Variable Cerebral Dysfunction During TiltInduced Vasovagal Syncope

FABRIZIO AMMIRATI, FURIO COLIVICCHI, GIANCARLO DI BATTISTA,*FAUSTO FIUME GARELLI,* GLAUDIO PANDOZI, and MASSIMO SANTINI

From the *Heart Disease Department and Neurological Sciences Department,S. Filippo Neri Hospital, Rome, Italy

AMMIRATI, F., ET AL.: Variable Cerebral Dysfunction During Tilt Induced Vasovagal Syncope. Elec-troencephalographic (EEG) monitoring was performed during head-up tilt testing (HUT) in a group of 63consecutive patients (27 males, 36 females, mean age 41.5 years) with a history of recurrent syncope ofunknown origin despite extensive clinical and laboratory evaluation. Syncope occurred in 27/63 patients(42.8%) during HUT and was cardioinhibitory in 11/27 (40.7%) and vasodepressor in 16/27 (59.3%). Allpatients with a negative response to HUT had no significant EEG modifications. In patients with vasode-pressor syncope a generalized high amplitude 4-5 Hz (theta range) slowing of EEG activity appeared atthe onset of syncope, followed by an increase in brain wave amplitude with a reduction of frequency at1.5-3 Hz (delta range). The return to the supine position was associated with brain wave amplitude re-duction and frequency increase to 4-5 Hz, followed by restoration of a normal EEG pattern and arousal(mean total duration of syncope 23.2 s). In patients with cardioinhibitory syncope, a generalized high am-plitude EEG slowing in the theta range was noted at the onset of syncope, followed by a brain wave am-plitude increase and slowing in the delta range. A sudden reduction of brain wave amplitude ensued lead-ing to the disappearance of electroencephalographic activity ("flat" EEG). The return to the supineposition was not followed by immediate resolution of EEG abnormalities or consciousness recovery, bothoccurring after a longer time interval (mean total duration of syncope 41.4 s). EEG monitoring during HUTallowed the recording and systematic description of electroencephalographic abnormalities developing inthe course of tilt induced vasovagal syncope. (PACE 1998; 2l[Pt. II):2420-2425)

syncope, electroencephalography, tilt testing

Introduction

The current hypothetical pathophysiologicalmechanism of vasovagal syncope maintains that arapid ventricular preload reduction causes an ex-aggerated inotropic response due to an overabun-dant cathecolamine release. ̂ "̂ This increased my-ocardial contractility in the setting of preloadreduction activates cardiac mechanoreceptors,mediating via the brain stem an abnormal en-hancement of parasympathetic activity, togetherwith sympathetic withdrawal.^"^ The resultinghypotension and bradycardia cause a reduction incerebral blood flow and secondary impairment ofneurological function. Electroencephalography al-lows the dynamic assessment of neurological

Address for reprints: Fabrizio Ammirati, M.D., Via Attilio Frig-geri, 95, 00136-Rome, Italy. Fax; 39-6-33062489; e-mail:fabamm@tin.it

function,^ while head-up tilt testing is currentlyused to provoke vasovagal syncope in susceptibleindividuals.^'^ The hypothesis behind the presentclinical investigation was that the inclusion ofelectroencephalographic monitoring during head-up tilt testing could significantly improve the un-derstanding of the cerebral events occurring dur-ing tilt induced vasovagal syncope.

Methods

The study population was composed of 63consecutive patients {27 males and 36 females,mean age 41.5 ± 11.4 years) with a history of re-current syncope of unknown origin undergoinghead-up tilt testing for further diagnostic evalua-tion. Patients were included if they had suffered atleast two episodes of syncope during the preced-ing 6 months. In all cases a cardiac, neurological,or metabolic cause of syncope had been excluded

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by extensive clinical and laboratory testing. The63 patients and a control group of 10 asymp-tomatic healthy subjects (6 females and 4 males,mean age 35.5 ± 12.4 years), with no history ofsyncope, granted their informed consent and un-derwent head-up tilt testing according to a proto-col, which, in our Institution, includes electroen-cephalographic [EEG) monitoring throughout theprocedure.

The test was performed in the morning, in thefasting state, in the absence of pharmacologicaltherapy. An electronically controlled tilt table(Ferrox VDE 0551; C,I.A,R. s,r.l.), with a weight-bearing foot board and restraining belts was usedfor the procedure. The table takes 10 to 18 secondsto reach the horizontal position from a 60° incli-nation, depending on patient weight. Continuouselectrocardiographic (ECG) monitoring of heartrate and rhythm was performed, and a standardmercury sphygmomanometer was used to mea-sure the hlood pressure at 5-minute intervalsthroughout the test. At the time of symptom de-velopment, blood pressure measurements wereperformed at 1-minute intervals. Continuous EECmonitoring was performed by a standard ESAOTEBIOMEDICA VECA 24 device with electrodesplaced according to the International 10—20 sys-tem with 18 channels of recording.^ Electrodeswere held in place by collodion to avoid move-ment artifacts. An experienced neurophysiologistcoded the EEG using a conservative interpreta-tion.^ This study used the previously described"Westminster" protocol for head-up tilt testing.^The test was considered positive if syncope, de-fined as a sudden transient loss of consciousnesswith concomitant loss of postural tone and spon-taneous recovery, occurred in association with hy-potension, bradycardia, or both.̂ ** If syncope de-veloped during the test, the table immediately waslowered to the supine position and the procedureended. In agreement with previous reports,^""'^^two main forms of positive response to head-uptilt test were observed. A pure vasodepressor form(syncope associated with a systolic blood pressuredecrease to 60 mmHg or less without significantheart rate reduction) and a cardioinhibitory form(syncope associated with a systolic blood pressuredecrease to 60 mmHg or less and a decrease inheart rate to less than 40 beats/min). All data areexpressed as mean ±SD and were analyzed by un-

paired Student's f-test for continuous variablesand X^ for categorical variables.

Results

A positive response occurred in 27/63 pa-tients, for an overall positive rate of 42.8%, and anegative response was noted in the remaining 36patients (57.2%). The mean time to symptom on-set was 14.8 ± 6.8 minutes (range 2 to 25 min).Eleven of the 27 patients with a positive responseduring head-up tilt (40.7%) developed significantbradycardia (mean duration of longest RR intervalon the ECG 15,2 ± 11.7 s, range 1.8-40 s) at thetime of symptoms onset that was associated withor rapidly followed by hypotension (mean reduc-tion of 68.6 ± 12.7 mmHg for systolic and 40.9 ±18.9 mmHg for diastolic blood pressure) and wereconsidered to have had a cardioinbibitory re-sponse.^"~*^ The rest of the patients with a posi-tive response (16/27, 59.3%) developed hypoten-sion (mean reduction of blood pressure of 85.8 ±16.6 mmHg systolic and 57.6 ± 17.8 mmHg dias-tolic) with minor changes in heart rate (mean re-duction of 13.4 ± 8.7 beats/min) in associationwith sudden loss of consciousness and were con-sidered to have had a vasodepressor response.^°"^^This group included significantly more femalesthan the cardioinhibitory group (14/16, 87.5%versus 4/11, 36.3%, P < 0.01), while no significantage difference was measured between the twogroups. At the time of syncope, 10 of the 11 pa-tients in the cardioinhibitory group (90.9%) had aflexed rigid posture, followed by a rigid extendedposture and bilateral myoclonic rhythmic jerks ofbrief duration (1-5 s). A similar pattern of convul-sive syncope was noted in only 4 of 16 patientswith vasodepressor syncope (25%, P < 0.01).

All subjects included in the control group hada negative response to head-up tilt testing.

Electroencephalography

All study participants had a normal baselineEEG. Patients with a negative response to the head-up tilt, as well as all control subjects, developed nosignificant EEG abnormalities during the test.

EEG Findings in Patients with VasodepressorSyncope (Fig. 1)

The 16 patients with a vasodepressor re-sponse to the head-up tilt showed a homogeneous

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28 yrs, female

FplF3

SYNCOPE CONSCIOUSNESSRECOVERY

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Figure 1. Electroencephalographic modifications in a patient with vasodepressor vasovagalsyncope during head-up tilt testing. T = theta waves; D = delta waves.

pattern during EEG monitoring. Prodromal symp-toms, consisting of dizziness or iight-headednessfor a mean duration of 110.6 ± 77.7 s (range30-300 s) preceded the loss of consciousness andwere not associated with significant EEG changes.Subsequently, the initially normal EEG patternwas followed hy a diffuse generalized high ampli-tude 4-5 Hz (theta range) slowing of hrain activitystarting at the moment of syncope (mean duration4.0 ± 2.1 s. range 2-7 s). These alterations werethen followed hy a further increase in brain waveamplitude and slowing at 1.5-3 Hz (delta range)for a mean duration of 17.0 ± 11.3 s. (range 6-A7s). However, no spike or spike wave activity wasrecorded, even in patients with tonic-clonic jerks(4/16, 25%). When patients were returned to thesupine position, the EEG showed a brief phase(mean duration 2.1 ± 1.2 s, range 0-5 s) of hrainwave amplitude reduction with frequency in-crease to 4-5 Hz followed by the return of a nor-mal EEG pattern and arousal. The mean durationof unconsciousness in these patients was 23.1 ±12.3 s (range 10-54 s).

EEG Findings in Patients with CardioinhibitorySyncope (Fig. 2)

A different, hut again homogeneous, patternof EEG modifications was observed in the 11 pa-tients with a cardioinhihitory response to head-uptilt. Their prodromal symptoms were significantlyshorter in duration (mean duration 8.7 ± 6.1 s,range 5-22 s, P < 0.01) and were accompanied byno EEG changes. At the onset of syncope, the ini-tially normal EEG changed abruptly to a diffuse,generalized high amplitude 4-5 Hz (theta range)hrain wave slowing, rapidly followed by furtherbrain wave amplitude increase and slowing at1.5-3 Hz (delta range) for an overall mean dura-tion of 7.6 ± 2.9 s (range 5-14 s). A sudden de-crease in both amplitude and frequency of brainwaves then was observed, leading to the disap-pearance of electroencephalographic activity("flat" record] for a mean duration of 15.9 ± 13.4 s(range 1—46 s).

The return to the supine position coincidedneither with the immediate resolution of the EEG

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EEG IN TILT INDUCED VASOVAGAL SYNGOPE

33 yrs, female SYNCOPE

TFpII-T

D F A

IF3C3

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P4O2v^-v-A"—>-«7V«—*t*V—-^—^ \y-^-'KJ^'T'^<l^(j\if'^^

ECG tBP unmeasurable

ECO

50 uV1 sec

T

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CONSCIOUSNESSIUICOVERY

Figure 2. Electroencephalographic modifications in a patient with cardioinhibitory vasovagalsyncope during bead-up tilt testing. T = theta waves; D = delta waves.

abnormalities nor with recovery of consciousness;complete normalization of the electroencephalo-gram and the concomitant restoration of full con-sciousness occurred after an additional time inter-val of a mean duration of 15.1 ± 6.0 s. (range 7-22

s). The prevalence of tonic-clonic jerks during lossof consciousness was significantly higher in pa-tients with cardioinhihitory response (10/11,90.9%) than in patients with vasodepressor syn-cope (4/16, 25%, P < 0.01). No spike or spike

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wave activity, lateralizing or focal abnormalitiescould be detected in any patient. In patients witha cardioinhibitory response, the onset of bradycar-dia preceded the development of EEG abnormali-ties by a mean time of 2.9 ± 2.5 s (range 0-8 s), andthe restoration of a normal cardiac rhythm was notfollowed by the immediate recovery of electroen-cephalographic activity (mean duration of delay8.1 ± 7.1 s, range 0-24 s). The mean durationof syncope in patients with cardioinhibitorysyncope was significantly longer than in patientswith vasodepressor syncope (41.4 ± 16,7 s, range21-78 s, P < 0.01). At the end of the test, the EEGhad returned to normal in all cases and no resid-ual neurological or cardiac abnormalities werenoted in any patient.

Discussion

Several studies have used head-up tilt testingto analyze the pathophysiological mechanisms andthe clinical manifestation of vasovagal syncope.^-^Conventional head-up tilt testing uses the con-comitant monitoring of cardiac rhythm and bloodpressure to make a distinction between vasode-pressor and cardioinhibitory patterns in tilt in-duced vasovagal syncope.^" Conventional elec-troencephalography is used in the evaluation ofpatients with recurrent unexplained syncope to ex-clude epilepsy or other significant neurological dis-orders.^ However, the method may also be relevantin the dynamic assessment of cerebral electrophys-iological modifications in other clinical settings. Intheir studies, Gastaut and coworkers^^ have exam-ined the EEG correlates of syncope induced by eye-hall compression.These classic EEG studies havefound that following cardiac asystole a stereotypedseries of modifications take place, including theearly appearance of slow high voltage activity inthe theta range, followed by further slowing in thedelta range.^^'^ The persistence of cardiac asystoledetermines the abrupt disappearance of electroen-cephalographic activity with the development of aflat EEG recording."'^^ The restoration of cardiacrhythm induces the reappearance of brain wave ac-tivity in the reverse order.̂ ^-^" This pattern of EEGchanges is consistent with severe generalized is-chemic anoxia of the central nervous system'^ andis similar to those recorded in our patients with car-dioinhibitory vasovagal sjoicope. In oin- series, the

EEG alterations appeared in a sequence similar tothat described by Gastaut,^^ although of longer du-ration. This difference may be related to the longerperiod of asystole associated with tilt inducedvasovagal reflex compared with the asystolic re-sponse caused by ocular compression. Data per-taining to EEG changes during tilt induced vasova-gal syncope have been collected by Grubb andassociates. ̂ ^ In a recent study, these authors haveperformed head-up tilt testing with simultaneouscontinuous EEG monitoring in patients with recur-rent unexplained convulsive syncopal episodes.^^During tilt induced convulsive syncope the EEGshowed diffuse generalized brain wave slowing,but neither spike nor spike wave activity was ob-served, thus allowing the differential diagnosisfrom epileptic seizures. Similar EEG modificationshave been noted in our series in patients with tiltinduced vasodepressor vasovagal syncope whonever showed periods of flat EEG recording duringloss of consciousness. In this study EEG monitoringallowed the recording and complete description ofthe sequence and relevance of electroencephalo-graphic abnormalities taking place during tilt in-duced vasovagal syncope. These EEG changes arethe expression of cerebral dysfunction during thecritical decrease in cerebral blood flow induced byhypotension and bradycardia. Two different EEGpictures were observed, corresponding to the twohemodynamic patterns of tilt induced vasovagalsyncope. Diffuse generalized brain wave slowingwas seen in patients who developed hypotensionalone (vasodepressor syncope), whereas periods ofelectroencephalographic silence (flat EEG) wereconsistently recorded in subjects with hypotensionand bradycardia (cardioinhibitory syncope). Fur-thermore, in agreement with previous reports,^^cardioinhibitory syncope was associated withshorter prodromes with a higher incidence of tonic-clonic jerks and a longer overall duration of syn-cope. These findings support the helief that the per-sistence of some cardiac activity during tiltinduced vasovaga] episodes may be associatedwith less compromise of cerebral perfusion and,therefore, with less severe clinical manifestations.In absence of conclusive data this hypothesis isnevertheless strengthened by the observation of aclinical improvement or elimination of tilt inducedsyncope by pacing.^^"'^ Our observations of thisstudy were made in a controlled laboratory setting

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where syncope was provoked by a standardizedprocedure. Therefore, the events recorded may notfully reproduce the spontaneous syncopalepisodes.^''•^^ In particular, spontaneous syncopecauses a loss of postural tone with sudden fall; sucha sequence allows the immediate recovery of cere-bral blood flow and is considered a protectivemechanism. With head-up tilt testing, patients arestrapped to the tahle, thus, the return to the supineposition may take some time, the length of whichdepends on the technical characteristics ofthe dif-ferent laboratory equipment. This time intervalmay contribute to the severity of symptoms andhemodynamic and electroencephalographic

changes. In this study, an electronically controlledtilt table was used, taking up to 18 seconds to reachthe horizontal position; this time interval may heexcessive, possibly contributing to the dramatichemodynamic and electroencephalographicchanges in our patients. Consequently, tilt tableswith a faster return to the horizontal position arepreferable to shorten the overall duration of syn-cope. However, in some cases, this situation alsomay occur spontaneously, e.g., in circumstanceswhere in the beginning of the vasovagal reaction(sitting, driving, standing in a confined space, etc.)the patient cannot he immediately returned to thesupine position.

References

1. Mark AL.The Bezold-Jarish reflex revisited: Clini-cal implication of inhibitory reflexes originating inthe heart. J Am Coll Cardiol 1983; 1:90-92.

2. Abboud FM. Ventricular syncope. N Engl J Med1989: 32:390-392.

3. Kapoor WN. ork-up and management of patientswitb syncope. Med Clin North Am 1995; 79:1153-1170.

4. Binnie CD. Electroencephalography. In J Laidlaw,A Richens, J Oxley (eds.): A Textbook Of Epilepsy,3rd edition, Edinburgh, Churchill Livingstone,1988. pp. 236-306,

5. Kenny RA, Ingram A, Bayliss J, et al. Head-up tilt:A useful test for investigating unexplained syn-cope. Lancet 1986; 1:1352-1355.

6. Benditt DG, Ferguson DW, Gruhb BP, et al. Tilttable testing for assessing syncope. ACC ExpertConsensus Document. J Am Coll Cardiol 1996;28:263-275.

7. Engel J Jr. Differential diagnosis of seizures. In JEngel, Tr (ed.): Seizures and Epilepsy, Philadel-phia, FA Davis Co.. 1989, pp. 340-341,

8. Engel J Jr. A practical guide for routine EEG stud-ies in epilepsy. J Clin Neurophysiol 1984; 1:109-142,

9. Fitzpatrick AP, Thedorakis G, Vardas P, et al.Methodology of head-up tilt testing in patientswith unexplained syncope. J Am Coll Cardiol1991; 17:125-130.

10. Kapoor WN, Smith MA, Miller NL. Upright tilttesting in evaluating syncope: A comprehensiveliterature review. Am J Med 1994; 97:78-88.

11. Brignole M, Menozzi C, Cianfranchi L, et al.Carotid sinus massage, eyeball compression andhead-up tilt test in patients with syncope of uncer-tain origin and in healthy control subjects. AmHeart J 1991; 122:1644-1651.

12. Sutton R, Petersen M, Brignole M, et al. Proposedclassification for tilt induced vasovagal syncope.Eur JCPE 1992; 3:180-183.

13. Castaut H, Syncopes: Generalised anoxic cerebralseizures. In PJ Vinken, GW Bruyn (eds,): Hand-book of Clinical Neurology. Amsterdam, Elsevier,1974, pp. 836-852.

14. Daly DD. Epilepsy and syncope. In DD Daly, TAPedley (eds.): Current Practice Of Clinical Elec-troencephalography. New York, Raven Press,1990, pp. 269-334.

15. Grubb BP, Gerard G, Roush K, et al. Differentiationof convulsive syncope and epilepsy with head-uptilt testing. Ann Int Med 1991; 115:871-876.

16. Fitzpatrick AP, Thedorakis G, Vardas P. et al. Theincidence of malignant vasovagal syncope with re-current syncope Eur Heart J 1991; 12:389-394.

17. Fitzpatrick AP. Theodorakis G, Ahmrd R, et al.Dual chamber pacing aborts vasovagal syncope in-duced by head-up 60 degree tilt. PAGE 1991:14:13-19

18. Petersen MEV, Chamberlain-Webber R, FitzpatrickAP, et al. Permanent pacing for cardioinhihitorymalignant vasovagal syndrome. Br Heart J 1994;71:274-281,

19. Ammirati F, Colivicchi F, Altamura G, et al. DDDpacing with rate-drop response function versusDDI pacing for cardioinhihitory vasovagal syn-cope. PACE 1998; 21(Part II):825'

20. Brignole M, Menozzi G. Methods other than tilttesting for diagnosing neurocardiogenic (neurallymediated) syncope, PACE 1997; 20(Part II):795-800,

21. Gruhb BP, Kosinski D. Tilt table testing: Gonceptsand limitations. PACE 1997: 20(Part II):781-787.

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