24.5.4 Syncope 5896 Andrew J. Larner

24.5.4 Syncope 5896 Andrew J. Larner

section 24  Neurological disorders 5896 FURTHER READING American Academy of Sleep Medicine (2014). The International Classi­ fication of Sleep Disorders, 3rd edition. AASM, Westchester, NY. Arnulf I, et al. (2005). Kleine–​Levin syndrome: a systematic review
of 186 cases in the literature. Brain, 128, 2763–​76. Bassetti C, Aldrich MS (1997). Idiopathic hypersomnia: a series of
42 patients. Brain, 120, 1423–​35. Chemelli RM, et al. (1999). Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell, 98, 437–​51. Cappuccio FP, Miller MA (2017). Sleep and cardio-metabolic dis- ease. Curr Cardiol Rep, 19, 110. Dauvilliers Y, Arnulf I, Mignot E (2007). Narcolepsy with cataplexy. Lancet, 369, 499–​511. Frank MG (2006). The mystery of sleep function: current perspectives and future directions. Rev Neurosci, 17, 375–​92. Garcia-Borreguero D, et al. (2013). The long-term treatment of rest- less legs syndrome/Willis-Ekbom disease: evidence-based guidelines and clinical consensus best practice guidance: a report from the Inter­ national Restless Legs Syndrome Study Group. Sleep Med, 14, 675–84. Harris CD (2005). Neurophysiology of sleep and wakefulness. Respir Care Clin, 11, 567–​86. Hattar S, et  al. (2003). Melanopsin and rod-​cone photoreceptive systems account for all major accessory visual functions in mice. Nature, 424, 75–​81. Lin L, et al. (1999). The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell, 98, 365–​76. Lu BS, Zee PC (2006). Circadian rhythm sleep disorders. Chest, 130, 1915–​23. Lu J, et al. (2006). A putative flip-​flop switch for control of REM sleep. Nature, 441, 589–​94. Mason TBA, Pack AI (2007). Paediatric parasomnias. Sleep, 30, 141–​51. Mignot E, Nishino S (2005). Emerging therapies in narcolepsy–​ cataplexy. Sleep, 28, 754–​63. Morin C, et al. (1999). Nonpharmacologic treatment of chronic insomnia. An American Academy of Sleep Medicine review. Sleep, 22, 1134–​56. Nishino S, Kanbayashi T (2005). Symptomatic narcolepsy, cataplexy and hypersomnia, and their implications in the hypothalamic hypocretin/​orexin system. Sleep Med Rev, 9, 269–​310. Olson, EJ, Boeve BF, Silber MH (2000). REM sleep behaviour disorder: demographic, clinical and laboratory findings in 93 cases. Brain, 123, 331–​9. Overeem S, et al. (2012). Narcolepsy. Sleep Med Clin, 7, 263–​81. Postuma RB, et al. (2012). Rapid eye movement sleep behavior dis- order and risk of dementia in Parkinson’s disease. Mov Disord, 27, 720–​6. Saper CB (2006). Staying awake for dinner: hypothalamic integration of sleep, feeding and circadian rhythms. Prog Brain Res, 153, 243–​52. Saper CB, Chou TC, Scammell TE (2001). The sleep switch: hypothal- amic control of sleep and wakefulness. Trends Neurosci, 24, 726–​31. Silber MH (2001). Controversies in sleep medicine:  periodic limb movements. Sleep, Med, 2, 367–​9. Thannickal TC, et al. (2000). Reduced number of hypocretin neurons in human narcolepsy. Neuron, 27, 469–​74. Turek FW (2004). Circadian rhythms: from the bench to the bedside and falling asleep. Sleep, 27, 1600–​2. 24.5.4  Syncope Andrew J. Larner ESSENTIALS Syncope is the most common identified cause of transient loss of consciousness, being ten times more frequent than epilepsy. It is a consequence of cerebral hypoperfusion due to reduced cardiac Subject complains of inappropriate naps during the day or if Epworth score more than 10 Is likely cause either insufficient sleep, shift work, or environmental factors? Is medication a likely cause? Is there a history of severe snoring or apnoea at night? Is typical cataplexy present? Are the legs restless and/or jerky at night? No clear diagnosis from history? Is there a likely underlying neurological cause such as Parkinson’s disease? NO NO NO NO NO NO YES YES YES YES YES YES ADVISE LIFESTYLE CHANGES ADJUST OXIMETRY AND/OR PSG CONSIDER MSLT OR CSF HCT ASSAY IF DOUBT CONSIDER EMPIRICAL TREATMENT TREAT CONSIDER PSG AND MSLT YES Fig. 24.5.3.5  Algorithm for the assessment of excessive daytime sleepiness. Most authorities regard a score of 10 or over on the subjective Epworth sleep scale as significant. Oximetry can usually be performed overnight in the patient’s home with a finger monitor. CSF, cerebrospinal fluid; HCT, hypocretin (also called orexin); MSLT, multiple sleep latency test; PSG, polysomnography.

24.5.4  Syncope 5897 output, often related to reduced venous return due to decreased peripheral vascular resistance with pooling of blood volume in de- pendent body parts. Causes These include (1)  neurally mediated—​vasovagal; situational (e.g. cough syncope; carotid sinus); (2)  orthostatic (postural) hypotension—​autonomic failure; drug-​induced; volume deple- tion; (3) cardiac arrhythmia; (4) cardiac/​vascular structural dis- ease (e.g. aortic stenosis). Diagnosis, prognosis, investigations, and treatment Diagnosis is clinical, based on history of the circumstances of the event obtained from the patient and reliable eyewitness(es). In most patients, particularly under 45 years of age, the condition is benign and self-​limiting, with an excellent prognosis, requiring little investigation beyond physical examination and electrocar- diogram to exclude heart disease. Cardiac causes of syncope may require specific treatment. Introduction Syncope can be defined as a transient loss of consciousness asso- ciated with loss of postural tone consequent upon acute reduction of cerebral blood flow. Presyncope is the term sometimes used for symptomatic episodes of cerebral hypoperfusion which do not pro- gress to transient loss of consciousness. Syncope and presyncope are among the most common problems seen in general neurological outpatient clinics, although the condition overlaps both neuro- logical and cardiological practice since syncope is a syndrome with various causes ranging from benign self-​limiting episodes with ex- cellent prognosis to recurrent and possibly life-​threatening attacks, the latter often associated with an underlying cardiac disorder. Correct diagnosis is therefore vital, since management will be de- pendent on cause. Differential diagnosis, most particularly from epi- lepsy, is often required. Pathogenesis The pathophysiology of syncope relates to cerebral hypoperfusion, perhaps most particularly affecting the hindbrain. This may follow reduced cardiac venous return, consequent upon reduced periph- eral vascular resistance with peripheral blood pooling, leading to reduced stroke volume and cardiac output, or to a primary cardiac disorder impairing cardiac output. Factors predisposing to and precipitating the pathophysiological changes causing syncope may be identifiable, but often the pathogenesis is multifactorial, particu- larly in elderly patients. Distinction may be made between two forms of syncope: vaso- vagal, also known as reflex, neurally mediated, or neurocardiogenic syncope; and cardiac or cardiogenic syncope. This dichotomization forms the basis of widely used classification systems for syncope (Table 24.5.4.1). Vasovagal syncope In vasovagal syncope, reduced peripheral vascular resistance al- lows pooling of blood in dependent body areas, most usually the lower limbs, hence reduced venous return and cardiac output with consequent cerebral hypoperfusion. This may be precipitated (‘triggered’) by activities such as standing from the sitting or lying posture or prolonged standing (i.e. orthostatic stress), or by pain, fear, or medical procedures (e.g. venepuncture). In the absence of an evident trigger, the term ‘atypical vasovagal syncope’ may be used. In vasovagal syncope there may be a paradoxical bradycardia (cardioinhibitory response), since standing normally induces a re- flex increase in heart rate. It was this observation that led investiga- tors to infer an increase in vagal tone and Sir Thomas Lewis to coin the term ‘vasovagal’. However, the pathophysiology may, at least in some cases, relate also to sympathetic withdrawal with hypotension (vasodepressor response). Despite hypotension and thoracic hypo- volaemia, a paradoxical cerebrovascular arteriolar vasoconstriction has been observed experimentally, sometimes without cardiovas- cular changes (‘cerebral syncope’). Table 24.5.4.1  Causes of syncope Neurally mediated (neurocardiogenic, reflex) syncope: Vasovagal syncope: Typical Atypical Exertion-​related Sleep syncope Situational syncope (e.g. cough, sneeze, swallow, defaecation, postexercise, postprandial) Spontaneous carotid sinus syncope Orthostatic (postural) hypotension: Autonomic failure: primary, secondary Drug-​induced Volume depletion Cardiac arrhythmias: Sinus node disease (e.g. sick sinus syndrome) Atrioventricular conduction disorders Paroxysmal supraventricular and ventricular tachycardias Inherited disorders: prolonged QT syndromes (Romano-​Ward syndrome, Jervell-​Lange-​Nielsen syndrome), Brugada syndrome Cardiac/​vascular structural disease: Cardiac valvular disease (e.g. aortic stenosis) Acute myocardial infarction, ischaemia Hypertrophic obstructive cardiomyopathy Atrial myxoma Pericardial disease Subclavian steal syndrome

section 24  Neurological disorders 5898 Situational syncope, such as cough or post-​tussive syncope, mic- turition syncope, swallow syncope, and defaecation syncope, may be subsumed under the category of neurally mediated or reflex syncope. Pathophysiologically, these entities share similar mechanisms related to reduced venous return, sometimes associated with performance of the Valsalva manoeuvre. The latter may also be relevant in syncope asso- ciated with diverse activities such as weight-​lifting or trumpet playing. Spontaneous carotid sinus syncope, related to carotid sinus hypersensitivity, may be precipitated by pressure on the neck or head turning. This clinical scenario is uncommon, although sensitivity as judged by carotid sinus massage may be found in patients without these particular triggers and forms an integral part of clinical inves- tigation of atypical vasovagal syncope. Sleep syncope is a recently characterized form of vasovagal syn- cope with attacks in the supine position, typically when waking with abdominal discomfort and an urge to defaecate followed by tran- sient loss of consciousness, often with associated autonomic features (sweating, nausea, palpitations, feeling warm). Orthostatic (postural) hypotension of any cause, such as use of certain drugs or autonomic failure, pregnancy, or in association with anaemia or reduced circulating blood volume, may predispose to syncope by impairing peripheral vascular resistance, likewise large meals with resultant postprandial hypotension. Cardiac syncope Cardiac syncope results from a fall in cardiac output which may be associated with arrhythmias, both brady and tachyarrhythmias, per- haps related to ischaemic heart disease or to specific disorders such as Brugada’s syndrome, or with structural cardiac disease such as hypertrophic cardiomyopathy (subaortic stenosis) or valvular dis- ease such as aortic stenosis. Vascular steal syndromes such as sub- clavian steal may also be associated with syncope due to diversion of blood away from hindbrain structures. Categories of idiopathic syncope (‘syncope of unknown origin’) and psychogenic syncope (or, more correctly, pseudosyncope) are also described, but these are both diagnoses of exclusion. The former is a useful diagnostic category since it is associated with a better prognosis than cardiac syncope. Psychogenic syncope (feigned un- consciousness) may be associated with various psychiatric diag- noses including panic attack, somatization, factitious disorder, and frank malingering. Epidemiology No age group is immune from syncope, although the cause does vary with age. In neurological practice, the diagnosis is most commonly made in adolescents or young adults who typically have neurally mediated syncope, with a marked predominance of females, and in older people where the possibility of a cardiac cause or multiple fac- tors is higher. Community-​based epidemiological surveys suggest that many individuals suffering a single or few syncopal episodes do not seek medical advice. Clinical features The clinical history is of paramount importance in making the diag- nosis of syncope. In this context, since patients are almost invariably seen after the event, the opportunity to question a reliable eyewit- ness, if need be by telephone, may be the most important investiga- tion. Equally, the clinician should guard against too great a readiness to accept witness statements that what they saw was a ‘seizure’ or ‘convulsion’. Symptoms before, during, and after the ictus should be ascertained (Table 24.5.4.2). It is recognized that in older subjects with a higher risk of cardiac syncope, the yield of the medical his- tory is lower. The circumstances preceding the event must be inquired about, questioning which aims to ascertain any provoking factors, par- ticularly emotional distress and orthostatic stress. Emotional or physical trauma, pain (including period pain, and eyeball pain or pressure:  the oculocardiac syndrome), and fatigue may increase the risk of syncope, as may sleep deprivation, either situational or in the context of sleep-​related disorders such as obstructive sleep apnoea-​hypopnoea syndrome. The stuffy atmosphere of hot and crowded environments may also predispose. Attacks while in the dentist’s chair, during venesection, or at the sight of blood are classic. Likewise, attacks immediately on rising from a recumbent position, or after prolonged standing, or up to 90 minutes after a large meal are suggestive of neurally mediated syncope. Cardiac syncope may be triggered by exercise, whereas postexertional syncope is more likely to be neurally mediated. Patients may be able to recall some premonitory, presyncopal, symptoms (Table 24.5.4.2), sometimes prompting their own Table 24.5.4.2  Symptoms in typical vasovagal syncope and approximate frequencies Prodrome TLoC Recovery Pallor (87%) Awareness of fainting (69%) Sweating (43%) Palpitations (33%) Blurred vision (31%) Weakness (31%) Nausea (26%) Feeling cold (18%) Feeling warm (15%) Abdominal discomfort (13%) Vomiting (10%) Tremors (8%) Yawning (3%) Abnormal movements (13%) Incontinence of urine (3%) Pallor (61%) Sweating (59%) Weakness (46%) Feeling cold (36%) Confusion (33%) Nausea (26%) Abdominal discomfort (10%) Vomiting (5%) Feeling warm (3%) TLoC, transient loss of consciousness.

24.5.4  Syncope 5899 comment that they have had a ‘faint’ or a ‘blackout’. These may in- clude a sensation of light-​headedness, as though they were going to pass out. Sometimes this is described by patients as ‘dizziness’, which must be distinguished from the ‘spinny dizziness’ (illusion of move- ment: vertigo) often reported in vestibular disorders. Patients may recall commenting on not feeling well, or being asked by witnesses if they were feeling all right. Patients may report that sounds such as voices were audible and intelligible but increasingly distant, or there may be tinnitus. Vision may shrink or become black leaving just ‘tunnel vision’, sometimes described as a feeling of distance. Patients may feel weakness or tingling (paraesthesia), or that they ‘need air’, and indeed may take action to leave the room or go outside before collapsing. Evasive action such as sitting or lying may be possible if presyncopal symptoms last one to two minutes, as may occur in neurally mediated syncope. Nausea, sweating (diaphoresis), feeling both hot and cold may also be remarked upon, suggesting autonomic activation; skin may feel clammy (cold and sweaty) to the touch. An enquiry about premonitory palpitations, during or independent of attacks of loss of consciousness, should also be made. However, not all syncopal episodes have premonitory symp- toms, in which case the likelihood of the attack being either atyp- ical vasovagal syncope or cardiac syncope is increased (Table 24.5.4.3). In addition, elderly people may have retrograde amnesia for syncopal episodes, and present to clinical services simply with ‘unexplained falls’. For events during the syncopal episode, the clinician is dependent on eyewitness accounts. These may note that the patient gradually slumps to the ground and lies still. The duration of loss of conscious- ness is usually brief, around 20 seconds, although on occasion it can be as long as minutes. Facial pallor, loss of colour or ‘greyness’ may be remarked upon. There may be some irregular twitching jerky (myo- clonic) movements of the limbs, ascribed to tonic brainstem motor activity, but not the sustained regular alternating tonic–​clonic move- ments typical of a generalized epileptic seizure (unless syncope is com- plicated by a secondary anoxic seizure, particularly if well-​meaning but misguided bystanders try to keep the patient in the upright pos- ition). Nonetheless an untrained observer may mistake myoclonic jerks for a ‘convulsion’ or ‘seizure’. Incontinence of urine may occur even in the absence of an epileptic seizure, and some studies have found that incontinence is not a useful discriminator between seizure and syncope. A slow pulse may be detected, should any bystander be both sufficiently quick-​witted and knowledgeable to assess this. Patients should be questioned about the next thing they remember after the blackout. Since the period of loss of consciousness is brief, patients may recollect coming round in the same location where they were at the onset of prodromal symptoms. Orientation to surround- ings should be inquired about; generally, patients are ‘with it’ and rec- ognize their surroundings fairly promptly, within a minute or two of coming round, and may ask what is going on. They may recall crowds of people around them. Eyewitnesses may also attest to a rapid recovery, without a prolonged period of postictal confusion. Disorientation after a blackout increases the likelihood that it was due to a seizure, as does increasing age. Facial pallor may persist after recovery from syncope, as may skin clamminess, and nausea and vomiting. Historical features may also be helpful in differentiating neurally mediated from cardiac syncope with high sensitivity and specificity (Table 24.5.4.3). Presyncopal features may last longer in neurally mediated attacks, and indeed may be entirely absent in some forms of cardiac syncope. Syncope with onset during exercise or in the supine position should always prompt consideration of a cardiac cause. Differential diagnosis The most important differential diagnosis of syncope is seizure, ei- ther epileptic or non​epileptic attack disorder. Other conditions to consider may also include drop attacks, transient ischaemic attack, cataplexy, and hyperekplexia, even though transient loss of con- sciousness is not a feature of these conditions. Patients with syncope are not infrequently reported to have had a fit or a seizure by bystanders, comments prompted perhaps by ob- servation of the myoclonic jerks which may occur. Various histor- ical and clinical features may argue for syncope and against epilepsy (Table 24.5.4.4), although it should be remembered that secondary anoxic epileptic seizures may complicate otherwise benign syncopal attacks; for example, if a patient is supported by bystanders and not allowed to fall to the floor. Hence, the diagnoses of syncope and seizure are not necessarily mutually exclusive. Atonic seizures may present a particular diagnostic problem, although these most often occur in combination with other types of epileptic seizure. Features which should raise the clinical index of suspicion for an epileptic seizure include lack of obvious provoking factors, am- nesia for the attack, a prolonged period of loss of consciousness, an eyewitness account of typical tonic–​clonic movements, attacks Table 24.5.4.3  Clinical clues to the differentiation of neurally mediated syncope from cardiac syncope Neurally mediated syncope Cardiac syncope Onset often subacute, with prodromal symptoms: faintness, weakness, paraesthesia, nausea, sweating Onset often sudden: palpitations, chest pain, dyspnoea may be present Precipitating and predisposing factors: emotional upset, trauma, pain, fatigue, assumption of upright posture, prolonged standing, postexercise, postprandial, hot enclosed environments, pregnancy Onset often spontaneous; may occur during exercise; may be history of cardiac disorder Often standing or sitting at onset Onset may occur standing, sitting, or supine (latter should increase suspicion of cardiac syncope) Appearance: facial pallor; usually patients lie still but irregular myoclonic twitches may occur; urinary incontinence may occur. May feel clammy (cold and sweaty) to touch. Bradycardia may be detected Similar, but urinary incontinence uncommon. Heart rhythm abnormality may be detected Post ictus: rapid recovery of orientation. Further episodes of syncope may occur with attempted standing Similar, unless prolonged hypoxia

section 24  Neurological disorders 5900 developing during sleep, prolonged postictal confusion, and the presence of physical injury sustained during the event (although in- juries such as bony fractures and subdural haematoma may be sus- tained during syncope). A simple point score of historical features may distinguish syncope from seizures with sensitivity and speci- ficity of over 90%. Various clinical features may prompt consider- ation of non​epileptic attack disorder in the differential diagnosis of blackout, including convulsive movements not typical of epileptic attacks, sometimes including pelvic thrusting; eye closure with re- sistance to eye opening; and superficial injuries such as carpet burns. Drop attacks, unexplained falls forward onto the knees, particu- larly in older people, are not associated with loss of consciousness, but since patients may have little recall of these events this clinical scenario should prompt consideration of syncope. Carotid transient ischaemic attacks are not associated with loss of consciousness, and vertebral transient ischaemic attacks seldom so, and the latter are invariably accompanied by other focal neurological signs (diplopia, vertigo). Cataplexy, loss of muscular tone leading to a brief fall in response to emotion such as laughter, may be a feature of the nar- coleptic syndrome or occur in isolation, but is not associated with transient loss of consciousness; likewise, hyperekplexia, the patho- logical exaggeration of the startle response which may provoke a fall. Postural orthostatic tachycardia syndrome is characterized by ex- cessive increase in heart rate on assumption of upright posture but without orthostatic hypotension, and the presyncopal symptoms may resemble vasovagal presyncope. Clinical investigation Clinical examination at the scene of the syncopal event is seldom possible, and delayed examination in a clinical setting may well be unremarkable. Signs of cardiac disease, arrhythmic or structural, should be sought. Checking the blood pressure in the lying and standing positions to look for orthostatic hypotension may be under- taken, but prolonged standing (minutes) may be necessary to ob- serve a drop in blood pressure. Standard 12-​lead electrocardiography (ECG) is indicated to exclude arrhythmias such as short PR interval, prolonged corrected QT interval (QTc), and Brugada syndrome (right bundle branch block with ST segment elevation in leads V1 to V3). If a standard ECG is normal, then no other investigations may be required, particularly in young and otherwise healthy individuals. In typical vasovagal syncope, diagnosis and management may be based on the history alone and require no additional investigation. Further investigation, if required, generally falls outwith the experience and expertise of neurologists. In suspected atypical vasovagal syncope, the key investigation is head-​upright tilt table testing, a continuous passive orthostatic stress, with or without additional carotid sinus massage, to reproduce syncope and/​or find evidence of cardioinhibitory (bradycardia, or asystole; ‘malignant syncope’) and vasodepressor (hypotensive) responses. Tilt table testing affords continuous ECG and blood pressure monitoring and is undertaken with resuscitation equipment to hand. Ambulatory ECG may be indicated if the clinical index of sus- picion for arrhythmia is high (e.g. history of palpitations, elderly patient, recurrent events), but is subject to limited specificity un- less rhythm disturbances are correlated with clinical symptoms. Monitoring of cardiac rhythm with loop recorders (external, implantable) may be considered, and may indicate the need for pacemaker insertion in some patients with recurrent syncope. Echocardiography may be performed when there is clinical suspi- cion of a valvular (e.g. aortic stenosis) or other cardiac structural abnormality (e.g. hypertrophic obstructive cardiomyopathy, atrial myxoma), or if there is a positive cardiac history or abnormal ECG, but it has no place in otherwise unexplained syncope. Blood tests to exclude anaemia and hyponatraemia may be ap- propriate. Biomarkers of syncope have yet to be identified, although some candidates have been reported (B-​type natriuretic peptides; copeptin, a stress hormone). Structural brain imaging (CT, MRI) and electroencephalogram (EEG) may be indicated if seizure seems more likely than syncope as the cause of loss of consciousness. Cognitive screening is sometimes advocated in patients with unex- plained falls. Recurrent syncope is listed as a supportive feature in diagnostic criteria for dementia with Lewy bodies. Treatment and prognosis Treatment should be individualized according to cause. Explanation and reassurance may be the only intervention required in young in- dividuals without heart disease and with a normal ECG since prog- nosis is excellent. Advice about avoiding recognized predisposing and precipitating factors of neurally mediated syncope may be appropriate, as may increasing fluid and salt intake. Physical counterpressure man- oeuvres, such as hand gripping or crossing legs, may be effective if prodromal symptoms last long enough to enact them. Prognosis is worse for cardiac syncope than neurally mediated syncope, and the presence of structural heart disease is a predictor Table 24.5.4.4  Clinical clues to the differentiation of syncope from seizure Syncope Seizure Subacute onset with prodromal features Sudden onset, sometimes preceded by symptoms of aura (e.g. olfactory hallucinations) Precipitating and predisposing factors often identifiable from history Onset often spontaneous; may be predisposing factors such as sleep deprivation, missing meals, or precipitating factors such as flashing lights Onset most often when standing or sitting Onset may occur standing, sitting, or supine Appearance: facial pallor; usually lie still but irregular myoclonic twitches may occur, likewise urinary incontinence May be cyanosed or flushed. Stertorous breathing. Stereotypic tonic–​clonic movements in generalized seizures. Urinary and faecal incontinence may occur. Tongue biting (sides > tip). Injury as a consequence of fall Recovery usually rapid, with prompt orientation to surroundings Recovery often delayed many minutes, and no recall of event. Residual neurological signs may be present (Todd’s paresis, aphasia)