic, · Situational faints: ‘short of air’, loss of hearing, nausea and – cough, – defecation, change in breathing pattern. Physical fin- – swallow, dings often reported by bystanders (if the – micturition, physician asks) in these cases include mar- – sneeze, ked pallor, damp and cold (“clammy”) skin, – swallow, and confusion. After the faint, if the patient is – venipuncture, permitted to remain recumbent, recovery – Other (e.g., brass instrument playing, weightlif- ting, postprandial) typically is very rapid, but a subsequent pe- · Glossopharyngeal and trigeminal neuralgia riod of fatigue of variable duration is quite · Inferior wall myocardial ischemia common. Typically, the diagnosis is made from the medical history alone and no testing is nee- may not be possible to assign a single cause ded. However, if the medical history does not for fainting. Patients often have multiple co- provide sufficient basis to make the diagno- morbidities and as a consequence they may sis, head-up tilt-table testing (HUT) may be have several equally probable causes of fain- helpful to support a diagnosis of vasovagal ting. syncope (19,20). Such testing, in the absence of pharmacological provocation, has a specifi- NEURALLY-MEDIATED REFLEX SYNCOPE SYNDROMES city of approximately 90%. HUT is not known Neurally-mediated reflex syncope refers to a to be useful in the other neurally-mediated group of related conditions in which sympto- reflex faints. matic hypotension occurs as a result of neural reflex vasodilatation and/or bradycardia (1,2). CAROTID SINUS SYNDROME The term ‘vasovagal syncope’ refers to a parti- Carotid sinus syndrome (CSS) and carotid si- cular type of neurally-mediated reflex syncope nus hypersensitivity (CSH) are two distinctly also known as the ‘common faint’ (16). Vasova- different entities. The first is a clinical syndro- gal syncope has many manifestations and is me resulting in syncope or near-syncope due to generally considered to encompass faints trig- bradycardia and/or vasodilatation secondary gered by emotional upset, fear, and pain, as to hypersensitivity of the carotid sinus baro- well as those occurring in less well-defined cir- roreceptor. CSH, on the other hand, is the cumstances. ‘Situational’ faints are essen- physiologic observation that may or may not tially identical to ‘vasovagal faints’, but occur have any clinical sequelae. If it is responsible as the result of readily identified triggers (e.g., for syncope, then the patient is diagnosed micturition, swallowing, etc). Carotid sinus with CSS. syndrome (CSS) also falls into this category. CSS is believed to be due to accidental ma- The neurally-mediated reflex faints, espe- nipulation of neck that results in external cially the vasovagal faint, are the most common pressure on the carotid sinus baroreceptors. causes of syncope overall, and are particularly The susceptible individual (usually older ma- prevalent in individuals without evidence of le patients >65 years of age or individuals underlying heart or vascular disease (Table 1). with previous neck surgery or irradiation) The principal pathophysiological mechanism is can often be demonstrated to exhibit carotid the triggering of a neural reflex resulting in sinus hypersensitivity (CSH) during delibe- both hypotension due to vasodilation and an rate diagnostic carotid sinus massage applied inappropriate chronotropic response (occasio- by a suitably experienced physician (21-23). nally marked bradycardia or asystole) (17,18). The incidence of spontaneous carotid sinus syndrome (CSS) as a cause of faints has VASOVAGAL SYNCOPE (COMMON FAINT) been thought to be relatively rare but recent In susceptible individuals vasovagal syncope studies from Newcastle UK, suggest that it may be triggered by prolonged periods of may be responsible for falls in the elderly far upright posture, relative dehydration, exces- more often than previously believed. Whet-

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her pacing can be an effective deterrent to ments, inadequate fluid intake or excessive ‘falls’ in the elderly is currently the subject of use of diuretics, anti-hypertensives or vasodi- clinical trials such as PERF-CSH (Pacing in lators. Chronic diseases such as diabetes, or Elderly Recurrent Fallers with Carotid Sinus peripheral neuropathy secondary to alcohol Hypersensitivity) (23). or other agents, may predispose patients to orthostatic syncope. Less commonly, orthos- SITUATIONAL SYNCOPE tatic hypotension is the result of a primary Situational faints are diagnosed by their dis- autonomic diseases with inadequate reflex tinctive history, and it is usually unnecessary adaptations to upright posture (e.g., multisy- to evaluate these fainters in the clinical labo- stem atrophy or Parkinson’s disease) (26,28). ratory. As noted above, the pathophysiology of situational faints is similar to that of the CARDIAC ARRHYTHMIAS AS PRIMARY CAUSE OF SYNCOPE conventional vasovagal faint except that the Primary cardiac arrhythmias (i.e., those that afferent trigger is identifiable. Thus, these are not secondary to neural-reflexes) are less faints include micturition syncope, degluti- commonly the cause of syncope than is either tion or swallowing syncope, etc. Cough may neurally-mediated reflex faints or orthostatic also trigger reflex hypotension (24), although hypotension. However, given the propensity other non-reflex mechanisms for cough for arrhythmias to accompany other health syncope have been proposed as well. conditions, and especially structural heart disease, the prognosis associated with ORTHOSTATIC SYNCOPE arrhythmic syncope is of concern (albeit not Orthostatic hypotension (OH) leading to usually due to the syncope per se, but more of- syncope (orthostatic syncope), as its name im- ten as a result of the nature and severity of plies, occurs as a result of a transient excessi- the underlying heart disease). ve cerebral hypotension that may occur when Cardiac tachyarrhythmias or brad- susceptible individuals arise from a lying or yarrhythmias may be the primary cause of sitting to a standing position (25-27). Two basic syncope if the abnormal heart rate (in con- forms are recognized. The first is so-called junction with vascular compensatory respon- ‘immediate or initial hypotension’ and occurs ses) cannot maintain stable cerebral flow. almost immediately upon ‘active’ standing, Either or both may occur as a result of: and can be observed in young healthy indivi- 1) ‘intrinsic’ disease of the cardiac conduc- duals as well as in older patients. In fact, tion system (e.g., intrinsic sinus node many healthy individuals experience a minor dysfunction or AV conduction system di- form of ‘immediate hypotension’ when they sease, or accessory conduction pathways), need to support themselves momentarily as or they stand up. Essentially, in these instan- 2) channelopathies (e.g., long QT syndrome, ces, ‘immediate hypotension’ causes a tran- Brugada syndrome), or sient self-limited ‘grey-out’. However, imme- 3) structural cardiac or cardiopulmonary di- diate hypotension may not always be benign; sease (i.e., structural cardiac or cardiopul- instability and falls are a risk in more frail in- monary abnormalities, or dividuals, and frank syncope can also occur. 4) extrinsic effects such as drug-induced The second form of orthostatic hypotension is proarrhythmia. the classical form, otherwise termed the ‘delayed’ form. Symptoms usually occur several Determining which, if any of the cardiac moments after standing up. The patient has arrhythmias are responsible for syncope in a already walked some distance, then collap- given individual can be difficult, especially if ses. The cause in both cases is deemed to be symptomatic events are infrequent. Elec- the failure of autonomic nervous system to trophysiological testing may be helpful in respond to a sudden upright posture, but the some cases, but more often than not the fin- delayed form tends not to reverse until gra- dings are non-specific. Ambulatory ECG mo- vity intervenes (i.e., the patient has fallen). nitoring offers the opportunity to obtain Either extrinsic factors or primary auto- symptom-arrhythmia concordance. However, nomic failure may account for orthostatic 24-hour or 48-hour Holter type monitoring is syncope. Extrinsic factors include dehydra- not very effective because the likelihood that tion from prolonged exposure to hot environ- syncope will occur in that relatively brief time

58 SYNCOPE: AN OVERVIEW OF DIAGNOSIS AND TREATMENT DAVID G BENDITT

Figure 2. Paroxysmal AV block resulting in transient bradycardia in an older woman with recurrent syncope. A pacemaker was placed. period is small. Longer-term monitoring (e.g., cardia while awake (< 40 beats per minute) ECG ‘event’ recorders, mobile cardiac outpa- and repetitive sinoatrial block or sinus pau- tient telemetry (MCOT) systems, implanta- ses longer than 3 seconds may be used to jus- ble Loop recorders [ILRs]) increases the chan- tify pacemaker implantation. However, it is ce of finding a correlation. In particular, essential to continue clinical surveillance MCOT recorders and ILRs are especially va- using the diagnostics within implanted devi- luable as they offer not only long recording ces to ascertain whether the correct course of periods, but also can detect and store events action has been taken. automatically (29-32). ATRIOVENTRICULAR CONDUCTION DISORDERS SINUS NODE DYSFUNCTION Paroxysmal or persistent atrioventricular Symptoms in patients with sinus node (AV) block can cause severe bradycardia and dysfunction may be due to either brady- or thereby lead to syncope (Figure 2). If a patient tachyarrhythmias. Thus, while sinus/junctio- is found to have Mobitz type II second degree nal bradycardia, sinus arrest or a sinus pause AV block, third degree AV block or alterna- are common, paroxysmal atrial tach- ting left and right bundle branch block, a cau- yarrhythmias fall into this category as well. sative diagnosis for the basis of syncope can In either case, the heart rate (HR) may be ina- be made with reasonable certainty. In any ca- dequate to support cerebral blood flow. In so- se, these diagnoses generally warrant pace- me patients both brady- and tachycardia may maker implantation. The American Heart be contributory; for example, an abrupt spon- Association/American College of Cardio- taneous termination of an atrial tachycardia logy/Heart Rhythm Society pacemaker prac- may be followed by long asystolic pause prior tice guidelines provide further details (34). to recovery of a stable heart rate. Other observations that may be suggesti- Electrophysiologic (EP) laboratory testing ve of an AV conduction disorder being the is of limited value in most patients with sus- cause of syncope, but at best provide only in- pected sinus node dysfunction (33). Although direct evidence, include: measures such as sinus node recovery time 1) bifascicular block (left bundle branch (SNRT) and sinoatrial conduction time (SACT) block, right bundle branch bock with left exhibit a high level of specificity for sinus node anterior or left posterior fascicular block), disease, they are not very sensitive and do not and provide essential symptom-arrhythmia con- 2) Mobitz type I second degree AV block in ol- cordance upon which to base treatment re- der persons (usually defined as >70 years commendations. MCOT and ILR recorders of age). In such cases further tests (such as with direct rhythm-symptom correlation are MCOT and/or ILR monitoring, or EP tes- better for this application. If, however, a co- ting) may be essential. rrelation cannot be established despite reasonable effort, then it may be necessary to make Once again, direct symptom-arrhythmia a clinical treatment judgment based on other correlation by recording a spontaneous event indirect evidence. Thus, severe sinus brady- is the best means of directing appropriate

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therapeutic intervention. However, a tentati- case usually focus on ablation. Similarly, SVT ve diagnosis can be made in case of ventricu- or atrial fibrillation in the setting of preexci- lar pauses > 3 seconds in duration when the tation syndrome (i.e., WPW syndrome) is patient is awake, or if Mobitz type II second usually sufficient to warrant accessory con- degree or third degree (i.e., complete or ‘high nection catheter ablation. grade’) AV block is discovered. In the setting In the case of VT, EP study is of value of nothing more than bifascicular block or mainly in the subset of patients with ischemic non-specific intra-ventricular conduction de- heart disease. In other scenarios (see below) lay, invasive EP study may be helpful. EP testing is usually not considered to be In the EP laboratory, the cardiac conduc- helpful, or at best its use is controversial. tion system can be ‘stressed’ by pacing and / or Further, even in the setting of ischemic disea- drug infusions (e.g., procainamide, ajamline) se, the potential for induction of non-specific with the objective of unmaking susceptibility tachyarrhythmias in the EP laboratory is a to higher levels of conduction block that problem. Given that limitation, it would be might induce syncope. Thus, a typical study helpful to have effective non-invasive ‘risk strategy would incorporate measurement of stratification’ tools in order to improve the li- the infra-His conduction time (H-V interval), kelihood that an invasive study will be pro- incremental atrial pacing to ascertain the ductive, but these not yet available. Tests conduction capability of the AV node-His- that have at various times been advocated to Purkinje system, and if needed provocative risk stratify patients include signal averaged testing with direct acting intravenously ad- ECG (SAECG), heart rate variability (HRV) ministered antiarrhythmic drugs, such as aj- and micro-volt T wave alternans. Unfortuna- maline (not available in USA) or procainami- tely, experience indicates that while these de. tests have a reasonable ‘negative predictive EP laboratory findings can generally only value’, they exhibit only a low positive predic- provide a presumptive basis for syncope. tive value. Thus, if the H-V interval is greater than Ventricular tachyarrhythmias (VT) tend 100ms, or if incremental atrial pacing produ- to be more closely associated with syncope ces second or third degree AV block at heart than are SVTs, particularly if structural rates £120 beats/minute, or if high degree AV heart disease is present. Thus, VT occurring in block is observed at relatively slow paced ra- the setting of ischemic heart disease, valvular tes (typically £120/minute) after drug provo- heart disease or certain dilated cardiomyopat- cation, a basis for symptoms may be presu- hies may result in symptomatic hypotension. med (35,36). However, although a pacemaker Similarly, VT in obstructive cardiomyopathies may be justified, further monitoring to ascer- and arrhythmogenic right ventricular dyspla- tain whether future syncope is prevented is sia / cardiomyopathy (ARVD/C) may cause essential; consequently, it is best to use an syncope. However, VT also occurs in some in- implanted device with comprehensive moni- dividuals with important examples are long- toring capability. QT syndrome, and Brugada syndrome. In terms of presenting with syncope, tor- SUPRAVENTRICULAR AND VENTRICULAR sade de pointes ventricular tachycardia is a TACHYARRHYTHMIAS particularly important form of VT to keep in Supraventricular tachycardia (SVT) and ven- mind (Figure 3). This arrhythmia is a charac- tricular tachyarrhythmias (VT) account for a teristic feature of the long-QT syndromes, minority of syncope cases, but are important may be very fast and is often it is self- given their potential for cure by ablation in terminating. Consequently syncope may oc- the case of SVT, and concern regarding prog- cur (37). However, on occasion progression of nosis in VT patients. the arrhythmia to ventricular fibrillation can The diagnostic evaluation of patients with happen; this emphasizes the importance of suspected SVT or VT, in the absence of ‘hard’ not overlooking these diagnoses. ECG evidence during ambulatory ECG moni- Non-sustained VT (NSVT) is a common toring, usually entails EP testing. In the case finding during evaluation of syncope patients of SVTs, reproducible induction of tachycar- (whether by Holter or by extended-duration dia can be relied upon as likely unmasking AECG monitoring), but is diagnostically a the cause and the therapeutic options in that much less specific finding than is sustained

60 SYNCOPE: AN OVERVIEW OF DIAGNOSIS AND TREATMENT DAVID G BENDITT

Figure 3. Example of no-sustained Torsade de Pointes VT in a patient with long QT syndrome and syncope.

VT. The isolated presence of NSVT, particu- cost will be expended with low diagnostic larly in the absence of evident structural car- yield. diac disease or ECG evidence of a ‘channelo- Migraines are probably the most important pathy’ should not typically be considered a condition in this group of causes of syncope ‘causative’ diagnosis. On the other hand, if (58,59). However, as a rule, migraines do not cau- monomorphic sustained VT is reproducibly se syncope directly. Evidence suggests that inducible during EP study, a basis for synco- migraine may trigger a neurally-mediated va- pe seems likely. In such instances, therapy sovagal reflex syncope in most cases. (drugs, ablation) directed at the arrhythmia is appropriate. Implantable device prophylaxis (e.g., implantable cardioverter-defibrillator, SYNCOPE MIMICS AND PSEUDO-SYNCOPE ICD) may also be warranted. However, while There are two important groups of conditions ICDs are helpful to prevent sudden which may present with real or apparent T- arrhythmic death, they may not prevent epi- LOC but that should not be considered as sodes of dizziness or syncope, which may oc- ‘syncope’. First of this group are conditions cur at the onset of the abnormal rhythm befo- which cause true TLOC, but their pathoph- re the device is activated. ysiological mechanism differs from true syncope. These may be considered as ‘Non- CARDIOVASCULAR AND CARDIOPULMONARY DISEASE syncope TLOC’, with epilepsy being the most Syncope may occur as a direct result of severe important example, but trauma leading to underlying cardiac or cardiopulmonary di- concussion (such as might occur after an acci- sease. The most common causes are acute co- dental fall in an older patient) must be kept in ronary syndromes (ACS), and acute myocar- mind as well. The second group of conditions dial infarction. Others, although less com- comprises those in which consciousness is ne- mon, are severe aortic stenosis or hypertrop- ver really lost. These are best termed ‘Pseu- hic obstructive cardiomyopathy (HOCM), dosyncope’ (neurologists may use the term acute aortic dissection, and severe pulmo- ‘pseudoseizure’). The most important cause is nary hypertension. In each of these, despite psychiatric conversion disorders. Malinge- the potential for important hemodynamic ring might also present as pseudosyncope, consequences of the conditions, it is generally but this seems to be rare. Since these two believed that the syncope is due to a neurally- groups of conditions are not ‘true’ syncope, mediated reflex, rather than a direct conse- they are not discussed further here. However, quence of disturbed hemodynamics. ‘drop attacks’ warrant additional mention. ‘Drop attacks’ belong in the ‘pseudosyncope’ group. In ‘classical’ description, the CEREBROVASCULAR DISEASE AND RELATED CONDITIONS ‘drop attack’ is an uncommon condition in Cerebrovascular disease and related condi- which postural tone is lost abruptly and pa- tions (with the possible exception of syncope tient (most often females) falls to the ground. associated with migraine) are very rare cau- The history-taker can determine by careful ses of syncope. Evaluation of these conditions questioning of the patient’s recollection du- (e.g., vertebrobasilar transient ischemic at- ring the attack whether consciousness was tacks, subclavian steal syndrome) should be retained. Nevertheless, in some cases the pa- reserved to those few instances in which the- tient may actually have lost consciousness re is strong medical history evidence favoring and simply has no recollection of having done the possibility. Otherwise, much energy and so. Consequently, in some individuals these

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TABLE 2. CLINICAL FEATURES SUGGESTING SPECIFIC (Table 2). However, obtaining a reliable his- SYNCOPE CAUSES tory may be a problem. Elderly patients and those with cognitive impairment may not be Neurally-mediated reflex syncope syndromes · Absence of cardiac disease able to remember all events, while other pa- · Long history of recurrent syncope tients may not volunteer a complete history · After sudden unexpected sight, sound, smell or due to risk of losing their job, or driving privi- pain leges. Consequently, witnesses to symptoma- · Prolonged standing or crowded, hot places tic events should be included in the history- · Nausea, vomiting associated with syncope · During the meal or in the absorptive period after a taking process, whenever possible. meal In brief, it is essential that as many · With head-rotation, pressure on carotid sinus (as symptom events be assessed in detail. The pre- in tumors, shaving, tight collars) ceding circumstances, premonitory symptoms, · After exertion and subsequent outcome should be documen- · After specific activities such as voiding, swallo- ted for as many episodes as possible. If a pat- wing, etc (see text) tern emerges, the diagnosis may become evi- Orthostatic hypotension with syncope dent without the need for further testing. Simi- · After standing-up (may occur abruptly, or be dela- larly, careful note should be made of patient’s yed by several minutes) co-morbidities (for example diabetic neuro- · Temporal relationship with start of medication leading to hypotension or changes of dosage pathy, autonomic dysfunction). A pre-prepared · Prolonged standing especially in crowded, hot pla- patient questionnaire may prove helpful to sa- ces ve time and still acquire the needed details. · Presence of autonomic neuropathy or Parkinso- Based on the initial evaluation, it should nism be possible to classify patients into one of · History of diabetes or chronic alcohol abuse · After exertion three categories: Certain diagnosis, Suspec- ted diagnosis or Unknown diagnosis. The- Cardiac arrhythmic syncope reafter, the diagnostic flow can reasonably fo- · Presence of definite structural heart disease llow the strategy depicted in Figure 4 which · Syncope during exertion has been modified from that devised by the · Syncope while supine · Preceded by palpitation European Society of Cardiology Syncope Gui- (2) · Family history of sudden death delines Task Force . The goal is to choose · Long QT or Brugada pattern on ECG subsequent diagnostic tests in a careful manner to maximize cost-effectiveness and mini- Cerebrovascular syncope mize the number of studies. · Findings suggesting subclavian steal with arm exercise SHOULD THE DIAGNOSIS BE PURSUED IN HOSPITAL OR IN THE OUTPATIENT SETTING? episodes can be mistaken for syncope, whe- reas in others they may actually have been a In general, the driving force determining ‘true’ syncope. Establishing a certain diagno- whether the patient with presumed syncope sis is challenging and may be frustrating. should be hospitalized for diagnostic evaluation and if necessary for treatment initiation, Clinical experience suggests that many is most often concern regarding the indivi- patients with pseudo-syncope often have a dual’s immediate mortality risk. Secondary history of ‘true’ syncope as well. Perhaps, the issues include potential for physical injury rare true faints lead to psychiatric- or stress- (e.g., falls risk) and to a lesser extent whether related responses that ultimately result in an certain treatments inherently require hospi- increasingly frequent series of ‘syncope-like’ tal monitoring for safe initiation. Thus, for episodes (i.e., ‘pseudosyncope’). example, patients with syncope accompan- ying complete heart block, ventricular tachycardia, acute aortic dissection, or pulmonary ESTABLISHING THE CAUSE OF SYNCOPE embolism, should be admitted to the hospital and preferably to an ECG monitored unit. On INITIAL EVALUATION OF THE PATIENT WITH SUSPECTED the other hand, most vasovagal fainters can SYNCOPE be sent home after careful discussion of the The evaluation of patients with suspected nature of the problem and simple preventati- syncope begins with a careful history taking ve maneuvers (e.g., hydration, avoidance of

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Figure 4. Diagnostic flow of Syncope (adapted from reference 2) hot crowded environments, etc). Clinic follow- At present, it is not possible to determine up suffices in most of these cases. whether one or other risk stratification sche- For syncope patients in whom the etiology me is superior to the others. Head-to-head remains unknown after the initial emergency testing is needed. In this regard, the Risk department or ambulatory clinic evaluation, Stratification Of Syncope in the Emergency the need for hospitalization is less well defi- Department (ROSE) study compared the per- ned and consequently so-called “risk stratifi- formance of OESIL score, and the SFSR re- cation” methods have been advocated (38-45).In commendations with emergency department essence, the goal is to ascertain the relative guidelines of a single center in United King- risk for adverse outcome using patients’ clini- dom (Royal Infirmary of Edinburgh) (44). The cal features and presenting characteristics. latter institution used a guideline based on Based on this assessment one attempts to de- ESC, American College of Physicians and termine if hospitalization is prudent. ACEP guidelines. The goal was to determine The risk stratification methods differ in which of these Risk Stratification tools best various published studies. Nonetheless, the predicted short-term (1 week and 1 month) Syncope Evaluation in the Emergency De- and medium-term (3 months) serious outco- partment Study (SEEDS), The Osservatorio mes for patients presenting with syncope. In Epidemiologico sula Sincope nel Lazio this regard, each of the scores was able to (OESIL) study, The San Francisco Syncope identify an increased probability of medium- Rule (SFSR) study, and the European Society term serious outcome in patients with synco- of Cardiology and American College of Emer- pe. The SFSR showed good sensitivity at the gency Physicians (ACEP) guidelines (40-45) expense of an increased frequency of admis- each uses clinical data that is readily accessi- sion to the hospital. On the other hand, the ble to the ED physician or general practitio- Royal Infirmary’s center’s own guideline, and ner. These data include symptoms, signs, ba- the OESIL score, was not sufficiently sensiti- sic laboratory results and clinical experience ve to be able to reduce admissions without (‘judgment’). missing patients at risk of serious outcome.

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Figure 5. Recording of ECG leads !, II, aVL, and V1, and arterial pressure during carotid sinus massage (CSM) in an older male with syncope and suspected carotid sinus syndrome. Note that despite recovery of the heart rate after the initial asystolic period, the blood pressure remains well below baseline value. This observation (i.e., the persistent hypotension) is supportive of a ‘vasodepressor’ component to the CSM response in addition to the induced bradycardia (also known as the cardioinhibitory aspect of the CSM response).

ROLE OF SYNCOPE MANAGEMENT UNITS (SMUS) rred to ED’s of 11 Italian general hospitals was An as yet incompletely answered question is investigated in EGSYS-2 (46), and facilitated by whether “SMUs” can help solve the problem use of purpose-designed software in addition of too many low- and intermediate-risk synco- to personnel training at test sites. A definite pe patients being admitted to hospital where diagnosis was established in 98% of cases, they often are submitted to unneeded expen- with the vast majority being either neurally- sive diagnostic tests as pointed out in the mediated reflex or orthostatic faints. The ini- EGSYS (The Evaluation of Guidelines in tial evaluation (history, physical examination, Syncope Study) reports (69). In this regard, 2 and electrocardiogram) established a diagno- recent prospective observational studies de- sis in 50% of cases. The investigators further monstrated improved syncope management compared the outcomes of 745 patients mana- in the hospital by using guideline-based deci- ged with this “standardized care” system to sion making software and a team of specially- 929 patients managed with usual care. In the trained personnel in a SMU. In the SEEDS group designated to “standardized-care”, hos- study (46), 103 patients were randomized to pitalizations were fewer, in-hospital stay was ‘standard care’ or SMU after initial assess- shorter, fewer tests were performed per pa- ment. The study found that a presumptive tient, and cost per patient and mean cost per diagnosis of the cause of syncope was signifi- diagnosis were lower. cantly increased from 10% in the ‘standard care’ patients to 67% among those who under- went SMU evaluation; hospital admission TREATMENT was reduced from 98% among the ‘standard Treatment of the syncope patient may be divi- care’ patients to 43% among the SMU pa- ded into 2 parts. The first is management of an tients. Similarly, the total length of patient- acute syncopal event. Although physicians are hospital days was reduced by >50% for pa- only infrequently involved in this aspect of ca- tients in the SMU group. re, treatment of the acute episode requires The potential for the ESC Guidelines to fa- protection of the patient from injury, assuring cilitate management of syncope patients refe- that the victim is placed safely in a gravitatio- nally neutral position, and documenting ade-

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quacy of respiration and circulation. Thereaf- sively lengthening periods of enforced ter, recovery is spontaneous. The second part upright posture, the goal of which is to impro- is prevention of syncope recurrences. ve tolerance to upright posture (51). In addition, a number of pharmacologic approaches NEURALLY-MEDIATED REFLEX FAINTS have been proposed for vasovagal syncope. In most cases, vasovagal syncope or situatio- However, most of these have not been studied nal faints are solitary or at most very infre- in randomized, controlled trials. Examples of quent events. Therefore, most patients need such medications include fluorocortisone, be- little more than reassurance and education ta-adrenergic blocking drugs, and vasocons- about the nature of this condition and the trictor agents like midodrine and serotonin types of circumstances that might increase re-uptake inhibitors. Although these may their risk of recurrence (e.g., prolonged stan- work well in individual patients, only mido- ding, warm environments, etc.). However, in drine has shown effectiveness in controlled (52-54) certain individuals, the faints are more fre- studies . quent for at least a period of time during their Cardiac pacing has received considerable lives. In these cases, should also be taught to study as a potential treatment option in pa- be alert to warning symptoms such as feeling tients with very frequent vasovagal faints. of being hot or cold, sweaty, clammy, short of However, despite early favorable reports, pa- breath, or nauseated. The goal is to educate cing is not considered very effective for pre- susceptible individuals to recognize impen- venting syncope in most patients. On the ot- ding events and take action in order to pre- her hand, the ISSUE-2 trial indicated that if vent the episodes (e.g., sitting or lying down marked bradycardia during spontaneous with feet elevated). Similarly, if a patient syncope has been documented by ILR recor- knows that sight of blood could bring about a ding, then pacing may be warranted in recu- vasovagal faint, he/she may either avoid the rrent fainters (30). ISSUE-2 was an observa- situation or possibly be preconditioned to per- tional study. ISSUE-3, which just concluded form maneuvers to prevent the faint (e.g., ag- enrollment in November 2010, is reassessing gressive hydration, arm-tensing, leg cros- this issue in a randomized controlled study. sing). Carotid sinus syndrome (CSS) is a special With regard to techniques for acute inter- form of neurally-mediated reflex syncope vention to abort an imminent vasovagal or si- that tends to occur in older individuals. Falls tuational faints, patients who have warning and injury is a real concern in these patients symptoms should be educated about specific if untreated (23,55). In CSS, despite the presen- physical counter-maneuvers (PCM); thus, ce of both cardioinhibitory and vasodepressor squatting, arm-tensing, leg-crossing, and leg- features, pacing appears to be highly effective crossing with lower body muscle tensing have for preventing recurrences (Figure 5). proved useful for averting an abrupt vasovagal reaction (47-50). In the recent Physical ORTHOSTATIC SYNCOPE Counterpressure Manoeuvres Trial (PC- Treatment of orthostatic syncope parallels in Trial), van Dijk et al. demonstrated that many respects the strategy discussed earlier physical counterpressure maneuvers (PCM) for vasovagal and situational faints. The can reduce the total burden and recurrence principal differences are: 1) the duration of rate of syncopal events (50). Consequently, treatment is likely to be longer, 2) affected in- PCM education should be part of the treat- dividuals are typically older and more frail ment strategy, especially in patients with making physical maneuvers more difficult to warning symptoms prior to their faints. employ, and 3) patients are more prone to su- Longer-term prevention of vasovagal pine hypertension thereby complicating the syncope recurrences focuses on use of fluids overall treatment strategy. rich in electrolytes and increased dietary In many cases, syncope associated with salts. Examples would include ‘sport drinks’ postural change may be caused by low circu- although those with lowest carbohydrate con- lating plasma volume, or inadequate vascu- tent are preferred. Highly motivated patients lar constriction upon moving to the upright could also be provided with instructions re- posture (often drug-induced), or both. Conse- garding upright standing training (so-called quently, one of the basic tenets of treatment is tilt-training). ‘Tilt training’ involves progres- expanding central circulating volume. Addi-

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tionally, affected individuals should be ins- tion system disease (e.g., wide QRS), or in ol- tructed to try and avoid certain predisposing der individuals (>70 years of age) pacemaker conditions (e.g., prolonged exposure to hot en- therapy is indicated. Similarly patients who vironments) or medications that decrease vo- have Mobitz type II AV block carry a high risk lume status (e.g., diuretics) or that impair va- for intermittent high grade AV block causing soconstriction (e.g., vasodilators, beta- syncope, and are candidates for pacing the- adrenergic blockers). In some severe cases, rapy. On the other hand, these same patients use of vasoconstrictors (like midodrine) or vo- often exhibit substantial structural heart di- lume expanders (e.g., fludrocortisone) may be sease and therefore, and are also prone to necessary to maintain adequate cerebral per- ventricular tachyarrhythmias. Management fusion. Finally, patients who exhibit poor au- in such cases may be better accomplished by tonomic function may benefit from tilt- ICD therapy. training (discussed earlier), counter-pressure When reentrant paroxysmal supraventri- clothing such as fitted stockings and abdomi- cular tachyarrhythmias are deemed to be the nal compression devices. In patients with se- cause of syncope transcatheter ablation is the vere pure autonomic failure, bolus water in- treatment of choice in most cases. Drug the- take, especially before arising from bed in the rapy remains an option, however, given the morning, may result in a substantial and sus- high success rate with ablation and its ready tained increase in blood pressure (56). availability, the ablation track seems more desirable. Similarly, most atrial tach- PRIMARY CARDIAC ARRHYTHMIAS yarrhythmias are now subject to cure by The treatment of cardiac arrhythmias cau- transcatheter ablation technique. This cer- sing syncope is determined by the specific tainly is true for atrial flutter, most ectopic arrhythmia that is deemed to be at fault. Gi- atrial tachyacrdias and increasingly for pa- ven the numerous possibilities and the many roxysmal atrial fibrillation. However, drug factors that go into selecting appropriate the- therapy remains the most commonly used ap- rapies for these arrhythmias, only a very brief proach by most physicians. In this regard, overview is provided here. drugs that reduce heart rate in tachycardia As noted earlier, sinus node disease may may be sufficient to prevent syncope. The cause syncope either due to bradycardia or most common of these agents are: beta- tachycardia mechanisms as discussed ear- adrenergic blockers, and calcium channel lier. When a temporal correlation between blockers. If the desire is also to try and sup- syncope and bradycardia has been establis- press tachycardia recurrences, a membrane hed, pacemaker implantation is the treat- active antiarrhythmic drug is also needed. Fi- ment of choice. Dual-chamber or atrial pacing nally, in the case of refractory symptomatic is preferred. In the case of a tach- atrial tachyarrhythmias (particularly atrial yarrhythmia-induced syncope, both an- fibrillation) with rapid ventricular rates, tiarrhytmic drugs and ablation are reasona- treatment by His Bundle ablation and place- ble treatment considerations. The final choi- ment of a permanent pacemaker has proved ce depends on specific clinical circumstances to be safe and highly effective (57). and patient preferences. The treatment of ventricular tach- Treatment of AV conduction system disea- yarrhythmias in syncope patients depnds on se in syncope patients does not differ measu- the clinical circumstance. Patients with is- rably from their treatment in other patients. chemic heart disease or dilated cardiomyo- However, once again it is crucial to obtain pathies and severely diminished left ventri- concordance between syncopal episodes and cular function (i.e., LV ejection fractions bradycardia. If such a correlation is found <35%) have a high mortality rate and benefit and the cause of AV block is irreversible, pa- from ICD therapy. As alluded to earlier, cemaker implantation is a class I indication. whether syncope will be prevented by ICD In general, first degree AV block and Type treatment is less certain since the devices I second degree AV block (Wenkebach type) must take time before intervening with pa- with a narrow QRS do not cause syncope and cing or shock treatment (58). Consequently, in are not indications for a pacemaker. Howe- the syncope patient concomitant an- ver, when second degree Type I block occurs tiarrhythmic drug therapy and/or ablation in the setting of evident infra-nodal conduc- may be needed.

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Ventricular tachyarrhythmias arising CEREBROVASCULAR from the Right Ventricular Outflow Tract As noted previously, cerebrovascular disease (RVOT) or Left Ventricular Outflow Tract is rarely the cause of syncope. Migraines may (LVOT) or the intraventricular fascicular be the most important consideration. The ba- system or bundle-branch system (i.e., bundle- sis for the faints in migraineurs is unclear, branch reentry) are infrequent causes of but there is an established relationship bet- syncope. However, when they are responsible ween migraines and autonomic dysfunction for symptoms, transcatheter ablation is pro- (59). In any case, the medical management in- bably the treatment of choice. In arrhythmo- cludes use of â-blockers and cranial/basilar genic right ventricular dysplasia (ARVD), artery vasoconstrictors such as sumatriptan treatment strategies are controversial. Medi- (60). cal treatment has not been found to be very ef- Strokes and carotid system transient is- fective. Furthermore, since there are poten- chemic attacks (TIA) are almost never the tially many regions of the heart that are affec- cause of syncope. On the other hand, verte- ted, long-term efficacy of transcatheter abla- brobasilar TIAs are a possible but extremely tion is limited. Therefore, syncope patients rare cause of faints. Treatment includes anti- with ARVD, in whom ventricular tach- platelet agents or anti-coagulation. When yarrhythmias have been documented, may be diagnoses in this category are suspected, neu- best served by placement of an ICD. Once rological or neurosurgical consultation again, however, syncope may not necessarily should be sought. be completely averted and concomitant medi- Subclavian steal syndrome is another, but cations may be needed. also very rare cause of syncope in this cate- Long QT syndrome, Brugada syndrome, gory. Its treatment requires intervention, eit- and other ‘channelopathies’ are increasingly her surgically or by catheter based angio- recognized as causes of syncope due to poly- plasty (61). morphous VT (so-called ‘torsades de pointes’) (Figure 4). If there is no evidence for a reversi- SYNCOPE MIMICS ble problem, the use of ICD therapy may be The ‘syncope mimics’ include serious medical essential to prevent further syncope and also conditions like epilepsy, diabetic coma, into- reduce sudden death risk. xication, severe hypoxia or hypercapnia. Whi- le these conditions require urgent medical at- STRUCTURAL CARDIOVASCULAR OR CARDIOPULMONARY tention, they are not the cause of true syncope DISEASE (see earlier discussion). Among the condi- In these conditions, syncope may be only one tions that are defined as syncope mimics, subset of symptoms being experienced by the psychogenic pseudo-syncope often accompa- patient. Correction of the structural lesion or nied by anxiety attacks and hyperventilation its consequence is usually the treatment of is among the most common, and is very diffi- choice. As an example, patients with valvular cult to treat. In these patients it is very easy aortic stenosis, pericardial disease, atrial for health care providers to overlook serious myxoma and congenital cardiac anomaly be- underlying health issues. Only when one is nefit from a direct corrective approach. In ot- convinced that there is no clinically signifi- her cases, such as primary pulmonary hyper- cant cardiac or pulmonary problem should tension or restrictive cardiomyopathy, the subsequent care be directed toward psychia- structural lesions are not correctable. In the tric consultation, and biofeedback. case of HOCM, modification of the outflow gradients surgically may be accompanied by substantial risk and morbidity, and medical CONCLUSIONS therapy is not very effective. If it is clear that Syncope is a form of transient loss of cons- syncope is due to the obstruction (as opposed ciousness (TLOC) that is self-limited and re- to arrhythmias discussed earlier) cardiac pa- versible due to transient spontaneously re- cing to diminish dynamic outflow gradients versible cerebral hypoperfusion. Delineating and transcatheter alcohol septal ablation the underlying causes and the risk of adverse may prove helpful. outcome may be challenging. However, careful assessment is important as syncope tends to recur; physical injury resulting from falls

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