PR O GRE S S I N C ARDI O VAS CU L AR D I S EAS E S 5 5 ( 2 0 13 ) 33 9 3 4 4

Available online at www.sciencedirect.com

www.onlinepcd.com

Clinical Classification of Syncope

Richard Sutton
Emeritus Professor of Clinical Cardiology, Imperial College, London, UK

A RT I C LE I N F O Keywords: Reflex syncope Orthostatic hypotension Arrhythmic syncope Risk stratification Insertable loop recorder

A B ST R A C T Syncope is a presenting symptom, and in itself is not a diagnosis. An etiology or a mechanism must be sought in all cases. Currently, most clinicians classify syncope on clinical grounds by attempting to ascertain its etiology. They then use this classification to guide further management. Using this approach, reflex syncope is the most common form of syncope, occurring in approximately 60% of syncope presentations. Orthostatic hypotension presents in around 15% with arrhythmic syncope in 10% and structural heart disease as the cause of syncope in 5%; in 10% of patients no diagnosis is made. An alternative classification system uses the mechanism of syncope derived from an implanted ECG loop recorder (ILR). While this approach may be of value for optimizing therapy, it cannot be considered as the primary classification since ILRs are not typically implanted early in the evaluation process of most patients. ILRs are usually placed after risk stratification in those deemed not to be at high risk but remain in the uncertain etiology category. Furthermore, there exists, in current ILR technology, lack of ambulatory blood pressure monitoring capability. Thus, vasodilation leading to hypotension, the main trigger of cerebral hypoperfusion other than bradycardia, cannot be detected and is currently unavailable for use in a mechanistic-based classification. Thus, the etiological classification remains the basis for both risk stratification and subsequent clinical management. 2013 Elsevier Inc. All rights reserved.

The etiological classification of syncope is made by clinicians to provide a basis for risk stratification and subsequent management. One of the major challenges of syncope management is that it involves a very broad range of physicians including cardiologists, neurologists, internists, emergency physicians, pediatricians and geriatricians.1 Unfortunately, communication between these specialties is not always optimal; the result is often disparate views of the same condition, with adoption of advances in one subspecialty being delayed or overlooked in another. Risk stratification is proving difficult to achieve at least in part because so many different and sometimes inexperienced

physicians are involved at the outset of the diagnostic process, for example, in the emergency department. Excellent results can be achieved when patients are seen by experienced physicians but this is seldom feasible in everyday practice.2 Clinical classifications of syncope should provide logical separations of types of presentation, usually on etiological grounds. However, the classification must also offer clinical care pathways beginning with separation of syncope from other causes of transient loss of consciousness (Fig 1), continuing with risk stratification of syncope and progressing through diagnosis of specific causes and management.

Statement of Conflict of Interest: see page 343. Address reprint requests to Richard Sutton, DSc, FRCP, FACC, FESC, FAHA, FHRS, ICCH Building, 59-61 North Wharf Road, London, W2 1LA, UK. E-mail address: r.sutton@imperial.ac.uk. 0033-0620/$ see front matter 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pcad.2012.11.005

340
Abbreviations and Acronyms AV = atrioventricular AVB = atrioventricular Block BP = blood pressure EEG = electroencephalogram ESC = European Society of Cardiology ILR = insertable loop recorder

PR O GRE S S I N C ARDI O VAS CU L AR D I S EAS E S 5 5 ( 2 0 13 ) 33 9 3 44

Today, classifications should also permit computer algorithm generation to spread expertise and improve care standards across countries, not merely in academic centers.3

Table 1 Transient loss of consciousness (TLOC). Trauma induced

Not trauma induced

Concussion
Syncope Seizure Intoxication Metabolic disorder TLOC mimics: Psychogenic Pseudosyncope/ Pseudoseizure Drop attacks Cataplexy

Not true LOC

Classification

Transient loss of consciousness (TLOC) MI = myocardial infarction (Table 1) is the inclusive initial diagnosis TLOC = transient loss of requiring assessment. consciousness Syncope is defined as VPS = Vasovagal Pacemaker a form of TLOC with Study relatively rapid onset, VT = ventricular tachycardia brief duration and usually rapid full recovery due to transient global cerebral hypoperfusion. The most common form of syncope is reflex, which implies that it is neuraly mediated (Fig 2). Among those with reflex syncope seen in all age groups, the vasovagal faint is by far the most frequently encountered. Other forms of reflex syncope include carotid sinus syndrome, which is a presentation seen almost exclusively in older people (mostly males). It is thought to have a prevalence in the population of more than 40 per million. 4 Situational syncope is less prevalent than carotid sinus syndrome. There are many phenomena represented in this category. Included are those faints triggered by any of the following: cough, swallow, micturition, defecation, and so on. Some wish to include here syncope due to the sight of blood, post-exercise or the

ISSUE = International Study on Syncope of Uncertain Etiology

Abbreviation: LOC = loss of consciousness.

experience of pain but this author prefers to consider these as forms of vasovagal syncope. An expansion of this subclassification can logically be made based on involved body systems (Table 2). In terms of incidence, the second most important category is syncope associated with orthostatic hypotension (OH) or orthostatic syncope. Orthostatic syncope is common in older people and in those taking medical therapy, usually for hypertension. Rare causes of OH are neurological. The third major syncope category is arrhythmic syncope caused either by bradycardia or by tachycardia. The latter group includes patients with genetically determined channelopathies. The final category is structural heart disease. Structural heart disease is often obstructive in nature, such as: 1. pulmonary embolism or arterial disease leading to pulmonary hypertension on the right side of the heart, or 2. aortic stenosis, mitral valve obstruction including by a left atrial ball thrombus or left atrial myxoma, hypertrophic cardiomyopathy, myocardial infarction or dissection of the aorta primarily affecting the left side of the heart. All of these conditions reduce cardiac output causing cerebral hypoperfusion. However, many of these same conditions may also be associated with tachyarrhythmias. Other structural (whether they be obvious or molecular biologic in nature) heart conditions are usually associated with tachyarrhythmias such as in arrhythmogenic (right) ventricular cardiomyopathy and most channelopathies (although conduction system disease and potential for bradyarrhythmia is associated with a few of these). It must also be borne in mind that vasovagal syncope is no less common in these patients with structural heart disease than in the general population and, furthermore, in some cases such as aortic stenosis and hypertrophic cardiomyopathy the tendency to reflex syncope may be enhanced, possibly triggered by mechanoreceptor activation initiated by elevated left ventricular chamber pressure. There remain about 10% of patients with syncope for whom no diagnosis is made. In part, this difficulty is increased by the fact that when seen by a physician, the event has passed and there may be no evident physical abnormalities. This is particularly the case with reflex

Fig 1 Syncope and transient loss of consciousness (TLOC). Diagram illustrating an approach to the evaluation of patients presenting with transient loss of consciousness (TLOC). Syncope is a subset of this clinical presentation. Adapted from ESC guidelines.9

PR O GRE S S I N C ARDI O VAS CU L AR D I S EAS E S 5 5 ( 2 0 13 ) 33 9 3 4 4

341

Fig 2 Classification of causes of true syncope. The principal causes of syncope are indicated in descending order of frequency from left to right. This classification has been substantially endorsed by the European Society of Cardiology syncope practice guidelines.9 Abbreviations: ANS = autonomic nervous system, AV = atrioventricular, Brugada = Brugada syndrome, CSS = carotid sinus syndrome, HCM = hypertrophic cardiomyopathy, LQTS = long-QT syndrome and other channelopathies, MI = myocardial infarction, N-M-S = neurally mediated reflex syncope (reflex syncope), SVT = supraventricular tachycardia, VT = ventricular tachycardia, VVS = vasovagal syncope.

syncope. The other three categories, OH, arrhythmic and structural heart disease, may be easier for the physician because there may be physical signs, although this is less likely in arrhythmic syncope.

Defining the cause of syncope in the individual patient

Reflex syncope and its separation from arrhythmic syncope present the greatest challenge as physical signs are often absent. This is compounded by lack of ECG abnormalities or their subtle presence rendering recognition difficult. These two cardiac-related diagnoses are further complicated by the need to separate them from epilepsy. Here also, there may be a lack of physical signs as in all these cases the crisis has resolved by the time the patient is seen. When faced with a lack of physical signs the physician must rely on the history however difficult it may be to obtain.

Table 2 Classification of situational syncope.

Respiratory Cough Sneeze Laugh Wind musical instrument playing Weight lifting Swallow Defecation Post-prandial Micturition Orgasm

Gastrointestinal

Genitourinary

The history from the patient is necessarily limited by the period of unconsciousness, thus demanding additional history from a witness to provide the details of how the patient looked throughout and what happened when the patient was unconscious. In this eye-witness history lies the potential for separation of the various contending diagnoses. However, not infrequently eye-witness recollection is imperfect. In the end, the physician must bear in mind the common nature of reflex syncope, which occurs with a frequency that is approximately 10 times that of epilepsy presenting in the emergency department. Psychogenic pseudosyncope is a condition included in Table 1 but not Table 2 for the logical reason that it is not a true loss of consciousness. This condition is considered rare but it is probably less rare than has been thought. It is seen in approximately 10% (range 5%20%) of patients attending specialist syncope clinics. Moreover, it is most likely to be the same condition as pseudoseizure presenting to specialist epilepsy clinics.58 Both conditions prove difficult for many physicians to diagnose and treat.9 The correct diagnosis hinges first on careful appraisal of what actually happens and the frequency of episodes, which tends to be very high,7 and secondly on demonstration of an apparent syncope or seizure-like episode despite concomitant normal physiological data (ECG, blood pressure and, ideally, an EEG).5,9,10 The latter observation may be obtained during a spontaneous event, or during laboratory triggering of a pseudofaint or pseudoseizure by tilttable testing, active standing test or even during carotid massage. If exclusion of epilepsy is essential, the diagnosis is made with certainty during a spontaneous or provoked episode with in-hospital continuous video-EEG recording.6,810 In addition home or telephone video (often

342

PR O GRE S S I N C ARDI O VAS CU L AR D I S EAS E S 5 5 ( 2 0 13 ) 33 9 3 44

available on modern mobile telephones) recordings of attacks can be helpful. Patients with pseudosyncope/seizure are predominantly, but not exclusively, young females, many of whom have experienced abuse. These two phenomena have been combined as they are considered manifestations of the same underlying psychopathology, with cardiologists preferring the term pseudosyncope and neurologists using the term pseudoseizure. Epilepsy and its relation to syncope have recently been thoroughly reviewed.10 This cerebral condition is a transient loss of consciousness that is distinct from syncope by there being no cerebral hypoperfusion. Even experienced neurologists may find it difficult to be certain of epilepsy as a diagnosis. The medical history may be unclear and quite often the interictal EEG is normal. It has been shown by using ILRs that an important minority of patients, who were thought to be manifesting drug refractory epilepsy, have been experiencing arrhythmic syncope.11 The converse has not been the subject of sufficient study. How many syncope patients may actually be having epilepsy is not known. In any case, as has been well demonstrated in Manchester, UK, close collaboration between neurologists and cardiologists should now be standard practice when the basis of TLOC is not readily apparent.12 Patients with orthostatic hypotension are usually easily diagnosed by the medical history and in the clinic provided that blood pressure (BP) is assessed by repeated cuff measurements over at least 35 min of active standing. Most of those with a fall in BP in 35 min will be receiving excessive medication for Hypertension. A few will have neurological disease, who will have additional historical points, such as disturbance of other aspects of the autonomic nervous system and many are likely to have physical signs reflecting their disease.13 Arrhythmic syncope due to bradycardia may be obvious at presentation (e.g., AV block observed on ECG) but this is frequently not the case. Long-term ECG monitoring, best achieved with an ILR, may be necessary to make the diagnosis. Indirect provocative testing with adenosine triphospahte injection may have a place in diagnosis but remains controversial.9 In general, the conditions associated with bradycardia are more often benign than those arrhythmias due to tachycardia. The list of causes of syncope, especially the channelopathies, includes conditions that may be revealed by careful study of the ECG. Many episodes of syncope, the mechanism of which is tachycardia, are not benign and an ILR strategy, appropriate in many cases for bradycardiac syncope, is not optimal when tachycardia is the cause. Physical signs are typically absent in those where bradycardia is the mechanism as well as those for whom it is tachycardia. For the tachycardia patients and those with structural heart disease risk stratification is most important. Structural heart disease usually presents physical signs but they may be difficult to appreciate; a thorough physical examination and echocardiographic assessment is necessary to detect the cause of syncope in some of these patients. Special attention to persistent hypotension is necessary as this is a pointer to a serious condition being present. There are

many possible causes of structural heart disease and it is essential to maintain a very open diagnostic mind.

Computer-based diagnosis
In order to attempt to promote expertise and, ultimately, better patient management, introduction of diagnostic computer algorithms in the form of interactive decisionmaking software is most likely to be of value in the emergency and urgent care settings at the sites where the majority of decisions are made with reference to hospital admission. By applying these algorithms, admissions can be decreased without increased risk to patient and with considerable healthcare cost reductions. An early report from the EGSYS-2 study yielded an improved rate of diagnosis up to 98%.14,15 A further report from these investigators found that the diagnostic yield was 95% when European Society of Cardiology (ESC) guidelines9 were applied as opposed to 80% in a parallel group of patients receiving usual care. Admission rates were reduced from 47% in the usual care group to 39% in those managed under the ESC guidelines with also a shorter hospital stay 7.2 vs 8.1 days and fewer diagnostic tests performed 2.6 vs 3.4 in the ESC guideline patients.16 One algorithm is currently available and has an initial favorable report on its use. 3,17 Further studies are required to define fully the potential benefit of this novel method.

Alternative classification
The recent proposal of an alternative classification of syncope according to mechanism is logical as this permits application of the most appropriate therapy. 17 The proposal suggests that ascertaining the mechanism of syncope provides the rhythm disturbance responsible for the syncope. This is usually achieved by recording a spontaneous syncope with an implanted loop recorder. The documented ECG abnormality indicates an appropriate therapy. This has been well exemplified by the ISSUE 2 registry and the ISSUE 3 study. 18,19 The ISSUE 2 registry patients who were treated according to their ILR findings had much better outcomes than those who did not. This raised the possibility that better patient selection for pacing, by documenting asystole in a spontaneous event, would permit more refined selection of patients for pacing resulting in effective treatment. The first two randomized trials of pacing in vasovagal patients, VPS 2 and SYNPACE20,21 had failed to show a benefit from pacing but had used less rigorous selection processes. ISSUE 3 was a controlled trial to test pacing in patients, with a mean age of 63 years, according to ILR documented asystole showing a clear pacing benefit. This is considered persuasive evidence in favor of defining the mechanism of syncope and allowing it to indicate the therapy. It will, however, be necessary to maintain the established etiological classification for the first step, which should then be followed by adoption of the mechanistic approach. The mechanistic approach reveals that using the etiological

PR O GRE S S I N C ARDI O VAS CU L AR D I S EAS E S 5 5 ( 2 0 13 ) 33 9 3 4 4

343

Statement of Conflict of Interest

The authors declare that there are no conflicts of interest.

REFERENCES

Fig 3 Classifications of syncope according to etiology and mechanism (adapted from Brignole and Hamdan17). The lines indicate that virtually any of the etiologies on the left can result in any of the arrhythmic outcomes indicated on the right. The abbreviations: 1 and 2 autonomic failure = primary and secondary autonomic failure. AV = atrioventricular, AVB = atrioventricular block, BP = blood pressure, B-T-S = bradycardia tachycardia syndrome, CSS = carotid sinus syndrome, PSVT = paroxysmal supraventricular tachycardia, MI = myocardial infarction, SAND = sinoatrial node disease or dysfunction, VT = ventricular tachycardia.

method generates some lack of correlation (Fig 3) between the two approaches but recognizing this possibility and adapting to it allows for both to be used for best patient care. As physicians caring for patients with syncope, we attempt to achieve the best understanding of the patient's problem and then act upon it. We are hampered by the lack of any long-term device that can offer a surrogate of blood pressure. With present ILRs we have excellent recording possibilities of the ECG but we can only guess what is happening to the blood pressure at the time of a reported event. In some cases, blood pressure may change substantially without any evident arrhythmia or heart rate variation. Clinicians have a real need for devices that provide some level of blood pressure information.

Conclusion
Syncope has traditionally been classified on etiological grounds but a recent proposal suggests that this should be replaced by a mechanistic approach. While this has undoubted benefits in terms of matching the therapy to the patient's syncope mechanism with improved outcomes, there remains a need to make an initial etiological assessment leading to risk stratification. For those not at high risk the mechanistic method must now be considered optimal.

1. Sutton R, Brignole M, Benditt DG. Key challenges in the management of syncope. Nat Rev Cardiol. 2012;9:590-598. 2. Grossman SA, Fischer C, Kancharla A, Lipsitz LA, Mottley L, Zimetbaum P, et al. Can benign etiologies predict benign outcomes in high-risk syncope patients? J Emerg Med. 2011;40: 592-597. 3. Daccarett M, Jetter TL, Wasmund SL, Brignole M, Hamdan M. Syncope in the emergency department: comparison of standardized admission criteria with clinical practice. Europace. 2011;13:1632-1638. 4. Brignole M, Menozzi C, Lolli G, Oddone D, Gianfranchi L, Bertulla A. Pacing for carotid sinus syndrome and sick sinus syndrome. Pacing Clin Electrophysiol. 1990;12:2071-2075. 5. Kouakam C, Vaksmann G, Pachy E, Lacroix D, Rey C, Kacet S. Long-term follow-up of children and adolescents with syncope: predictor of syncope recurrence. Eur Heart J. 2001;22: 1618-1625. 6. Benbadis SR, Chichkova R. Psychogenic pseudosyncope: an underestimated and provable diagnosis. Epilepsy Behav. 2006;9:106-110. 7. Plug L, Reuber M. Making the diagnosis in patients with blackouts: it's all in the history. Pract Neurol. 2009;9:4-15. 8. Hall-Patch L, Brown R, House A, Howlett S, Kemp S, Lawton G, et al. Acceptability and effectiveness of a communication strategy for the diagnosis of non-epileptic attacks. Epilepsia. 2010;51:70-78. 9. Moya A, Sutton R, Ammirati F, Blanc JJ, Brignole M, Dahm JB, et al. The Task Force for the Diagnosis and Management of Syncope of the European Society of Cardiology (ESC). Guidelines for the diagnosis and management of syncope (version 2009). Eur Heart J. 2009;30:2631-2671. 10. van Dijk JG, Thijs RD, Benditt DG, Wieling W. A guide to disorders causing transient loss of consciousness: focus on syncope. Nat Rev Neurol. 2009;5:438-448. 11. Ziadi A, Clough P, Cooper P, Scheepers B, Fitzpatrick AP. Misdiagnosis of epilepsy: many seizure-like attacks have a cardiovascular cause. J Am Coll Cardiol. 2000;36:181-184. 12. Petkar S, Bell W, Rice N, Iddon P, McKee D, Curtis N, et al. Initial experience with a rapid access blackouts triage clinic. Clin Med. 2011;11:11-16. 13. Freeman R, Wieling W, Axelrod FB, et al. Consensus statement on definition of orthostatic hypotension, neutrally mediated syncope and the postural tachycardia syndrome. Clin Auton Res. 2011;21:69-72. 14. Brignole M, Menozzi C, Bartoletti A, et al. A new management of syncope: prospective systematic guideline-based evaluation of patients referred urgently to general hospitals. Eur Heart J. 2006;27:76-82. 15. Brignole M, Ungar A, Bartoletti A, et al. Standardized care pathway versus usual management of syncope referred in emergency to general hospitals (EGSYS 2). Europace. 2006;8: 644-650. 16. Brignole M, Ungar A, Casagrande I, et al. Prospective multicentre systematic guideline-based management of patients referred to the syncope units of general hospitals. Europace. 2010;12:10-118. 17. Brignole M, Hamdan MH. New concepts in the assessment of syncope. J Am Coll Cardiol. 2012;59:1583-1591.

344

PR O GRE S S I N C ARDI O VAS CU L AR D I S EAS E S 5 5 ( 2 0 13 ) 33 9 3 44

18. Brignole M, Sutton R, Menozzi C, et al. International Study on Syncope of Uncertain Etiology 2 (ISSUE 2). Early application of an implantable loop recorder allows effective specific therapy in patients with recurrent suspected neurally mediated syncope. Eur Heart J. 2006;27:1085-1092. 19. Brignole M, Menozzi C, Moya A, et al. Pacemaker therapy in patients with neurally mediated syncope and documented asystole: Third International Study on Syncope of Uncertain Etiology (ISSUE-3): a randomized study. Circulation. 2012;125: 2566-2571.

20. Connolly SJ, Sheldon R, Thorpe KE, et al. VPS II Investigators. Pacemaker therapy for prevention of syncope in patients with recurrent severe vasovagal syncope: Second Vasovagal Pacemaker Study (VPS II): a randomized trial. JAMA. 2003;289:22242229. 21. Raviele A, Giada F, Menozzi C, et al. The vasovagal syncope and pacing trial [SYNPACE]. A randomised, double-blind, placebo-controlled study of permanent cardiac pacing for the treatment of recurrent tilt-induced vasovagal syncope. Eur Heart J. 2004;25:1741-1748.