© 2004 by European Society of Cardiology
REVIEW
Clinical spectrum of neurally mediated reflex syncopes
aDivision of Cardiology and Section of Arrhythmology Ospedale Civile, 44042 Cento (Fe), Italy; bSection of Arrhythmology, Department of Cardiology Ospedali Riuniti, Lavagna, Italy; cSection of Arrhythmology, Department of Cardiology Ospedale S. Maria Nuova, Reggio Emilia, Italy; dDivision of Cardiology Ospedale Umberto I, Mestre, Italy; eDivision of Cardiology Ospedale S. Pietro Igneo, Fucecchio, Italy
Manuscript submitted 4 March 2003. Accepted after revision 13 September 2003.
*Corresponding author. Tel.: +39-051-6838111; fax: +39-051-6838471. E-mail address: p.alboni{at}ausl.fe.it (P. Alboni).
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Abstract |
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AIMS: The clinical features of the various types of neurally mediated reflex syncope have not been systematically investigated and compared. We sought to assess and compare the clinical spectrum of neurally mediated reflex syncopes.
METHODS AND RESULTS: Four hundred sixty-one patients with syncope were prospectively evaluated and 280 had neurally mediated reflex syncope. Each patient was interviewed using a standard questionnaire. A cause of syncope was assigned using standardized diagnostic criteria.
Typical vasovagal syncope was diagnosed in 39 patients, situational syncope in 34, carotid sinus syncope in 34, tilt-induced syncope in 142 and complex neurally mediated syncope (positive response to both carotid sinus massage and tilt test) in 31. The clinical features of situational, carotid sinus, tilt-induced and complex neurally mediated syncope were very similar. By contrast, typical vasovagal syncope differed from other neurally mediated syncopes not only in terms of its precipitating factors (fear, strong emotion, etc.), which constituted predefined diagnostic criteria, but also in the variety of its clinical features (lower age and prevalence of organic heart disease, higher prevalence of prodromal symptoms, and of autonomic prodromes, longer duration of prodromes, higher prevalence of symptoms during the recovery phase and lower prevalence of trauma).
CONCLUSION: The clinical spectrum of neurally mediated reflex syncopes demonstrates much overlap between them. However, when the afferent neural signals are localized in cortical sites, as in typical vasovagal syncope, symptoms are more frequent and of longer duration.
Key Words: syncope, vasovagal syncope, carotid sinus syncope, neurally mediated syncope, reflex syncope, tilt test
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Introduction |
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History is an essential and most important part of the workup of patients with syncope. Several clinical features regarding the modalities of presentation, the prodromal symptoms and the sequelae of loss of consciousness have been utilized. The historical findings of patients with neurally mediated syncope and cardiac syncope have been compared and some features appeared useful for the differential diagnosis [1–
6]. Up to now, the clinical spectrum of neurally mediated reflex syncopes, that is, typical vasovagal, tilt-induced, situational, carotid sinus and complex neurally mediated syncope has not been systematically investigated and compared. The aim of the present study was to assess and compare the clinical presentation of neurally mediated reflex syncopes so as to establish a spectrum.
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Methods |
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Patients were recruited if they had had a syncopal episode in the previous two months (defined as a brief, self-limited loss of consciousness with the inability to maintain postural tone) and were
18 years of age. Four hundred sixty-one consecutive patients with the aforementioned characteristics were referred to the "Syncope Unit" of the Cardiology Division of three hospitals (Cento, Lavagna and Reggio Emilia, Italy) from the emergency room, in-patient service and out-patient clinic between January and November 1999. All patients underwent a standardized initial evaluation consisting of a history, physical and neurological examinations performed by the same investigator in each hospital, evaluation of blood pressure in the supine and upright positions and standard electrocardiogram as recommended in the report of the Task on Syncope of the European Society of Cardiology [7]. Conventional blood laboratory tests were performed when a haemorrhagic or metabolic cause was suspected. When the results of the initial evaluation allowed us to define the cause of syncope, the investigational process was interrupted. When the results of the initial evaluation were inconclusive, further investigations were performed according to the guidelines of the Italian "Associazione Nazionale Medici Cardiologi Ospedalieri" [5,8]. For example, patients with heart disease first underwent noninvasive cardiac examinations, as appropriate and, in the event of negative results, an electrophysiological study. Patients without signs of heart disease first underwent both carotid sinus massage and tilt testing. When there were focal neurological symptoms before or after the loss of consciousness, witnessed prolonged loss of consciousness with tonic–clonic movements or a post-ictal state, migraine or a suggestion of a psychiatric disorder, the help of a consultant neurologist or psychiatrist was requested.
Diagnostic criteria for the cause of syncope were developed before enrolment, on the basis of an extensive review of the pertinent published data, and assignment of a cause was based on strict adherence to these criteria. The diagnosis was assigned by one of the investigators at the end of the diagnostic procedures. Presumed diagnoses made by the junior medical staff or attending physician were not accepted. Syncope was defined as typical vasovagal if a precipitating event, such as fear, severe pain, strong emotion or instrumentation, could be identified in the absence of another competing diagnosis for the cause of syncope [9]; and as situational syncope when the loss of consciousness occurred during or immediately after urination, defaecation, coughing or swallowing [9]. In the patients with syncope with an atypical presentation, the final diagnosis was made on the basis of positive response to the autonomic tests, i.e. tilt test and/or carotid sinus massage. Syncope with an atypical presentation includes: tilt-induced syncope when the loss of consciousness was induced during the tilt test associated with hypotension and/or bradycardia [10], sublingual nitroglycerin was used if the passive phase was negative, as previously described [11]; carotid sinus syncope when carotid sinus massage, performed with the method of symptoms, both in the supine and upright positions, induced syncope in the presence of bradycardia or hypotension, or both [12]; and complex neurally mediated reflex syncope when both tilt test and carotid sinus massage induced syncope. The diagnostic criteria for the other causes of syncope have been previously reported [5].
Typical vasovagal syncope and situational syncope were diagnosed during the initial evaluation. However, the patients with these two types of syncope were subjected to both tilt testing and carotid sinus massage in order to investigate the response to the autonomic tests, but the type of response was not utilized for diagnostic purposes.
Syncope questionnaire
The clinical findings of syncope were investigated, taking into account the last syncopal episode, by one of the authors, who used a standard questionnaire. The questionnaire was designed to identify 46 findings of the index syncopal episode, as previously described [5].
Statistical analysis
Student's t-test for unpaired data was used for comparison of continuous data between groups. The chi-square method was used to compare categoric variables. A p value of 
0.05 was considered significant. The data were analyzed with the StatSoft software, ver. 5.1, Tulsa, OK, USA, 1997.
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Results |
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During the recruitment period, neurally mediated reflex syncope was diagnosed in 280 patients. The mean age was 56±11 years; 141 were men. The clinical findings of the patients with typical vasovagal, situational, carotid sinus, tilt-induced and complex neurally mediated syncope are reported in Table 1.
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Typical vasovagal syncope
The mean age was 35±18 years; 15 (38%) were men. The mean duration of symptoms was 34±94 months and the mean number of previous syncopal attacks was 8±11. Thirty-one patients (79%) also had a history of presyncope. Four patients (10%) had hypertensive cardiovascular disease. Prodromal symptoms were present in 37 patients (95%) and autonomic prodromes (sweating, nausea, vomiting, abdominal discomfort, pallor, feeling of cold, feeling of warmth, yawning) in 35 (90%). The duration of the prodrome was >10 s in 27 patients (69%). Symptoms during the recovery phase were present in 37 patients (95%). Ten patients (26%) reported trauma without fractures.
Situational syncope
The mean age was 53±19 years; 19 (56%) were men. The mean duration of symptoms was 15±16 months and the mean number of previous syncopal attacks was 5±7. Twenty patients (59%) also had presyncope. Eleven patients (32%) had organic heart disease. Prodromal symptoms were present in 21 patients (62%) and these were autonomic in type in 18 (53%). The duration of the prodrome was >10 s in nine patients (26%). Symptoms during the recovery phase were present in 24 patients (70%). Nineteen patients (56%) reported minor trauma and one (3%) reported fractures.
Carotid sinus syncope
The mean age was 70±11 years; 22 (65%) were men. The mean duration of symptoms was 16±21 months and the mean number of previous syncopal attacks was 7±17. Twenty-one patients (62%) also had a history of presyncope. Eleven patients (32%) had organic heart disease. Prodromal symptoms were present in 21 patients (62%) and these were autonomic in type in 20 (59%). The duration of the prodrome was >10 s in seven patients (20%). Symptoms during the recovery phase were present in 23 patients (67%). Nineteen patients (56%) reported minor trauma and two (6%) reported fractures.
Tilt-induced syncope
The mean age was 57±21 years; 66 (46%) were men. The mean duration of symptoms was 25±56 months and the mean number of previous syncopal attacks was 9±21. Ninety-one patients (64%) also had presyncope. Forty-four patients (31%) had organic heart disease. Prodromal symptoms were present in 108 patients (76%) and these were autonomic in type in 103 (72%). The duration of the prodrome was >10 s in 51 patients (36%). Symptoms during the recovery phase were present in 99 patients (70%). Forty-nine patients (35%) reported minor trauma and four (3%) reported fractures.
Complex neurally mediated syncope
The mean age was 69±10 years; 17 (55%) were men. The mean duration of symptoms was 14±15 months and the mean number of previous syncopal attacks was 5±14. Sixteen patients (53%) also had a history of presyncope. Fifteen patients (48%) had organic heart disease. Prodromal symptoms were present in 18 patients (58%) and these were autonomic in type in 12 (39%). The duration of the prodrome was >10 s in nine patients (29%). Symptoms during the recovery phase were present in 23 patients (74%). Fifteen patients (48%) reported minor trauma and one (3%) reported fractures.
Response to carotid sinus massage and tilt test
Thirty-one of 207 patients (15%) with syncope of unknown origin after the initial evaluation experienced syncope during both carotid sinus massage and tilt testing (complex neurally mediated reflex syncope). Thirty-four patients with typical vasovagal syncope underwent tilt testing and carotid sinus massage; the former induced syncope in 24 patients (70%) and the latter in none. Twenty-nine patients with situational syncope underwent tilt testing and carotid sinus massage; the former induced syncope in 17 patients (59%) and the latter in one (3%).
Comparison between the various types of neurally mediated reflex syncope
Typical vasovagal syncope versus the other types of syncope (Table 1)
Patients with typical vasovagal syncope showed a significantly lower age, a higher prevalence of prodromal symptoms, in particular, awareness of being about to faint, of an autonomic prodrome (nausea, abdominal discomfort, sweating, feeling of cold), a longer duration of prodromal symptoms, a higher prevalence of symptoms during the recovery phase and a lower prevalence of minor trauma.
Comparison between situational, carotid sinus, tilt-induced and complex neurally mediated syncope (Table 1)
The clinical features of these types of syncope were very similar; however, some significant differences were found. Age was higher in patients with carotid sinus and complex neurally mediated syncope than in those with situational and tilt-induced syncope; the prevalence of a prodrome was higher in patients with tilt-induced syncope than in those with complex neurally mediated syncope; the prevalence of an autonomic prodrome was higher in patients with tilt-induced syncope than in those with situational and complex neurally mediated syncope; the prevalence of abdominal discomfort was higher in patients with situational syncope than in those with carotid sinus syncope; the prevalence of confusion during the recovery phase was lower in patients with situational syncope than in those with carotid sinus and tilt-induced syncope; and the prevalence of minor trauma was lower in patients with tilt-induced syncope than in those with situational and carotid sinus syncope. Syncope secondary to neck turning was more frequent among the patients with carotid sinus syncope (15%), even if the difference did not reach statistical significance.
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Discussion |
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Main findings
Typical vasovagal syncope differs from other neurally mediated reflex syncopes not only in terms of its precipitating factors (fear, strong emotion, etc.), which constitute predefined diagnostic criteria, but also in the variety of its clinical features. By contrast, situational, carotid sinus, tilt-induced and complex neurally mediated syncope display very similar clinical features. Of these, only situational syncope is diagnosed during the initial evaluation, the other forms being diagnosed on the basis of the response to autonomic tests.
Typical vasovagal syncope
Patients with this type of syncope have a significantly lower age and prevalence of organic heart disease, a higher prevalence of prodromal symptoms and an autonomic type of prodrome, a longer duration of prodrome, a higher prevalence of symptoms during the recovery phase and a lower prevalence of trauma. The lower prevalence of trauma and the higher prevalence of awareness of being about to faint are probably secondary to the longer duration of the prodrome. These results suggest that activation of the autonomic system is broader in typical vasovagal syncope than in the other types of neurally mediated reflex syncope.
Since typical vasovagal syncope is triggered by emotional stimuli, it is very likely that the afferent neural signals originate from higher cortical sites [13]. This suggests that, when the afferent signals originate from the central nervous system and not from peripheral receptors, they induce broader activation of the autonomic system and consequently more frequent and longer prodromal symptoms. However, these considerations are speculative and need further investigation.
Situational, carotid sinus, tilt-induced and complex neurally mediated syncope
These types of neurally mediated reflex syncope, in which the site of afferent neural signals is not always definable but can be located outside cortical sites, display similar clinical features. Indeed, they show a similar prevalence of prodromal symptoms, autonomic features of the prodrome, symptoms during the recovery phase and trauma, with significant differences only in a few variables. However, complex neurally mediated syncope tends to show a lower prevalence of an autonomic type of prodrome. Moreover, with regard to the predisposing and precipitating factors, warm surroundings and prolonged standing tend to be more frequent in tilt-induced syncope patients, and neck turning in carotid sinus syncope patients, even if these differences did not reach statistical significance. A rather unexpected result is the similarity between tilt-induced syncope and carotid sinus syncope; in current literature, the former is mainly assumed to be a form of vasovagal syncope, while the latter is believed to be characterized by very few prodromal symptoms and sudden onset. Actually, the clinical features of these two types of syncope have never been compared and our results suggest that activation of the autonomic system is similar in these two neurally mediated syncopal syndromes. The only significant differences observed between these two types of syncope were a higher age and a higher prevalence of minor trauma in patients with carotid sinus syncope (70±11 versus 57±21 years, p=0.001 and 56% and 35%, p=0.05, respectively). The higher prevalence of minor trauma could be related to the higher age in carotid sinus syncope patients.
Pathophysiological implications
Some results of our study suggest that the various types of neurally mediated reflex syncope are secondary to a common, central abnormality: (1) 15% of patients with syncope of unknown origin after the initial evaluation experienced syncope during both carotid sinus massage and tilt testing. We defined this type of syncope as "complex", since it fits neither with carotid sinus syncope nor with tilt-induced syncope. A positive response to both of these autonomic tests in patients with neurally mediated syncope has already been described [12,14,15]; (2) 59% of patients with situational syncope, in whom the spontaneous loss of consciousness is very probably triggered by a reflex derived from gastrointestinal, genitourinary or cardiopulmonary mechanoreceptor stimulation, experienced syncope during tilt testing, that is to say, in response to different afferent neural signals; (3) 70% of the patients with typical vasovagal syncope, in whom the afferent neural signals during spontaneous loss of consciousness are probably located in cortical sites, experienced syncope during tilt testing. A positive response to the tilt test in patients with situational and typical vasovagal syncope has already been described [16,17]. These results show that syncope may be precipitated by different manoeuvres and by different situations (different afferent pathways) and this finding suggests that neurally mediated reflex syncope results from a central abnormality rather than from a local pathology. However, it remains to be clarified why afferent neural signals located in cortical sites induce broader activation of the autonomic system.
In the patients with typical vasovagal and situational syncope, the prevalence of positive responses to carotid sinus massage was very low (0% and 3%, respectively). This finding seems to strengthen the hypothesis of a different role of the various afferent pathways in the genesis of neurally mediated syncopal syndromes. In a previous study, carotid sinus massage was performed in a group of patients with typical vasovagal or situational syncope, and a positive response was observed in 33% of cases [12]; however, the mean age of these patients was 10 years greater than that of our patients. In this regard, the relationship between neurally mediated syncope and age should be considered. Our results show that situational syncope and tilt-induced syncope are observed at all ages (53±19 and 57±21 years, respectively). By contrast, typical vasovagal syncope is observed in youth (35±18 years) and very rarely in old age. Since the elderly also undergo emotional stimuli (fear, severe pain, strong emotion), our results suggest that in old age the responsiveness to afferent neural signals located in cortical sites is decreased or altered. By contrast, positive responses to carotid sinus massage increase with age; indeed, patients with carotid sinus syncope and those with complex neurally mediated syncope are elderly (70±11 and 69±10 years, respectively). Since autonomic responses tend to decrease in old age, a positive response to carotid sinus massage probably implies a reduction in compensatory mechanisms in a part of the reflex arch. At present, the pathophysiological substrate responsible for the increase in positive responses to carotid sinus massage in old age is unknown.
Comparison with previous studies
To date, the clinical characteristics of the various types of neurally mediated reflex syncope have not been compared. In studies by Calkins et al. [4] and Graham and Kenny [18] investigating the clinical features of tilt-induced syncope, age, sex distribution, prevalence of heart disease and several historical aspects were similar to those found in our study. On analysing some clinical findings of carotid sinus syncope, McIntosh et al. [14] found a lower prevalence of prodromes than we did in our patients (44% versus 62%) and a higher prevalence of fractures (24% versus 6%). These differences could be related to the greater age of the patients of McIntosh et al. (81±7 versus 70±11 years).
Study limitations
In syncope there is no diagnostic gold standard against which other diagnostic tests may be measured; therefore, no set of criteria and no algorithm for diagnosing syncope may be considered ideal. The diagnostic criteria we adopted in the present study are those most commonly accepted. The prevalence of typical vasovagal syncope may be underestimated, as a population study showed that only 23% of patients with this type of syncope are referred to a hospital [19]. For this reason the results of the present study seem to reflect the distribution of patients who are referred to the syncope unit, rather than the distribution of patients with syncope in the general population. Mental health problems in the elderly are rather frequent and can make correct data collection difficult; we did not use tests such as Mini Mental State Examination to exclude patients with relevant cognitive impairment. The duration of the prodrome, estimated by the patient, is obviously very approximate; however, the approximation may be similar in the various types of reflex syncope, allowing a comparison to be made.
In conclusion, the clinical presentation of neurally mediated reflex syncopes has a relatively narrow spectrum. However, when the afferent neural signals are located in cortical sites, as they are in typical vasovagal syncope, symptoms are more frequent and of longer duration.
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