Neurol. Croat. Vol. 62, 1-2, 2013

Neurally mediated

A. Ljilja1, A. Mišmaš2, I. Adamec2, M. Habek1,3

ABSTRACT - Neurally mediated or vasovagal syncope is the most common cause of transient loss of con- sciousness. Too excessive response to diff erent triggers (emotional stress, scenes of blood, prolonged stand- ing, etc.) results in brief and self-limiting loss of consciousness caused by a sudden drop in with or without drop, which leads to transient brain hypoxia. Prior to the episode of syncope, the patient can have a sensation of , sweating, pallor, and visual fi eld narrowing. Although it is known that in the syncope background there is dysregulation of blood pressure control, the pathophysiology is still un- clear. Blood pressure regulation involves complex aff erent signals from the aortic arch processed by the cen- 3

tral and eff erent modulation of the heart and vascular system. Vasovagal syncope usually Number 1-2, 2013 does not require treatment. However, in some cases to rule out other causes of fainting, such as , a broad diagnostic work-up is required, for which head-up is most commonly used. Frequent vasovagal syncope adversely aff ects patient’s quality of life and pharmacological treatment with β-blockers, such as metoprolol, selective serotonin reuptake inhibitors and vascular constrictors like α-agonists can be administered. Other techniques to reduce hypotension are foot exercise, compressive stockings, increased fl uid and salt intake. In more serious cases of vasovagal syncope with bradycardia or asystole, insertion of the electric pacemaker is an option.

Key words: bradycardia, head-up tilt table test, hypotension, neurally mediated syncope

INTRODUCTION 1School of Medicine, University of Zagreb, Zagreb, Syncope is a transient loss of consciousness with Croatia complete and fast recovery of consciousness and 2Zagreb University Hospital Center, Clinical Depart- previous neurological functions. In general, it can ment of , Referral Center for Intensive Neu- rology of the Croatian Ministry of Health, Zagreb, be classifi ed as vasovagal (situational, neurally me- Croatia diated), cardiac or orthostatic syncope. Older pa- 3Zagreb University Hospital Center, Clinical Depart- tients are more prone to orthostatic syncope, ca- ment of Neurology, Referral Center for Demyelinating rotid sinus hypersensitivity and cardiac syncope, Diseases of the Central Nervous System of the Croatian while younger patients are more prone to vasova- Ministry of Health, Zagreb, Croatia A. Ljilja, A. Mišmaš, I. Adamec, M. Habek. Neurally mediated syncope Neurol. Croat. Vol. 62, 1-2, 2013

gal syncope (VVS). Other syndromes with similar Aff erent signals are transmitted from the aortic presentations are , metabolic and psycho- arch via vagal nerve and from the carotid sinus via genic disorders, and acute intoxication. glossopharyngeal nerve to the central nervous sys- tem. Distension of the vascular structures aft er car- Patients with frequent episodes have greater pos- diac systole results in discharge of aff erent nerves sibility of severe clinical disorders compared to pa- that converge from the nucleus tractus solitarius to tients with isolated syncope (1). VVS is a common the brainstem. At this point, eff erent sympathetic problem in the population. About 3.5% of people fl ow is inhibited and eff erent vasovagal fl ow is in- experience one or more episodes of VVS in life- creased (10). time (2). Approximately 40% of cases remain undi- agnosed, while 30% of patients experience recur- Th e most commonly used model for the neurally rent episodes (3). Th e pathophysiology of syncope mediated syncope is the Bezold-Jarisch refl ex in is a complex hemodynamic response with marked which excessive venous load begins a chain of hypotension, bradycardia and loss of conscious- events that culminate in vasodilatation and brady- ness. Syncope is caused by barorefl ex dysfunction, cardia, which consequently leads to hypotension neuroendocrine response, and inadequate respon- and loss of consciousness (11). se of the central nervous system to stressor. Epi- Excessive venous load of the lower extremities re- sodes of syncope in today’s lifestyle can cause dis- sults in decreased ventricular volume, which acti- comfort and inconvenience for the patient. In most vates sensory receptors in the inferoposterior wall cases, medical history, physical examination and of the left ventricle, which responds to pressure standard electrocardiogram (ECG) are suffi cient changes by increasing nerve outfl ow to the central for diagnosis (3). Although there are many diff er- nervous system via vagal nerve. Parasympathetic ent therapeutic measures to prevent syncope, its activity accompanied by vasodilatation and brady- treatment is largely empirical and suboptimal, cardia increases (12). It is believed that diff erent which is a result of heterogeneous patient popula- modulators of the central nervous system activity tion and the lack of controlled randomized trials can cause vasovagal syncope. Th e potential media- (4). In most cases, detailed medical history is tors in the development of vasovagal syncope are enough to determine the causes of fainting. Th e serotonin, adenosine and opioids. Th e β endorphin term ‘pre-syncope’ is used to describe a situation level is increased in patients during syncope. Dif- that resembles the prodromes of syncope, but is ferent clinical presentations of vasovagal syncope, 4 not followed by loss of consciousness. It is believed variable outcome and syncope induced by the tilt- that the pathophysiological mechanisms of pre- up test with drugs, such as isoproterenol, nitro- syncope are the same as in syncope (5). glycerin and clomipramine indicate that complex pathophysiological mechanisms cause vasovagal Epidemiology reaction. Syncope is a common clinical disorder with the Number 1-2, 2013 Number Neurohumoral theory annual incidence of 1.3 to 2.7 per 1,000 inhabitants (2). Epidemiological studies indicate that approxi- Experimental models have shown that the injec- mately 40% of people in the general population tion of serotonin into cerebral ventricular areas have experienced at least one episode of syncope can cause similar sympathetic withdrawal response (6). Clinical studies show that the peak incidence as in vasovagal syncope (13,14). Selective serotonin of syncope is between 10 and 30 years of age (7). In reuptake inhibitors (SSRI) can be successful in the younger patients, neurally mediated syncope is the treatment of vasovagal syncope (15). Some authors most common cause, whereas in older patients suggest that because the SSRI facilitate nerve trans- cardiovascular causes are more frequent (8). mission, they cause SSRI receptor down-regulation in the brainstem, which results in a blunted re- sponse to rapid shift s in the central serotonin levels Etiology and pathophysiology (15-18). Physiological regulation of blood pressure consists of the aff erent signals processed by the central Dysregulation of cerebral fl ow nervous system, and the eff erent modulation of the cardiovascular system (9). Normal regulation of More than 35 years ago, some authors suggested arterial blood pressure is controlled by barorecep- the patients with VVS to have abnormal cerebral tors located in the aortic arch and carotid sinus. vascular response to orthostatic stress, which may Neurol. Croat. Vol. 62, 1-2, 2013 A. Ljilja, A. Mišmaš, I. Adamec, M. Habek. Neurally mediated syncope

be associated with the pathophysiology of this syn- than half (56%) had a history of mood disorder drome (19). Th is concept is supported by fi ndings and 21% were taking psychotropic medications. on cerebral and reduced cerebral Psychological problems include suicidal thoughts, blood fl ow in patients with VVS. depression, panic attacks and chronic anxiety, which is similar to the level of emotional symptoms in chronic patients. CLINICAL PRESENTATION History data on environmental factors are impor- DIAGNOSTIC EVALUATION tant for the diagnosis, since syncope is oft en caused by the sight or loss of blood, sudden stressful or Th erapeutic and diagnostic guidelines of the Euro- painful experience, surgical manipulation or trau- pean Society of defi ne standards for ma. Precipitating symptoms and signs are pallor, the management of syncope and propose a model weakness, yawning, nausea, hyperventilation, blur- of organization for patient evaluation (23). Blood red vision and impaired hearing immediately be- tests, cardiac workup (ECG, echocardiography, fore syncope. Th e patient falls in horizontal posi- holter ECG), head-up tilt table test (HUTT), elec- tion and aft er a few seconds or minutes returns to troencephalography (EEG), transcranial vessel ul- consciousness. While regaining consciousness, the trasound and neuroimaging are diagnostic proce- patient may experience a feeling of weakness, but dures for syncope. Despite all clinical tests, the usually does not show signs of confusion. VVS is cause of syncope remains undetermined in 30% of mostly associated with benign prognosis. A small patients. proportion of patients have recurrent attacks of syncope, which can aff ect their quality of life, HUTT allows for reproduction of syncope and mainly due to frequent falls and (20). monitoring the patient’s physiological responses during syncope. Direct observation and documen- Although most patients shows typical signs of VVS tation of symptoms during the test give a precise such as and full recovery aft er a few min- diagnosis and information for treatment and con- utes, up to 30% of patients have an atypical presen- trol of the symptoms (28). In patients with cardiac tation (21). symptoms, echocardiography, stress testing, holter In case of a longer duration of cerebral hypoper- ECG, loop recorder and electrophysiological tests are recommended. fusion, cramping of body resembling epileptic sei- 5 zures may occur (22). Patients oft en report , Tests for neurally mediated syncope are HUTT Number 1-2, 2013 weakness, dizziness, sweating, blurred vision, tin- and carotid sinus massage, and in case of negative nitus and loss of vision. Some patients experience results, holter ECG and loop recorder. Patients trauma due to the fall, although severe traumatic with rare episodes of syncope probably have neu- injuries are rare. rally mediated syncope and diagnostic tests are Syncope in children is common. Most episodes are usually not needed (23). benign and neurally mediated. Only a small por- Clinical characteristics related to the specifi c caus- tion is potentially life threatening. Diagnosis is pri- es such as VVS are absence of cardiac disease, long- marily achieved by medical history and standard term history of syncope, provocation by unpleas- ECG (23). ant event, smell, sound or pain, prolonged stand- Patients with frequent syncope have a reduced ing, crowded, warm environment, nausea and quality of life, similar to that in patients with severe . Presence of structural heart disease, ap- rheumatoid arthritis or chronic low back pain (24). pearance during exertion, and sudden Patients report diffi culties in activities of daily liv- death in the family are typical for cardiac syncope. ing (71%), driving (60%), physical activity (56%) Psychiatric evaluation is recommended when and walking (42%). Patients with syncope have a symptoms suggest somatization disorder, or if the high incidence of psychological problems, espe- patient has a psychiatric disease. cially anxiety and depression (25). Basic laboratory tests are indicated in cases in Neurally mediated syncope is associated with ab- which syncope is caused by the loss of circulating senteeism from school in children and from work volume or in case of metabolic disorders. In pa- in adults (26). One retrospective study (27) col- tients with suspected heart disease, echocardiogra- lected data from medical records on the emotional phy, holter ECG and electrophysiological monitor- impact of VVS and expressed stressful aspect. More ing are recommended. For patients with chest pain A. Ljilja, A. Mišmaš, I. Adamec, M. Habek. Neurally mediated syncope Neurol. Croat. Vol. 62, 1-2, 2013

Table 1. VASIS classifi cation (34) is used for interpretation of head-up tilt table test

Type 1 – mixed Both blood pressure (BP) and heart rate (HR) are reduced. BP reduction precedes HR reduction. HR decreases by >10%, but HR does not decrease to less than 40 beats/min (Fig. 1) Type 2 – cardioinhibitory Decrease in both BP and HR, and BP decrease precedes decrease in HR. Type 2A: minimum HR is less than 40 (Fig. 2), type 2B: there is asystole for 3 seconds or more (Fig. 3) Type 3 – pure vasodepressor BP is decreased but HR does not decrease more than 10% (Fig. 4) Chronotropic incompetence No HR increase in spite of tilt Excessive HR rise Th is pattern is associated with postural orthostatic tachycardia (POT) (more than 130 beats/min) Positive carotid sinus massage Test needs to be terminated due to one of the criteria aft er carotid sinus massage

6 Fig. 1. Head-up tilt table test in a 22-year-old female Fig. 3. Head-up tilt table test in an 18-year-old patient patient with a history of recurrent loss of showing asystole (upper arrow) and lowest blood consciousness during vaccination, standing in line and pressure (lower arrow). Th e patient complained of piercing. Th e circle in the heart rate line shows drop in , dizziness and a feeling of confusion at that heart rate and the arrow in blood pressure line shows time. minimal blood pressure values at the time of syncope. Number 1-2, 2013 Number

Fig. 2. Head-up tilt table test in a 45-year-old female Fig. 4. Head-up tilt table test in a 90-year-old patient patient with recurrent syncope precipitated with pain. with a history of hypertension and postprandial In circle: drop of heart beat, frequency less than 40 syncope. Note the decrease in blood pressure (arrow), beats per minute. Th e arrow shows minimal blood without decrease in heart rate (circle) typical for the pressure during syncope. vasodepressor type of syncope. Neurol. Croat. Vol. 62, 1-2, 2013 A. Ljilja, A. Mišmaš, I. Adamec, M. Habek. Neurally mediated syncope

typical for ischemia, stress testing, echocardiogra- occur. If there are no symptoms aft er the initial 10 phy and ECG are recommended. HUTT is also min, a painful stimulus with subcutaneous inser- used for diagnosis of the postural orthostatic tachy- tion of 0.7 mm needle into the dorsum of the hand cardia syndrome (POTS). Cardinal criteria for this is performed. Th is test has a sensitivity of 65.9% syndrome are symptoms of orthostatic intolerance and specifi city of 89.7%. Compared to other tests, and absence of (29). For such as Calgary Syncope Symptom Score, it has a patients with syncope during or aft er exertion, higher diagnostic rate and provides a rapid alterna- echocardiography and stress testing are recom- tive to conventional methods (35). mended as the fi rst evaluation step. Cardiac pace- maker is recommended in patients with cardioin- hibitory syncope with the frequency of seizures TREATMENT more than 5 per year (23). Treatment approaches are mostly empirical and symptomatic. Specifi c treatment cannot be made Head-up tilt table test without knowing the cause of syncope. Major ther- apeutic innovations in recent years are isometric HUTT helps the diagnosis of diff erent types of backpressure maneuvers and compression of lower . It is used in younger patients with limbs, while most of the drugs do not have great no obvious or suspected heart disease with recur- performance. Th e basis of the treatment of young rent syncope of unknown origin, for distinction patients with VVS is education about the potential between syncope with myoclonic jerks and epilep- causes of syncope. In elderly patients, specifi c treat- sy, and for the evaluation of patients with unex- ment is oft en necessary. Th e main goal of treatment plained falls or psychiatric disease (5). is to reduce the number of syncopes and psycho- Pharmacological agents are used for provocation logical trauma. of positive test results. Isoproterenol is oft en used Th e fi rst step in the treatment should be an infor- to increase vasovagal response. Other agents used mative talk with the patient about the nature and in tilt table testing are adenosine (vasodilator and prognosis of syncope. Th e patients need to be edu- direct activator of the sympathetic system), nitro- cated about avoiding heat, prolonged standing and glycerin and edrophonium ( activity) decreased fl uid intake. Substitute salt intake and (4). Th e sensitivity of tilt-up test is 26%-80% and isotonic drinks increase the circulating blood vol- specifi city 90% (30). ume and thus venous return. Education includes 7 Patients should be in the horizontal position before information about prodromal symptoms and how Number 1-2, 2013 testing and during HUTT under the angle of 60° to they can be prevented by sitting or lying. Backpres- 80° for 30 to 45 minutes (30). If there is no patho- sure maneuvers such as clamping of the arms or leg logical event and vital signs are normal, the test is crossing can inhibit the VVS by increasing the ve- repeated with pharmacological provocation. Th e nous return (23). most common protocol is infusion of isoproterenol Rare episodes of syncope with prodromal warning or administration of sublingual nitroglycerin. Th e symptoms do not require intervention except for test is considered positive if the patient has a symp- patient observation. In addition, it is important to tomatic decrease in systolic blood pressure and maintain suffi cient fl uid and salt intake, especially bradycardia. Th e room must be equipped with re- during summer. Many drugs have been tested in suscitation equipment. Patients must not consume the treatment of VVS, such as β-blockers, diso- fl uids for at least four hours and solid food for at pyramide, scopolamine, theophylline, ephedrine, least six hours before the test (32). During testing, midodrine, clonidine and SSRI, but there are no the patient’s condition is monitored by ECG and clear data on the gold standard therapy (22). continuous noninvasive blood pressure measure- ment. In patients older than 40 years with a his- Th e most commonly used pharmacological agents tory of syncope, carotid sinus massage is advised are β-blockers, anticholinergics, disopyramide, ad- (33). Th e VAsovagal Syncope International Study enosine receptor blockers, SSRI, α-adrenergic ago- (VASIS) classifi cation (34) is used for interpreta- nists, mineralocorticoids, anticonvulsants, and tion of the HUTT (Table 1). permanent pacemaker as a non-pharmacological treatment (5). Th ese drugs are mainly symptomatic Pain provoked HUTT (PP-HUTT) is a test for con- treatment and are oft en associated with side eff ects, fi rmation of VVS. Th e subjects are tilted to 70° for which make them inappropriate in younger age a maximum period of 10 min or until symptoms groups. , midodrine and compres- A. Ljilja, A. Mišmaš, I. Adamec, M. Habek. Neurally mediated syncope Neurol. Croat. Vol. 62, 1-2, 2013

sion stockings are frequently used in the initial 7. Ganzeboom KS, Colman N, Reitsma JB, Shen treatment of patients with borderline low pressure WK, Wieling W. Prevalence and triggers of syn- and the consequent orthostatic syncope. β-block- cope in medical students. Am J Coll Cardiol ers have been the fi rst choice in the treatment for 2003; 91: 1006-8. a number of years. According to the guidelines of 8. Colman N, Nahm K, Ganzeboom KS et al. Epi- the European Society of Cardiology, β-blockers demiology of refl ex syncope. Clin Auton Res should not be used for the treatment of refl ex syn- 2004; 14 Suppl 1: 9-17. cope (5). Midodrine eff ects smooth muscle cells of 9. Rea RF, Th ames MD. Neural control mecha- arteries and without aff ecting heart rate and nisms and vasovagal syncope. J Cardiovasc Elec- has no eff ect on the central nervous system (30). In trophysiol 1993; 4: 587-95. three randomized, placebo-controlled trials, mido- drine had a positive eff ect on reducing the frequen- 10. Wallin BG. Intraneural recordings of normal cy of symptoms, symptoms during HUTT and and abnormal sympathetic activity in man. In: quality of life (35). SSRI, in contrast to the vaso- Bannister R, ed. Autonomic Failure: A Textbook constrictor, can reduce the activity of the sympa- of Clinical Disorders of the Autonomic Nervous nd thetic nervous system (36). Some studies show that System. 2 ed. New York: Oxford University SSRI can reduce the incidence of VVS. Results Press, 1988, 177-95. showed that 17.6% of patients who received paroxe- 11. Shen WK, Gersh BJ. Fainting: approach to man- tine had repeated syncope compared with 52.9% in agement. In: Low PA, ed. Clinical Autonomic the placebo group (37). Disorders: Evaluation and Management. 2nd ed. Philadelphia: Lippincott-Raven, 1997, 649-79. 12. Th ames MD, Mopfenstein HS, Abboud FM, CONCLUSION Mark AL, Walker JL. Preferential distribution of inhibitory cardiac receptors with vagal aff erents Vasovagal syncope is the most common cause of to the inferoposterior wall of the left ventricle transient loss of consciousness, especially in young- activated during coronary occlusion in the dog. er patients. It is mostly associated with benign Circ Res 1978; 43: 512-9. prognosis but if it recurs oft en, it greatly aff ects the 13. Elam RF, Bergmann F, Feuerstein G. Th e use of patient’s quality of life. Th e diagnostic and thera- anti-serotonergic agents for the treatment of peutic goal is correct diagnosis, reduction in the acute hemorrhagic shock of cats. Eur J Pharma- 8 number of episodes, and better quality of life. col 1985; 107: 275-8. 14. Kosinski D, Grubb BP. Neurally mediated syn- cope with an update on indications and useful- REFERENCES ness of head-upright tilt table testing and phar- 1. Gauer LR. Evaluation of Syncope. Am Fam Phy- macologic therapy. Curr Opin Cardiol 1994; 9: sician 2011; 84: 640-50. 53-64. Number 1-2, 2013 Number 2. Savage DD, Corwin L, McGee DL, Kannel WB, 15. Di Girolamo E, Di Iorio C, Sabatini P, Leonzio Wolf PA. Epidemiologic features of isolated syn- L, Barbone C, Barsotti A. Eff ects of paroxetine cope: the Framingham Study. 1985; 16: hydrochloride, a selective serotonin reuptake 626-9. inhibitor, on refractory vasovagal syncope: a randomized, double-blind, placebo-controlled 3. Mohan L, Lavania AK. Vasovagal syncope: an study. J Am Coll Cardiol 1999; 33: 1227-30. enigma. J Assoc Physicians India 2004; 52: 301-4. 16. Grubb BP, Wolfe DA, Samoil D, Temesy-Armos 4. Fenton AM, Hammill SC, Rea FR, Low PA, Shen P, Hahn H, Elliott L. Usefulness of fl uoxetine hy- WK. Vasovagal syncope. Ann Intern Med 2000; drochloride for prevention of resistant upright 133: 714-25. tilt induced syncope. Pacing Clin Electrophysiol 5. Moya A, Sutton R, Ammirati F et al. Guidelines 1993; 16: 458-64. for the diagnosis and management of syncope: 17. Grubb BP, Samoil D, Kosinski D, Kip K, Brews- the Task Force for the Diagnosis and Manage- ter P. Use of sertraline hydrochloride in the treat- ment of Syncope of the European Society of Car- ment of refractory neurocardiogenic syncope in diology (ESC). Eur Heart J 2009; 30: 2631-71. children and adolescents. J Am Coll Cardiol 1994; 24: 490-4. 6. Soteriades ES, Evans JC, Larson MG et al. Inci- dence and prognosis of syncope. N Engl J Med 18. Grubb BP, Kosinski D. Preliminary observations 2002; 347: 878-85. on the use of venlafaxine hydrochloride in re- Neurol. Croat. Vol. 62, 1-2, 2013 A. Ljilja, A. Mišmaš, I. Adamec, M. Habek. Neurally mediated syncope

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Neuralno posredovana sinkopa

SAŽETAK - Neuralno posredovana ili vazovagalna sinkopa je najčešći uzrok prolaznog gubitka svijesti. Pretjerana reakcija na različite podražaje (emocionalni stres, vađenje krvi, dugotrajno stajanje i sl.) rezultira kratkim i prolaznim gubitkom svijesti uzrokovanim padom krvnog tlaka sa ili bez istovremenog pada srčane frekvencije i posljedičnom prolaznom cerebralnom hipoksijom. Česti prodromalni simptomi su osjećaj mučnine, znojenje, bljedilo, sužavanje vidnog polja. Iako je poznato kako je u podlozi sinkope disregulacija fi ziološke kontrole krvnoga tlaka, patofi ziologija tog poremećaja još je nejasna. Kontrola krvnog tlaka uključuje složene aferentne signale iz luka aorte koji se obrađuju u središnjem živčanom sustavu te eferentnu modulaciju srčane funkcije i funkcije vaskularnog sustava. Vazovagalna sinkopa obično ne zahtijeva liječenje. No, u slučaju kada treba isključiti druge uzroke gubitaka svijesti, poput srčanih aritmija, potrebna je šira dijagnostička obrada i tada se se najčešće koristi “head-up tilt table” test. Česte vazovagalne sinkope nepo- voljno utječu na kvalitetu života te je tada moguće uvesti farmakološku terapiju β-blokatorima, npr. meto- prololom, selektivnim inhibitorima ponovne pohrane serotonina ili vazokonstriktorima α-agonistima. Preporučuju se vježbe za donje ekstremitete, nošenje kompresivnih čarapa, povećani unos tekućine i soli u prehrani. U težim slučajevima vazovagalnih sinkopa s bradikardijom ili asistolijom postoji mogućnost ugradnje srčanog stimulatora.

Ključne riječi: bradikardija, head-up tilt table test, hipotenzija, neuralno posredovana sinkopa

10 Number 1-2, 2013 Number