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¿What´s New in Syncope?

Adelqui Peralta, MD

EP Lab, Sanatorio Güemes, Buenos Aires and Private Community Hospital,
Mar del Plata, Buenos Aires, Argentina

INTRODUCTION
   Syncope is the transient loss of consciousness with loss of postural tone, followed by spontaneous recovery. It is a symptom, which may be due to different causes, often difficult to identify. Diagnosing the cause of syncope frequently causes expensive admissions, and delay in starting therapy until the cause has been determined, with the additional risk with the additional risk of recurrences. This review will summarize the advances made in syncope diagnosis, specifically the usefulness of the implantable holter, the evaluation of convulsive syncope and the limitations of the electrophysiologic study (EPS), as well as new data on therapy for vasovagal syncope.

WHAT DID WE KNOW ABOUT SYNCOPE?
   Before getting into advances in syncope, let´s summarize a few aspects of what we know about it. Syncope represents 3% of emergency visits and up to 6% of admission to a general hospital. The Framingham study, following 5209 patients between 30 and 62 years of age, for over 26 years, showed that 3% of men and 3.5% of women will develop syncope. Since syncope is a symptom and not a disease, it may be caused by many potential causes. The diagnosis will be based on history and physical examination and a carefully selected group of tests. Interrogation and physical examination has been shown to offer the cause of syncope in up to 45% of patients in whom a diagnosis will be made. Once history and physical examination have been done, tests will be individualized for each patient. The wide range of tests available for diagnosis, makes it necessary to order only those tests which will help in providing a diagnosis.

   The electrocardiogram (ECG) allows diagnosis in about 5% of the patients with syncope, usually due to bradyarrhythmias or ventricular tachycardia (VT) and less frequently due to acute myocardial infarction. Although the percentage of patients with syncope who are diagnosed with this test is low, the fact that the ECG is widely available makes it a routine exam in these patients.

   Carotid sinus massage (CSM) is not performed frequently but should be used routinely in the work up of patients with syncope. Less than 1% of patients who present with syncope will have carotid sinus syndrome, although the percentage will be greater in the elderly population.

   Most of the findings in the echocardiogram are suspected before the study is performed, but unsuspected findings can be seen in about 5% of patients, as it happens with the ECG.

   Holters are useful to correlate symptoms with the presence or absence of arrhythmias. Studies that have used more than 12 hours of recording and have included more than one hundred patients have shown that about 4% of patients will develop syncope associated with a rhythm abnormality. However, about 13% of the patients will develop syncope and no rhythm abnormality, and a similar percentage will have arrhythmias with no symptoms.

   The electroencephalogram (EEG) is of little help if used as a routine test in patients with syncope. Kapoor showed that 1% of patients with syncope have some form of epilepsy in the EEG, but in these cases, epilepsy had been suspected before the performance of the EEG.

   In 1986, the introduction of tilt test by the Westminster group, showed that this test revealed a vasovagal reaction in 67% of the patients with unexplained syncope, establishing a landmark in the diagnosis of syncopal patients. As of today, there is not a universal protocol and the current methods vary in terms of duration, tilting degree, or drugs used to sensitize the test. Many centers are using Dr. Fitzpatrick´s recommended protocol of tilting the patient 60 degrees for 45 minutes, which is beyond 2 standard deviations from the mean of time to syncope (24 minutes). If the test is negative and the patient has a high pretest probability of having vasovagal syncope, then isoproterenol may be added

   The signal average ECG has a good sensitivity (between 70 and 80%) to predict induction of VT in the EPS in patients with syncope. The drawback is the relatively high figure of false positives. The diagnostic value of an EPS depends upon the presence or absence of structural cardiac disease (SHD). En general terms, in patients with SHD the EPS reveals VT in 21% and bradyarrhythmias in 34% of patients, compared to 1% and 10% in patients with no SHD.

WHAT'S NEW IN SYNCOPE?
Usefulness of the Implantable Loop Recorder
   The implantable loop recorder (Reveal ILR, Medtronic, USA Inc) is a small device designed to be implanted in the prepectoral area to provide monitoring by recording a lead by using two electrodes. It has a mechanism for freezing the recording that can be activated with a magnet placed over the device by the patient after the syncopal episode. The Reveal investigators reported in 1999 their experience in addressing the cause of syncope in 85 patients (44 men, mean age: 59 years old), with syncope of unknown etiology. Patients had to have at least 2 syncopal episodes in the last 6 months or only one syncopal episode but with prior history of presyncope. Patients had a mean of 5.1±5.5 (median: 3) episodes in the last year. Cardiac disease was present in 62% of the patients. Most of the ILRs were implanted in the EP lab. During a mean follow-up of 10.5±4 months, syncope recurred in 58 (68%) patients after a mean of 2.3±2.6 (median: 1.7) months. Failure to freeze the recording occurred 24 times in 14 patients. Six of these patients, were able to freeze the device appropriately in subsequent episodes. The rest of the patients recorded 120 episodes. During follow-up, 27 patients did no have episodes and were still followed. An arrhythmia episode was seen in 42% of the patients who registered a rhythm during syncope. Seven patients had vasovagal syncope, 5 with bradycardia and 2 with normal sinus rhythm. Patients who had presyncope had less frequently an arrhythmia episode recorded during the episode. There were no adverse effects during the recurrent syncopal episodes. The infection rate of the pocket where the device was implanted was 3.5% (3/85). More recently, Seidi et al reported their results in 33 patients with recurrent syncope of unknown etiology. During a mean follow-up of 11 months, 83 (62%) patients had syncope or presyncope, and in 72 of them the diagnosis was made by the ILR. The causes of syncope were arrhythmic in 32 (bradyarrhythmias en 21, tachyarrhythmias en 10, and both in 1), and non-arrhythmic in 40 patients. They concluded that the ILR was diagnostic in 54% of the patients. These studies show that long term monitoring with the ILR is effective and safe in patients with syncope of unknown etiology. It is necessary to stress to the patient the importance of freezing the device appropriately after the episode. Also, the implant must be performed under the same circumstances than a pacemaker implant, to avoid pocket infection.

   Given the initial good results with the ILR, the RAST study (Randomized Assessment of Syncope Trial) tested the hypothesis that this device should be used early in the diagnosis of syncopal patients. Therefore they randomized 60 patients (age: 66±14 years), with unexplained syncope and an EF > than 35%, to ILR implant or conventional testing. All patients had a baseline interrogatory, physical exam, an echocardiogram and a holter. The cause of syncope was diagnosed in 6/30 (20%) patients in the conventional arm versus 11/23 (48%) patients in the ILR arm who completed the follow-up until the data was published (p = 0.032). However if all the patients assigned to the ILR arm are included (n: 30), the difference is not significant. Also, it is surprising the low yield found in the conventional arm (20%).

   In summary, the ILR is a useful tool to be considered in patients with syncope of unknown etiology after the conventional algorithm but not instead of the usual testing.

Convulsive Syncope
   Although the presence of seizures must raise the suspicion of a neurologic cause, many patients treated for years with anticonvulsive therapy with no improvement have a definite cause of syncope and seizures. Zaidi et al studied 74 patients with diagnosis of epilepsy who persisted with seizures despite medication, or with no clear diagnosis of epilepsy. Patients were tested with CSM and tilt test and 10 patients had an ILR implanted. An alternative diagnosis was found in 31 (42%) patients. Thirteen of them were under anticonvulsive medications. Vasovagal syncope was diagnosed in 20 (64.5%) patients, 7 patients had carotid sinus syndrome, 2 had bradycardia with symptoms in the ILR and 2 had psycogenic syncope. Careful attention deserve patients with seizures and no improvement in appropriate therapy or no clear diagnosis of epilepsy, since an alternative cause of syncope can be found in a significant proportion of them.

Limitations of the Electrophysiologic Study
   If the sensitivity of the EPS were not high enough, arrhythmic causes could not be identified with the resulting recurrence of syncope and even incidence of sudden death. Link et al studied 186 patients with syncope and SHD in whom ventricular tachyarrhythmias was found in 78 (42%), bradyarrhythmias in 14 (8%), and non-diagnostic EPS in 68 patients. This last group was followed for 30 months, during which 4 (6%) patients, all with EF < 25%, had a malignant ventricular tachyarrhythmia (manifested by 2 sudden deaths and 2 appropriate shocks in patients with an ICD), and 8 (12%) patients had bradycardia. The EPS showed a sensitivity of 95% for VT and 62% for bradyarrhythmia, which means that in patients with SHD, the EPS has higher sensitivity for VT than for bradyarrhythmias. However, if the patient has a low EF and syncope, even with a negative study, there is a substantial risk of VT. Dr. Link et al, recommended ICD implant in these patients, irrespective of the results of the EPS.

Treatment of Vasovagal Syncope
   Vasovagal is the most common form of neurocardiogenic syncope. The results of therapy for vasovagal syncope has been difficult to evaluate, in part due to the fact that this form of syncope may spontaneously improve, or that the episodes tend to occur in clusters and after that, there may exist a period free of any symptoms, under no treatment. In addition, for most of the drugs, there are no randomized controlled studies. Most of the published studies are not controlled and showed the accumulated experience in small group of patients, and many times in a retrospective fashion. Recently, there have been a number of published studies that in a prospective manner have tested different measures for the treatment of vasovagal syncope.

   The efficacy of betablockers in the treatment of vasovagal syncope was questioned by Madrid et al. They reported 50 patients with vasovagal syncope by clinical definition in which a tilt test at 80 degrees for 45 minutes was performed. Twenty (40%) of these patients had an abnormal response to tilt. IV atenolol prevented syncope when re-tilted in only 5 (25%) of these patients. Subsequently all the patients were randomized to atenolol 50 mg/day (n: 26) or placebo (n: 24). The study was completed in 40 patients. During the following year 16 (61%) patients in the atenolol arm and 11 (45%) in the placebo arm had recurrent syncope (p = 0.09). They concluded that atenolol was not effective to prevent recurrences in patients with clinically defined vasovagal syncope, although given the fact that only 40% of them had a positive tilt, the findings may be applicable to the patients with clinical evidence of vasovagal syncope, but not shown on tilt, which may dilute the significance of the study.

   Midodrine, an alpha agonist, mainly used for treatment of orthostatic hypotension, has been the center of research as therapy for vasovagal syncope in some studies. In a small controlled study, 16 patients with more than two syncopal episodes and with a positive tilt test were randomized in a crossover, double blind fashion, to placebo or midodrine (5 mg TID) for a month. During midodrine treatment, patients had better quality of life and a positive tilt test was found in 6 versus 14 patients in placebo (p = 0.01) at the end of treatment. The conclusion of the study was that midodrine had a beneficial effect en the frequency of symptoms, quality of life and the response to tilt test.

   Another vasoconstrictor agent, etilephrine, was prospectively tested in the VASIS (Vasovagal Syncope International Study) study, in which 126 patients with positive tilt test, with history of at least three syncopal episodes in the last two years, and at least one episode in the last six months and with an interval between the first and the last episode greater than 6 months, were randomized in a double blind fashion to etilephrine (25 mg TID) or placebo. Patients were re-tilted after three to six days of the initiation of therapy, and independently of the results, treatment was continued and the patients followed for a year or up to the first recurrence of symptoms (end point). The results are shown in table 1. Etilephrine was not better than placebo.

   The inhibitors of re-uptake of serotonin, have also been used in the treatment of vasovagal syncope. A recent study randomized 68 patients with refractory vasovagal syncope, to paroxetine or placebo. At one-month follow-up, patients were re-tilted. Paroxetine treatment gave a negative tilt in 61.8% of the patients compared to 38.2% on placebo (p<0.001), whereas in the follow-up at 25 months, syncope recurred in 18% of patients in paroxetine versus 53% of patients in placebo (p<0.0001).

   Given the fact that bradycardia contributes to symptoms in vasovagal syncope there may be a place for pacemaker implant in these patients. Two major studies have been done in this regard, one in America and another one in Europe. Both studies randomized patients with history of recurrent vasovagal syncope of the cardioinhibitory type to pacer implant or no pacer. They tested the hypothesis that the decision to implant a pacer in these patients would reduce the incidence of syncope. The North American Vasovagal Pacemaker Study (VPS) included patients with at least 6 episodes of syncope (which gives a recurrence rate of 50% in one year), and a positive tilt test with syncope or presyncope and relative bradycardia, that is a heart rate of < 60 bpm without isoproterenol, or a heart rate of < 70 bpm with up to 2 ug/min of isoproterenol, or a heart rate of < 80 bpm with more than 2 ug/min of isoproterenol. The pacemaker used was a DDD with a rate drop feature. This feature allows the pacer to go from a lower rate to a higher rate for a brief period when an abrupt descent in the spontaneous heart rate occurs. In this study, the lower rate was 60 BPM and the rate for the "rate drop" was 100 bpm, which was maintained for two minutes. The end point of the study was the first recurrence of symptom, which correlates with the eventual frequency of recurrences. Patient enrollment started in June 1995 and by April 1997 there were 54 patients enrolled (27 patients in each group) with follow-up data of only 46 patients, when the first revision was done. The study was prematurely terminated due to a beneficial effect in the pacemaker group (table 2). There was an 85% risk reduction of syncope with the pacemaker and the mean time to syncope prolonged from 54 days without a pacemaker to 112 days with pacemaker. However, there was no difference in the incidence of presyncope. As the follow-up was stopped after the first recurrence, the benefit on the total burden of syncope could not be determined. Despite randomization, the median of the total number of syncopal episodes pre-randomization was 35 (20-100) in the control group and 14 (8-35) in the pacemaker group, and the median of syncopal episodes in the last year was 6 (3-40) in the control group and 3 (2-12) in the pacemaker group. In studies in which the number of patients is small as in this one, small baseline differences may impact in the final results. Therefore there was an adjusted Cox model analysis, but none of the variables tested were predictive of the final results, and the adjusted efficacy of the pacemaker therapy was almost similar to the initial efficacy (unadjusted). Despite this adjusted analysis, careful interpretation of the results of this study is recommended, given the small group of patients, the lack of a placebo group or a standard alternative medical treatment, the unblinded design, and the fact that although there was improvement if syncope, there was no benefit in terms of presyncope.

   The VASIS (Vasovagal Syncope International Study) was a prospective controlled randomized study which used a DDI pacemaker with the aim of reducing the recurrence rate of syncope. The primary objective was to prolong the interval to the first syncopal episode. Secondary objectives were to assess the effect on the total burden of syncope, to determine the natural history of vasovagal syncope, and to evaluate the effect of pacing on the tilt test. As mentioned above, patients had to have a history of at least three syncopal episodes in the last two years, at least one episode in the last six months and with an interval between the first and the last episode greater than 6 months. Patients were older than 40 years old or younger than 40 but refractory to medication. They all had to have a positive tilt test with a cardioinhibitory response 2A, where a blood pressure fall precedes a heart rate falls of < 40 bpm for > 10 seconds, or with pauses > 3 seconds; or 2B, where the blood pressure falls simultaneously or after a fall in heart rate < 40 bpm for > 10 seconds, or with pauses > 3 seconds. The randomization was to DDI implant at 80 bpm with hysteresis at 45 bpm, versus no pacemaker. After randomization, patients were re-tilted at 2 weeks. Forty-two patients were included, 19 in the pacemaker group and 23 in the no pacemaker group. A pause > 3 seconds was seen in 86% of the patients in the baseline tilt test, with a median duration of the pause of 11.5 (3-34) seconds. The results are shown in table 3. There was a significant difference in the incidence of syncope, which was maintained at 5 years of follow-up. The median time to syncope was prolonged from 5 months to 15 months. The tilt test on treatment did not predict the long-term response. The natural history was seen in the untreated patients in whom syncope recurred in 70% of the patients, with a rate of 0.44 episodes/year.

   In the VASIS, there was no screening book, so there is no certainty of what percentage of patients with vasovagal syncope are represented in the study. Although the authors speculate that is in the range of 3.5% of patients, most likely is much less than that. The rate of enrollment was excessively low. For a total of 18 participating centers, the enrollment rate was about 0.5 patients per center per year. Also, it should be noted that the study deals with patients with severe cardioinhibition. The VPS and the VASIS show that pacemaker implantation, either in the DDD mode with a rate drop feature or a DDI, is beneficial in a selected group of patients with cardioinhibitory form of vasovagal syncope. The impact of the placebo effect can not be established from these studies, and it is currently being evaluated in the Vasovagal Pacemaker Study II, in which all the patients have pacemaker implants and are randomized to have them "on" or "off".

CONCLUSIONS
   Syncope is a symptom, which has been the center of extensive research from the pathophysiology up to the treatment and care of the patient. We have learnt that the ILR is useful when used in the right time, that vasovagal syncope may have a convulsive form, and that the EPS results must be interpreted carefully in these patients, and that there is a widening about different forms of therapy for vasovagal syncope. Topics such as the first line drug for vasovagal syncope or how much of the effect of pacing is placebo effect, are at this time unresolved, and will be revealed in the subsequent years.

REFERENCES

1. Savage DD, Corwin L, McGee DL, Kannel WB. Wolf PA. Epidemiologic features of isolated syncope: the Framingham Study. Stroke 1985;16:626-629.

2. Linzer M, Yang EH, Estes NAM, Wang P, Vorperian VR, Kapoor WN. Diagnosing syncope. Part 1: Value of history, physical examination, and electrocardiography. Ann Intern Med 1997;126:989-996.

3. Seidl K. Rameken M. Breunung S. Senges J. Jung W. Andresen D. van Toor A. Krahn AD. Klein GJ. Reveal-Investigators. Diagnostic assessment of recurrent unexplained syncope with a new subcutaneously implantable loop recorder. Europace 2000;2(3):256-262.

4. Krahn AD, Klein GJ, Yee R, Skanes AC. Randomized assessment of syncope trial (RAST): Conventional investigations vs. Implanted loop recorder. Circulation 2000;102 SupplI:370.

5. Zaidi 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.

6. Link, MS, Kim KMS. Homoud MK. Estes NAM, Wang PJ. Long-term outcome of patients with syncope associated with coronary artery disease and a nondiagnostic electrophysiologic evaluation. Am J Cardiol 1999;83:1334-1337.

7. Madrid AH, Ortega J,Rebollo JG, Manzano JG, Segovia JG, Sa A, Pena G, Moro C Lack of efficacy of atenolol for the prevention of neurally mediated syncope in a highly symptomatic population: a prospective, double-blind, randomized and placebo-controlled study. J Am Coll Cardiol 2001;37:554-559.

8. Ward CR, Gray JC, Gilroy JJ, Kenny RA. Midodrine: a role in the management of neurocardiogenic syncope. Heart 1998; 79:45-49.

9. Raviele A, Brignole M, Sutton R, Alboni P, Giani P, Menozzi C, Moya A. Effect of Etilefrine in Preventing Syncopal Recurrence in Patients With Vasovagal Syncope: A Double-Blind, Randomized, Placebo-Controlled Trial. Circulation 1999;99:1452-1457.

10. Di Girolamo E, Di Lorio C, Sabatini P, Leonzio L, Barcone C, Barsotti A. Effects of paroxetine hydrochloride, a selective serotonin reuptake inhibitor, on refractory vasovagal syncope: a randomized, double-blind, placebo controlled study. J Am Coll Cardiol 1999; 33:1227-1230.

11. Connolly SJ, Sheldon R, Roberts RS, Gent M. The North American Vasovagal Pacemaker Study (VPS). A randomized trial of permanent cardiac pacing for the prevention of vasovagal syncope. J Am Coll Cardiol. 1999;33:16-20.

12. Sutton R, Brignole M, Menozzi C, Raviele C, Alboni P, Giani P, Moya A, for the Vasovagal Syncope International Study (VASIS) Investigators. Dual-Chamber Pacing in the Treatment of Neurally Mediated Tilt-Positive Cardioinhibitory Syncope Pacemaker Versus No Therapy: A Multicenter Randomized Study Circulation. 2000;102:294-299.

 

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2nd Virtual Congress of Cardiology

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