J Neurol (2011) 258:366–372 DOI 10.1007/s00415-010-5759-1
ORIGINAL COMMUNICATION
Cerebral blood flow abnormalities in patients with neurally mediated syncope Eun Yeon Joo • Seung Bong Hong • Minjoo Lee • Woo Suk Tae • James Lee • Suk Won Han • Ki-Hwan Ji • Minah Suh
Received: 7 June 2010 / Revised: 12 September 2010 / Accepted: 14 September 2010 / Published online: 1 October 2010 Ó Springer-Verlag 2010
Abstract The aim of this study is to investigate regional cerebral blood flow (rCBF) in patients with syncope. We compared brain single photon emission computed tomography (SPECT) images of neurally mediated syncope patients with those of age/sex matched healthy volunteers. 99m Tc-ethylcysteinate dimer (ECD) brain SPECT was performed in 35 patients (M/F = 17/18, mean 36.6 years) with syncope during the asymptomatic period, and in 35 healthy volunteers. For statistical parametric mapping (SPM) analysis, all SPECT images were spatially normalized to the standard SPECT template and then smoothed using a 14-mm full width at half maximum Gaussian kernel. The mean duration of syncope history was 4.9 years and the mean number of syncope episodes was 6.3. In all patients, syncope or presyncope episodes occurred during head-up tilt tests, and all were the vasodepressive type. SPM analysis of brain SPECT images showed significantly decreased rCBF in the right anterior insular cortex, left parahippocampal gyrus, bilateral fusiform gyri, bilateral middle and
E. Y. Joo S. B. Hong (&) M. Lee S. W. Han K.-H. Ji Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul 135-710, Korea e-mail:
[email protected];
[email protected] W. S. Tae Neuroscience Research Institute, Kangwon National University College of Medicine, Chunchon, Korea J. Lee Department of Biochemistry, College of Arts and Sciences, University of Washington, Seattle, WA, USA M. Suh Department of Biological Science, Sungkyunkwan University, Suwon, Korea
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inferior temporal gyri, left lingual gyrus, bilateral precuneus and bilateral posterior lobes of the cerebellum in syncope patients at a false discovery rate corrected p \ 0.05. There were no brain regions that showed increased rCBF in syncope patients. Furthermore, we found a negative correlation between the total number of syncopal episodes and the rCBF of the right prefrontal cortex, and between the duration of syncope history and the rCBF of the right cingulate gyrus at uncorrected p \ 0.001. Decreases of rCBF in multiple brain regions may be responsible for autonomic dysregulation and improper processing of emotional stress in neurally mediated syncope patients, and frequent syncope episodes may lead to frontal dysfuction. Keywords Syncope SPECT Cerebral blood flow Statistical parametric mapping Prefrontal cortex
Introduction Syncope is defined as a transient, self-limited, loss of consciousness and postural tone caused by a reduction in blood flow to the reticular activating system, the neuronal network in the brain stem responsible for maintaining consciousness. Neurally mediated syncope is the result of an autonomic reflex that has a final effect of reducing the sympathetic drive, increasing vagal activity and, consequently, causing bradycardia and hypotension [1]. Syncope is usually attributed to cerebral hypoperfusion secondary to systemic hemodynamic collapse. Until now, little data have been available on cerebral perfusion in patients with syncope. To assess regional differences in cerebral blood flow, brain single photon emission computed tomography (SPECT) has been performed during tilt testing in pediatric patients with
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syncope [17]. This study demonstrated that passive orthostatism can cause a diffuse and left hemisphere-dominant reduction in cerebral perfusion. Another SPECT study was conducted prior to and following provocation with isoproterenol in seven subjects with cardiovascular vasodepressor reflex syncope [34]. Mean cerebral perfusion, expressed as average count densities, decreased upon provocation compared with baseline and the hypoperfusion was most pronounced in the frontal lobe. These results suggest that cerebral perfusion decreases markedly in subjects with cardiovascular vasodepressor syncope, but these studies were performed during syncopal episodes and the method with region of interest was adopted for cerebral perfusion analysis [17, 34]. In the present study we used a statistical parametric mapping (SPM) technique for localizing brain regions with significant rCBF changes during the asymptomatic period in syncope patients. SPM is a proven method for the voxel-by-voxel analysis of functional images [13, 25], and SPM analysis for detecting regional cerebral blood flow (rCBF) changes has been shown to allow the examination of regional cerebral hemodynamics with good localizing power [19, 20]. The advantage of this approach lies in its promise of fully automated neurophysiological imaging analysis throughout the entire brain using various statistical approaches. We performed 99mTc-ethylcysteinate dimer (ECD) brain SPECT in neurally mediated syncope patients during the asymptomatic period and in healthy volunteers, and then analyzed the rCBF differences between the two groups using SPM.
Methods Patients and healthy volunteers Thirty-five patients with neurally mediated syncope and 35 age- and sex-matched healthy volunteers were included in the study. The mean age of the study participants was 36.6 years. Inclusion criteria were as follows: (1) age 18–55 (2) absence of cardiac disease (3) absence of autonomic neuropathy or parkinsonism, and (4) history of at least two episodes of syncope. Healthy volunteers were recruited using an advertisement in the local community and none had any history of loss of consciousness by any cause. Patients and healthy volunteers were free of cardiovascular disease, metabolic or systemic disease, other neurological disorders, psychiatric illness and history of head trauma. All subjects were not taking any medication. The following tests were performed in patients to determine the cause of syncope: a complete history and physical examination, complete blood count, 13 lead electrocardiography (ECG), chest X-ray, 24-h ambulatory ECG monitoring, exercise test, echocardiography,
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complete neurological examination, EEG recording, and head-up tilt test. The results of these tests, except for the tilt test, revealed no abnormalities known to cause syncope. Informed consent was obtained from all patients and healthy volunteers after explaining the study protocol and the potential hazards of radioisotope injection. The Institutional Review Board at Samsung Medical Center approved the informed consent form and the study protocol. Head-up tilt test The head-up tilt test was performed at 9 AM for each patient to avoid the effects of diurnal rhythms in the fasting state. A 20 gauge intravenous line was placed in the left hand or forearm for the injection of isoproterenol. Patients were connected to a standard ECG monitor for continuous monitoring of heart rate and rhythm. A standard sphygmomanometer was used to measure blood pressure every 3 min. After a 30 min rest period and baseline measurements of blood pressure and heart rate, each patient was positioned at an angle of 70° from the horizontal position on a standard electrically driven tilt table with footboard for as long as 60 min or until syncope occurred. If syncope or presyncope developed, the table was rapidly lowered to the supine position and the test was ended. If syncope or presyncope did not occur during passive tilting, provocation using pharmacological stimulation (1–5 lg/min of isoproterenol intravenously) was performed. If syncope by pharmacological stimulation did not develop, the test was ended after 45 min. Syncope was defined as a loss of consciousness and postural tone and presyncope was defined as lightheadedness with symptoms like nausea, fatigue, dizziness and blurred vision. The response pattern to tilting was classified tilt negative when neither syncope nor presyncope was induced, and tilt positive when syncope or presyncope was induced [27]. 99m
Tc-ECD brain SPECT
99m
Tc-ECD was injected intravenously for the SPECT studies. A brain SPECT scan was performed within 30–60 min of radiotracer injection (25 mCi) using a threeheaded Triad XLT system equipped with low-energy and high-resolution collimators (Trionix Research Laboratory, Twinsburg, OH, USA). The transaxial system resolution of this camera was 6.9 mm full width at half maximum. Images were reconstructed by filtered back-projection using a Butterworth filter. Attenuation correction was performed using Chang’s method (attenuation coefficient = 0.12 cm-1) [6]. The SPECT voxel dimension was 3.56 9 3.56 9 3.56 mm (x, y, z). All participants were asked to refrain from drinking caffeinated beverages but were allowed to drink water from 07:00 until the end of the
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SPECT study. 99mTc-ECD was injected when the patient had been free of syncopal episodes for at least 72 h. SPM analysis of SPECT studies SPECT images of the syncope patients and healthy volunteers were manipulated using MATLAB 7.1 (The MathWorks, Natick, MA, USA) incorporated into SPM 2 software (Wellcome Department of Cognitive Neurology, Institute of Neurology, University of London, UK). Raw SPECT images (interfile 3.0 format) were converted to 16 bits Analyze format. All of the SPECT images of the healthy volunteers and syncope patients were spatially normalized to the standard SPECT template with the default options. The accuracy of the spatial normalization was checked using a cross-registration function. Spatially normalized images were then smoothed by convolution using an isotopic Gaussian kernel with a 14-mm full width at half maximum to increase the signal to noise ratio [19, 20]. The count of each voxel was normalized to the mean intensity of the white matter to remove differences in the global CBF between individuals [33]. The results were superimposed on the 2-D planes of the averaged MRI template of normal subjects which was normalized to Montreal Neurological Institute (MNI) space. Statistics A one-way ANOVA with covariates of age and gender was used for the rCBF difference between the two groups. To correct for multiple comparisons, the results were corrected using a false discovery rate (FDR) analysis, and voxel clusters were corrected with an extent threshold of kE [ 200 voxels. Partial correlation analyses were performed by SPM2 with the covariates of age, gender and the independent variables of age onset of syncope, duration of disease, frequency of syncope (episodes per year), and total number of episodes in neurally mediated syncope patients. Coordinates were defined using the MNI coordinate system and cluster regions were named as described in Henri M. Duvernoy’s atlas [11].
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age at the onset of syncope was 31.7 ± 12.9 years (16–51). The mean frequency of syncope was 2.3 ± 1.6 episodes/ year (0.2–7.5). The mean total number of syncopal episodes was 6.3 ± 6.2 (2–30). All patients showed vasodepressive type syncope on the head-up tilt test. Summarized results of the tilt testing are given in Table 1. Brain MRIs were performed in all subjects to exclude the possibility of organic brain lesions that might influence cerebral perfusion. None of the patients showed any evidence of structural lesions or abnormal findings on the brain MR images. SPM analysis of
99m
Tc-ECD SPECT
Compared to healthy volunteers, the rCBF of the neurally mediated syncope patients was significantly reduced in the right anterior insular cortex, right parahippocampal gyrus, left and right fusiform gyri, left and right middle and inferior temporal gyri, left lingual gyrus, left and right precuneus, and left and right posterior lobes in the cerebellum at the level of FDR corrected p \ 0.05 (see Table 2; Fig. 1). No brain regions showed increased rCBF. Total number of syncopal episodes was negatively correlated with the rCBF of the right inferior frontal cortex (x, y, z = 50, 44, 12; uncorrected p = 0.0003, r = -0.697) and the duration of syncope history was also negatively correlated with the rCBF of the right cingulate gyrus (x, y, z = 12, 20, 38; uncorrected p = 0.0002, r = -0.693) (Fig. 2).
Discussion We hypothesized that syncope patients with positive tilttesting would have a rCBF abnormality during the asymptomatic period, which may be related to syncopal
Table 1 BP and heart rate changes during head-up tilt test in patients with neutrally mediated syncope Patients (N = 35)
Results Clinical characteristics Age distribution, sex ratio, and education level were not statistically different between patients and healthy controls and all of them were right-handed. The mean age of the patients at the time of SPECT scanning was 36.6 ± 13.8 years (21–54) and their mean
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Baseline systolic BP (mmHg)
118.8 ± 14.7
Baseline diastolic BP (mmHg)
71.2 ± 10.1
Mean heart rate (beats/min)
64.9 ± 10.3
Mean change in systolic BP during tilt test (mmHg) -44.5 ± 14.9 Mean change in diastolic BP during tilt test (mmHg) -28.9 ± 14.3 Mean change in heart rate during tilt test (beat/min) ?21.7 ± 24.2 Mean dose of isoproterenol injection (lg/min) BP blood pressure
3.8 ± 1.5
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Table 2 Brain regions with significant rCBF decrease in syncope patients compared to healthy volunteers Location
Side
MNI coordinates (mm) X
Y
Peak Z
T
*FDR p
\0.0001
z
Anterior insular cortex
Right
54
-42
18
4.33
4.68
Parahippocampal gyrus
Right
30
-16
-24
3.94
4.2
0.0004
Fusiform gyrus
Left
-48
-80
32
2.85
2.95
0.0022
Right
\0.0001
46
-82
30
4.89
5.4
-50
-56
10
2.97
3.08
0.0020
Right
56
-42
-8
3.86
4.12
0.0006
Left Right
-58 58
-48 -42
0 -4
3.92 3.87
4.18 4.12
\0.0001 0.0006
Inferior lingual gyrus
Left
-30
-42
-4
3.71
3.93
0.0001
Precuneus
Left
-4
-56
36
3.37
3.54
0.0004
4
-60
30
3.03
3.15
0.0012
-34
-84
-32
3.7
3.93
0.0001
36
-88
-26
4.6
5.03
0.0002
Middle temporal gyrus Inferior temporal gyrus
Left
Right Cerebellum (posterior lobe)
Left Right
rCBF regional cerebral blood flow, FDR false discovery rate, MNI Montreal Neurological Institute * The FDR corrected p value, extent threshold kE [ 200
episodes. The present study showed significantly decreased rCBF in the anterior insular cortex, basal and lateral temporal areas, medial parieto-occipital area and cerebellum in syncope patients relative to healthy volunteers. Vasovagal syncope, the most common form of neurally mediated syncope, is known to be a part of the dysautonomic syndrome classified under the reflex variant of neurally mediated responses associated with orthostatic intolerance [14, 32]. It is induced by emotions, pain or prolonged orthostatism and many patients in this study reported emotional upset or long periods of standing in hot weather prior to syncope. A chronic autonomic dysfunction profile [23] and altered vagal tone to the heart [22] were reported in patients with vasodepressive syncope. The insula plays a role in diverse functions usually linked to emotion and the regulation of homeostasis. It controls autonomic functions through the regulation of the sympathetic and parasympathetic systems [8, 28]. The right insular cortex is known to exert sympathetic effects on the cardiovascular system (tachycardia, increase in blood pressure), whereas the left insula induces mainly parasympathetic effects such as bradycardia and the reduction of blood pressure [7, 28, 29, 36, 37]. The anterior insula is known to be connected mainly to the entorhinal and periamygdaloid cortices [18]. The close anatomical relationship between these areas may explain the decrease in rCBF in the anterior insula and the adjacent basal and lateral temporal areas in this study. A previous SPECT study performed in pediatric patients showed that subjects with a positive tilt test had regional differences in brain perfusion, with significantly lower perfusion of the right peri-insular, posterior parietal and temporal regions compared to
negative tilt test patients [17] and the reduction in rCBF in these specific areas is known to be a direct effect of the enhanced vagal reflex that leads to syncope. An rCBF decrease confined to the right insula is known to be the final trigger responsible for the reduction of heart rate and blood pressure [12]. These findings were reproduced in this study. All patients enrolled in the study were tilt-positive. Seventeen out of 35 patients underwent autonomic function tests. The autonomic function test consisted of sympathetic skin response, heart rate variance during resting state and hyperventilation, and Valsalva ratio. Eleven of them (65%) showed the electrophysiologic abnormalities suggesting sympathetic dysfunction. Two patients showed the parasympathetic dysfunction. One had both sympathetic and parasympathetic dysfunction. The remaining three patients had no autonomic dysfunction. The finding that most patients with a positive tilt test result had autonomic dysfunction in our study may suggest the possible relationship between the rCBF decrease in the insula and adjacent temporal areas and a baseline autonomic dysregulation in syncope. The precuneus is known to be pivotal for conscious information processing together with the posterior cingulate cortex [35]. The highest levels of cerebral glucose metabolism are found in these two areas in wakefulness and conversely glucose metabolism is the most reduced in these areas during anesthesia [5, 35]. These observations suggest that the rCBF decreases in the precuneus observed in this study may be related to loss of consciousness during syncope. We found that cerebral perfusion in the bilateral posterior lobes of the cerebelli was significantly decreased in
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Fig. 1 A Statistical Brain Map showing brain regions with decreased rCBF in patients with neurally mediated syncope compared to healthy volunteers. a rCBF was reduced in syncope patients compared to healthy volunteers at a FDR corrected p \ 0.05 (independent t test) in the following regions: right anterior insular cortex, right parahippocampal gyrus, bilateral fusiform gyri, bilateral inferior temporal gyri, left inferior lingual gyri, bilateral precuneus, and bilateral cerebellar
Fig. 2 A statistical map generated by SPM correlation analysis. Partial correlation analyses showed that the rCBF of the right inferior frontal gyrus was negatively correlated with the total number of syncopal episodes (a) and the rCBF of right cingulate gyrus was also negatively correlated with the duration of syncope history (b) at uncorrected p \ 0.001. These findings suggest that the higher number of episodes and the longer duration of syncope history may be related to rCBF decrease in these brain regions. Scales in the colored bars are t scores
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cortices (posterior lobes) on coronal (top), sagittal (middle), and axial images (bottom). The results were superimposed on the 2-D planes of the averaged MRI template of normal subjects which was normalized to Montreal Neurological Institute (MNI) space (a). Scales in the colored bars are t scores. The left-hand sides of the images represent the left hemisphere of the brain. The overall areas with reduced rCBF are shown in a 3-D brain rendering view (b)
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syncope patients. Cerebellar blood supply is characterized by a lack of anastomoses between the cortical penetrator branches. Thus, ischemic border zone lesions in the cerebellum occur relatively more frequently than expected [2]. It has been reported that the earlier prodromal symptoms of syncope may be partially attributed to cerebellar hypoperfusion, suggesting exhaustion of the cerebellar autoregulatory reserve [24, 31]. Skin conductance is one of the indices of autonomic arousal and it can reflect sympathetic tone. In functional MRI study, a significant skin conductance response was related to activity in the right anterior insula, left lingual gyrus, right fusiform gyrus and left cerebellum in healthy volunteers [8]. Those areas were in accord with that showed the rCBF decrease in our syncope patients. It could explain that the impaired sympathetic tone in syncope patients, even during the asymptomatic period. An interesting finding of the present study is the negative correlation between the rCBF of the right inferior frontal cortex and the total number of syncopal episodes, and between the rCBF of the right cingulate cortex and the duration of syncope history. In patients with orthostatic hypotension, a characteristic hypoperfusion was observed in the frontal areas [9, 26]. The sleep disturbances associated with sleep deprivation or obstructive sleep apnea preferentially lead to dysfunction of the prefrontal cortex, a region of the brain that controls various executive functions [3, 21]. Intermittent hypoxia is a major pathological factor in the development of neural deficits associated with sleepdisordered breathing [16]. Therefore, these observations may suggest that frequent exposure to syncope may be related to the prefrontal dysfunction observed in the syncope patients in our study. The anterior cingulate cortex is implicated in affective processes and the medial prefrontal cortex is critically involved in the automatic and willful cognitive regulation of emotions [10]. Recently, diminished medial prefrontal cortex activity was noted in a functional MRI study of phobia patients after exposure to phobia-relevant and disgust-inducing pictures [15]. Thus, rCBF decrease in the cingulate cortex in patients with syncope may suggest the reduced cognitive control of emotions of patients. In the present study, the rCBF decrease was lateralized to the right insular cortex, which is consistent with lateralization of cardiovascular control within the insula, as proposed by Oppenheimer et al. [28]. However, we noted that rCBF was also decreased bilaterally in the temporal lobes, parieto-occipital lobes, and cerebellum. Despite the apparent association between the right insula and sympathetic arousal, functional imaging studies have not demonstrated a consistent lateralization of insular activity elicited by emotive and aversive stimuli [4, 30].
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It still remains unclear whether reduced rCBF in several brain regions may cause the clinical characteristics of syncope or be a consequence of recurrent syncopal events. However, most subjects had infrequent syncopal attacks and the total numbers or frequencies of syncope were correlated with CBF changes of only specific brain areas (left prefrontal and cingulate cortex). Thus, most findings in our study appear to be the intrinsic brain pathology of syncope patients rather than the consequences of repeated syncopal episodes. Conclusions Our patients who had neurally mediated syncope demonstrated decreased rCBF in the anterior insular cortex, basal and lateral temporal lobes, medial parieto-occipital area and the cerebellum. Additionally we found a negative correlation between the total number of syncopal episodes and the rCBF of the right prefrontal cortex, and between the duration of syncope history and the rCBF of the right cingulate gyrus. These findings may explain clinical characteristics such as autonomic dysregulation and improper processing of emotional stress seen in syncope patients, and suggest that frequent exposure to syncope may lead to prefrontal dysfunction. Acknowledgments This study was supported by a Grant (2010K000817) from Brain Research Center of the 21st Century Frontier Research Program funded by the Ministry of Education, Science and Technology, and by a grant of the Korean Health Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (No. A090579).
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