INTRODUCTION
One of the most common forms of reflex syncope is vasovagal syncope. The long-term influence of recurrent reflex syncope on the central nervous system (CNS) is not yet fully understood.
In recent years, plasma measurements of neuron-specific enolase (NSE) have been used in neurological diagnostics of nervous system damage. Neuronal damage leads to an increase in the concentration of this enzyme in blood plasma and is used as an indicator of brain damage in conditions where neurons are destroyed relatively rapidly [1, 2].
Only a few reports evaluating the influence of syncope on the CNS based on the measurement of enzyme markers can be found in the literature [3]. The goal of our study was to evaluate whether a single episode of vasovagal syncope leads to central nervous system damage, expressed by an increase in NSE concentration in plasma.
METHODS
Study population
The study included 42 consecutively enrolled patients with a history of recurring episodes of syncope, presyncope, or both, in whom cardiogenic syncope was excluded in the course of prior diagnosis, and who were qualified for further examination using the head-up tilt test (HUTT).
The exclusion criteria were:
- CNS conditions such as post-stroke status, transient ischemic attack, Alzheimer’s disease, Parkinson’s disease, epilepsy, and post-CNS trauma;
- Neuroendocrine tumors;
- Hemodynamically significant stenosis of the carotid arteries (USG Doppler);
- Pregnancy;
- Lack of patient consent;
- Age <16 and >75 years old.
Head-up tilt test
The head-up tilt tests were performed according to the guidelines of the European Society of Cardiology. In all patients, the Italian Study Protocol for HUTT was applied [4, 5]. During the HUTT, the following parameters were continuously monitored: electrocardiogram and blood pressure in a non-invasive “beat-to-beat” manner using the BMEYE NEXFIN monitor. Mechanisms of vasovagal reaction were classified according to the Vasovagal Syncope International Study (VASIS) classification into the following types of vasovagal syncope (VVS): mixed, cardiodepressive, and vasodepressive [6]. Additionally, the duration of hypotension (systolic blood pressure [SBP], <70 mm Hg) during HUTT was assessed and analyzed regarding the type of vasovagal syndrome.
Laboratory tests
Before starting the HUTT (NSE-1) and two hours after completion (NSE-2), plasma NSE concentration was assessed by electrochemiluminescence (ECLIA) using the Elecsys NSE reagent. Values below 16.3 ng/ml were considered normal, and any increase in NSE concentration was defined as an increase in NSE after HUTT. As the study population was dominated by patients with a positive HUTT result, the analysis of NSE concentrations focused mainly on the hemodynamic mechanism of syncope, not only on its occurrence.
Statistical methods
Statistical analyses were performed using JMP software, version 15.0.0 (SAS Institute Inc.). Categorical variables were presented as numbers and percentages. Continuous variables were expressed as mean, standard deviation (SD), or median (interquartile range [IQR]). Differences between groups for continuous variables were compared using Student’s t-test, Mann-Whitney test, or Kruskall-Wallis test, depending on the distribution of the variables and the number of compared groups. In order to compare the concentrations of NSE-1 with NSE-2, the Wilcoxon signed-rank test was used. Pearson χ2 test or Fisher’s exact test (if 20% of cells had an expected count fewer than 5) compared categorical variables. Receiver operating characteristic (ROC) curves for selected variables were plotted to identify cut-off points differentiating populations, depending on the presence or absence of an increase in NSE concentration after the test. The Pearson linear correlation between the duration of hypotension and NSE-2 concentration was presented [7]. The observed differences were considered statistically significant if the P-value was below 0.05.
Ethics
The study protocol complied with the Declaration of Helsinki and was approved by the Ethics Committee of the Jagiellonian University Medical College (nos. 122.6120.150.2016 and 122.6120.95.2017). Each participant signed written informed consent before enrollment in the study.
RESULTS AND DISCUSSION
A total of 42 patients were enrolled. The complete, planned biochemical diagnostics were performed in 34 patients. The head-up tilt test was performed in all 42 patients.
In some patients (47.1%; 16 of 34 patients), there was an increase in the plasma concentration of NSE after the HUTT but, despite the observed dynamics, these values mostly remained within the accepted laboratory norm (<16.3 ng/ml). The NSE value exceeded the accepted norm in one person before the test (16.99 ng/ml) and in two people after the HUTT (20.39 ng/ml and 21.66 ng/ml).
We found that the plasma concentration of specific neuronal enolase before (NSE-1) and two hours after the HUTT (NSE-2) did not differ significantly (P = 0.98) (Supplementary material, Table S1), and there were also no statistically significant differences in the plasma concentration of NSE after the HUTT regarding its result (positive, negative, or doubtful) (P = 0.51) (Supplementary material, Table S2) or syncope occurrence during the HUTT (Supplementary material, Table S3).
We observed that there was a statistically significant correlation between the NSE-2 value and the duration of hypotension during the HUTT, defined as SBP <70 mm Hg, regardless of the HUTT result. Moderate linear correlation between the duration of hypotension and NSE-2 concentration was observed (r = 0.53; P = 0.002). More frequently, a statistically significant increase in NSE-2 was observed in the mixed type than in the cardiodepressive type of vasovagal reaction. The hypotonia duration was also significantly longer in the mixed type of VVS (Table 1).
|
VVS type |
P-value |
||
|
Cardiodepressive |
Mixed |
||
|
Age, years, mean (SD) |
39.9 (17.8) |
41.2 (18.8) |
0.84 |
|
Female sex, n (%) |
14 (82.4) |
14 (87.5) |
0.99 |
|
Hypotonia duration, seconds, median (IQR) |
57.4 (41–73.25) |
80 (60–148.75) |
0.03 |
|
NSE-1, ng/ml, median (IQR) |
8.21 (4.43–8.86) |
7.50 (5.74–9.02) |
0.75 |
|
NSE-2, ng/ml, median (IQR) |
7.58 (3.81–8.33) |
7.64 (5.68–9.58) |
0.16 |
|
NSE increase after HUTT (NSE-2>NSE-1), n (%) |
3 (25.0) |
10 (62.5) |
0.049 |
Further univariate analysis allowed for the definition of prolonged hypotension (SBP <70 mm Hg, P = 0.010) as a risk factor for NSE increase after the HUTT. Analysis of the ROC curve showed that in a patient with a duration of hypotension accompanying syncope > 60 seconds, it can be predicted with sensitivity of over 93% and specificity of over 71% that it will cause CNS microdamage, expressed as an increase in NSE after the HUTT (area under the curve [AUC], 0.81; 95% confidence interval [CI], 0.65–0.97).
In the literature, some cases are described when syncope is accompanied by transient focal neurological symptoms [8, 9]. However, the potentially damaging influence of short-term, global hypoperfusion of the CNS during syncope may have a somewhat greater impact on higher cognitive functions, whose evaluation is not straightforward [1, 10, 11].
In this study, we observed that there was no statistically significant increase in plasma NSE concentration within two hours of the head-up tilt test. These observations are consistent with the results of the study by Lee et al. [3], who assessed the diagnostic possibilities of using plasma NSE assays for clinical differentiation of seizures and syncope.
Further analysis of our data showed that CNS microdamage occurs during syncope only when some hemodynamic features of a syncope episode, such as prolonged hypotension, are present. The hypotensive mechanism was also identified as the major causative factor in neurological complications of syncope in the study by Weihong Chu et al. [8] on post-HUTT aphasia. It has also been found that there is an association between the development of clinically symptomatic orthostatic hypotension and an increased risk of future mild cognitive impairment and dementia [12]. This raises the question of what the consequences of prolonged hypotension accompanying recurrent vasovagal syncope can be for the intellectual capacity of people experiencing it.
Limitations
Some of the limitations of our work are the relatively small study group, possibly higher values of NSE concentration in the hours after the HUTT, and the possible effect of undiagnosed neurological diseases or neuroendocrine tumors on NSE values.
Supplementary material
Supplementary material is available at https://journals.viamedica.pl/kardiologia_polska.
Article information
Conflict of interest: None declared.
Funding: None.
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