- Email: [email protected]
The Clinical and Electroencephalographic Spectrum of Tilt-Induced Syncope and “Near Syncope” in Youth
Pediatric Neurology 62 (2016) 27e33
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Original Article
The Clinical and Electroencephalographic Spectrum of Tilt-Induced Syncope and “Near Syncope” in Youth Geoffrey L. Heyer MD a, b, c, *, Caitlin Schmittauer RN d, Monica P. Islam MD a, b, c a
Division of Pediatric Neurology, Nationwide Children’s Hospital, Columbus, Ohio Department of Pediatrics, The Ohio State University, Columbus, Ohio c Department of Neurology, The Ohio State University, Columbus, Ohio d Department of Pediatrics, Nationwide Children’s Hospital, Columbus, Ohio b
abstract BACKGROUND: The aim of the study was to characterize the clinical and electroencephalographic (EEG) patterns associated with tilt-induced reflex syncope and delayed orthostatic hypotension without syncope in youth. METHODS: We conducted a prospective observational study of 95 patients referred to a pediatric neurology clinic for head-upright tilt testing. Clinical signs, symptoms, video EEG, and continuous blood pressure and heart rate were monitored. RESULTS: Eighty patients had reflex syncope, and 15 had delayed-onset hypotension without syncope. The mean age was 15.3 (standard deviation 2.3) years; 75 (78.9%) were female. All patients with hypotension only had corresponding signs and symptoms; 13 (86.7%) had corresponding EEG slowing. The duration of EEG slowing with hypotension far exceeded the presyncope interval from onset of slowing to loss of consciousness among patients with syncope (P < 0.001). Although prior near-syncope and presyncope episodes were reported commonly in both groups, patients with delayed hypotension without syncope were less likely to have experienced loss of consciousness during episodes of orthostatic intolerance (P < 0.001). Patients with syncope had either slow-flat-slow (n ¼ 23) or slow-only (n ¼ 57) EEG patterns. Compared to those with slow-only EEG patterns, patients with the slow-flat-slow pattern had greater rates of asystole (P < 0.001), myoclonic movements (P < 0.001), facial grimace (P ¼ 0.003), vocalizations (P ¼ 0.002), and arm flexion (P < 0.001) or extension (P ¼ 0.006) during tilt-induced syncope. CONCLUSIONS: Among otherwise healthy youth, orthostatic signs and symptoms vary across the spectrum of tilt-induced reflex syncope and delayed hypotension without syncope. Delayed hypotension without syncope may represent the poorly defined phenomenon of “near syncope” in some patients. Keywords: delayed orthostatic hypotension, orthostatic hypotension, pediatric, adolescent, electroencephalography, syncope, near syncope
Pediatr Neurol 2016; 62: 27-33 Ó 2016 Elsevier Inc. All rights reserved.
Introduction
Reflex (neurally mediated) syncope is a common cause of transient loss of consciousness among children and adults, with a lifetime cumulative incidence estimated as high as 35% to 40%.1-3 Syncope ultimately results from insufficient cerebral blood flow, but the precise afferent nerve pathways Article History: Received March 9, 2016; Accepted in final form May 14, 2016 * Communications should be addressed to: Dr. Heyer; Departments of Pediatrics and Neurology; Nationwide Children’s Hospital and The Ohio State University; 700 Children’s Drive, ED-5; Columbus, Ohio 43205. E-mail address: [email protected] 0887-8994/$ e see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2016.05.007
and central nervous system mechanisms underlying the process remain largely unknown.4 Electroencephalography (EEG) allows real-time assessment of dynamic cerebral changes during the syncope episode. Two EEG patterns have been described from predominantly adult studies of tilt-induced reflex syncope: a slow-flat-slow pattern and a slow-only pattern.5-13 The slow-flat-slow pattern represents a greater degree of cerebral hypoperfusion than the slow-only pattern,14 but why two patterns exist is not clear. Prospective studies of otherwise healthy youth with reflex syncope are lacking. We sought to further characterize the clinical and EEG patterns associated with tilt-induced reflex syncope in
28
G.L. Heyer et al. / Pediatric Neurology 62 (2016) 27e33
youth. As part of the research protocol, we asked that patients remain in the tilted position until loss of consciousness occurred. Some patients developed substantial hypotension with corresponding signs and symptoms of imminent syncope, but they did not experience loss of consciousness. These patients were also included in this study. A better understanding of the clinical and physiologic changes that occur with the spectrum of tilt-induced hypotension and syncope may help to elucidate the elusive neural mechanism(s) underlying these common clinical events and to aid clinicians in distinguishing syncope from epileptic seizures and other forms of transient loss of consciousness. Patients and Methods Subjects We conducted a prospective observational study of sequential patients referred to a pediatric neurologyebased clinic for head-upright tilt (HUT) testing between June 2014 and October 2015. Reasons for referral included refractory syncope, transient loss of consciousness of unclear etiology, and persistent orthostatic symptoms (e.g., lightheadedness, blackout spells, “near syncope”) with or without loss of consciousness. Study inclusion criteria were normal cardiac evaluation (minimally including 12-lead electrocardiogram and cardiac examination) and syncope or substantial orthostatic hypotension (OH) during HUT. The protocol allowed for all patient ages given their referral to a pediatric neurologyebased clinic and their ability to tolerate HUT testing. Patients were excluded from study if they had normal HUT tests; if their procedures were aborted prematurely for any reason; if the captured event was consistent with a psychogenic form of collapse; or if the patient had a genetic, autoimmune, metabolic, or neuropathic cause of OH. Patients with typical features of presyncope who requested lowering before loss of consciousness or less than 20 seconds after onset of hypotension were also excluded. To help distinguish delayed hypotension without syncope (see the later discussion) from presyncope, we chose 20 seconds based on our prior experience that most patients with syncope will lose consciousness within 20 seconds of symptomatic hypotension. Syncope was defined as a transient loss of consciousness associated with hypotension, with or without bradycardia. Bradycardia was defined as heart rate slowing 40 bpm for 10 seconds. Asystole was defined as an interval 3 seconds between QRS complexes. We defined
delayed-onset hypotension without syncope as a symptomatic drop in systolic blood pressure (SBP, 20 mm Hg), persisting 20 seconds without loss of consciousness, and occurring beyond three minutes of HUT.
Protocol All medicines that could affect orthostatic tolerance were discontinued 5 half-lives. Video EEG (Comet AS-40; GRASS systems, Warwick, RI) was synchronized with continuous heart rate and blood pressure (Portapres; Finapres Medical Systems, Amsterdam, The Netherlands) monitoring at baseline and during HUT testing. After 30 minutes of recumbency, patients were tilted upright (70 ), up to 45 minutes. Patients with syncope were lowered with onset of loss of consciousness. Patients who developed hypotension without syncope were encouraged to remain upright until symptoms became intolerable. They underwent simple cognitive testing during the hypotensive period (e.g., What is the name of this hospital? Where were you born?). Four patients with syncope were given sublingual nitroglycerin (0.3 mg) as part of their clinical protocol to provoke syncope. Medicine provocation was not given to any patient with hypotension only. Patients were asked to report all symptoms immediately upon symptom onset. Clinical signs were recorded in real time and confirmed by video review. On recovery, several individuals recalled prodromal symptoms that were not reported in real time, so precise timing of symptom onset could not be established. Amnesia of prodromal symptoms did not occur in any patient. EEGs were interpreted by a pediatric neurologist trained in neurophysiology (M.P.I.).
Standard protocol approvals The study was approved by the Institutional Review Board at Nationwide Children’s Hospital. Informed consent (parents and subjects 18 years of age) and assent (subjects 9 to 17 years) were obtained before all testing.
Statistical analysis Descriptive statistics were calculated for clinical and HUT characteristics. Baseline and nadir blood pressure data were calculated using mean values from 20-second epochs for patients with hypotension only. Sustained movement artifacts from convulsions prevented accurate and consistent assessments of nadir blood pressures in syncope patients. One-way analysis of variance with Bonferroni post hoc testing was used to compare variables between the three groups. The chi-square test or
FIGURE 1. Blood pressure changes with delayed orthostatic hypotension without syncope. An abrupt blood pressure drop (greater than 20 mm Hg) occurred at 992 seconds of head-upright tilt and persisted through table lowering at 1087 seconds. Table lowering takes an additional 12 seconds. Corresponding electroencephalographic changes were present for 51 seconds.
G.L. Heyer et al. / Pediatric Neurology 62 (2016) 27e33
29
TABLE 1. Clinical Characteristics of Syncope Versus Delayed Hypotension Without Syncope
Characteristic
Syncope, SFS, and Slow-Only (n ¼ 80); n (%)
Hypotension Without Syncope (n ¼ 15); n (%)
P Value*
Age (years) Females History of prior syncope episodes History of prior near-syncope (or presyncope) episodes Prodromal symptoms related to onset of hypotension Lightheadedness Vision change (dimming, tunnel vision) Nausea Warmth Headachey Hearing changes (diminished hearing, buzzing, ringing) Yawning Chest tightness Dyspnea or shortness of breath Neck pain Sensation of tingling Clinical signs during tilt-table testing Pallor Acrocyanosis Tearfulness (includes recovery period) Tongue biting Urinary incontinence
15.3 2.4 65 (81.3) 64 (80) 76 (95) 80 (100) 77 (96.3) 43 (57.5) 46 (57.5) 53 (65) 10 (12.5) 15 (18.8) 8 (10) 12 (15) 14 (17.5) 12 (15) 11 (13.8) 49 (61.3) 41 (51.2) 12 (15) 2 (2.5) 0 (0) 0 (0)
15.2 1.7 10 (66.7) 5 (33.3) 15 (100) 15 (100) 15 (100) 15 (100) 9 (60) 14 (93.3) 7 (46.7) 7 (46.7) 7 (46.7) 6 (40) 4 (26.7) 3 (20) 3 (20) 5 (33.3) 2 (13.3) 2 (13.3) 1 (6.7) 0 (0) 0 (0)
0.75 0.2 <0.001 1 1 1 0.09 1 0.033 0.002 0.019 <0.001 0.023 0.47 0.7 0.69 0.045 0.009 1 0.41 1 1
* y
Listed characteristics do not differ between slow-flat-slow (SFS) and slow-only groups (data not shown). Patients with chronic daily headache or headache before tilt (n ¼ 6) were excluded.
Fisher exact test was used to compare categorical variables between two groups, and the Student t test or the ManneWhitney U test was used to compare continuous variables between two groups. All statistical analyses were performed using SPSS Version 22 (SPSS Inc, Chicago, IL). The significance threshold was set at 5%.
Results
Our cohort consisted of 95 patients, 80 with neurally mediated syncope and 15 with delayed-onset hypotension without syncope. Patient age ranged from six to 21 years (mean standard deviation, 15.3 2.3 years); 75 (78.9%) were female. Seventy-nine patients evaluated during the study period were excluded from study: 76 did not meet inclusion criteria based on HUT results and three were eligible for study before testing but declined research participation. Hypotension without syncope
Fifteen patients (15.8% of the cohort) experienced an abrupt onset of prolonged hypotension without syncope (Fig 1). The delay in hypotension onset after initiation of tilt (mean, 1053 463 seconds; range, 286 to 1775 seconds) did not differ from the delay in syncope onset among the 80 patients with syncope (mean, 834.3 521 seconds; range, 123 to 2372 seconds), P ¼ 0.51. SBPs dropped by mean values of 34.3 to 71.6 mm Hg (grand mean, 51.5 14.9 mm Hg). Heart rate changes varied during hypotension with mean values from 20-second epochs ranging from 55.2 to 147.8 bpm. Bradycardia with or without asystole did not occur. The clinical features are compared between patients with hypotension without syncope and patients with syncope (Table 1).
Thirteen (86.7%) patients with hypotension only developed high-amplitude EEG slowing (theta and delta frequencies) that corresponded with hypotension, continued in a stuttering or continuous pattern, and resolved upon table lowering (Fig 2). The duration of EEG changes among the hypotension-only group (mean, 35.3 10.6; range, 21 to 55 seconds) exceeded both the intervals from onset of EEG slowing to loss of consciousness (mean, 7.3 4.9; range, 1 to 20 seconds) and the overall durations of EEG changes (mean, 21.5 7; range, four to 42 seconds) in the syncope group, both P < 0.001 (Fig 3). During the hypotensive period, all 15 patients were able to respond to at least one question, but most responses were abnormal because of excessive delays in response, abnormally long pauses between words, incorrect answers, or limited detail. On recovery, all patients remembered at least one of the questions and could correct any errors. All patients confirmed that the captured event was similar to prior episodes of orthostatic intolerance. Ten patients (66.6%) with hypotension only had frequent “near-syncope” spells as the primary reason for clinic referral and had never experienced loss of consciousness. The two patients with hypotension only but without EEG changes had shorter than average periods of hypotension (21 and 28 seconds) before requesting to be lowered. But differences in degree of hypotension (SBP drops of 43.7 and 38.7 mm Hg) or other clinical features were not apparent. Syncope (slow-flat-slow and slow-only EEG patterns)
Among the 80 patients with syncope during testing, 23 had a slow-flat-slow EEG pattern and 57 had a slow-only EEG pattern. Hypotension, with or without heart rate changes, was the first sign of imminent syncope in all cases.
30
G.L. Heyer et al. / Pediatric Neurology 62 (2016) 27e33
FIGURE 2. Electroencephalographic (EEG) slowing during a period of delayed-onset hypotension without syncope. This patient endured a period of hypotension lasting about 70 seconds with corresponding EEG slowing of 48 seconds. She was able to answer three of four questions correctly, but her responses were delayed by several seconds. Upon recovery, she described the period as “like a dream” and identical to past episode where syncope did not occur.
The slow-flat-slow and slow-only groups did not differ in terms of the timing of onset of EEG abnormalities once tilted upright (693 496 vs 891 524 seconds, P ¼ 0.12) or the total duration of EEG abnormalities during the syncope episodes (23.4 7.2 vs 20.7 6.9 seconds, P ¼ 0.11), but loss of consciousness occurred more rapidly once EEG slowing began in the slow-flat-slow group (4.6 2.3 vs 8.3 5.2 seconds, P < 0.001; Fig 3). Several clinical characteristics differed between syncope groups (Table 2). Compared to those with slow-only EEGs, patients with the slow-flat-slow EEG pattern had greater rates of asystole (P < 0.001) and more convulsive features including myoclonic movements (P < 0.001), facial grimace (P ¼ 0.003), vocalizations (P ¼ 0.002), and arm flexion (P < 0.001) or extension (P ¼ 0.006). In both syncope groups, the onset or offset of EEG changes infrequently showed brief lateralizing features (Table 2), which rapidly generalized at onset and rapidly normalized at offset. Patients with the slow-flat-slow EEG pattern exhibited a sequence of clinical signs that corresponded with each EEG phase (Fig 4). Not every patient developed every clinical sign, but the sequence appeared to be distinctive. The onset of asystole (n ¼ 19) preceded the onset of EEG slowing by 3.5 2.1 seconds and preceded the onset of clinical loss of consciousness by 7 3.6 seconds. The first phase of the slow-flat-slow EEG pattern consisted of high amplitude slowing initially in the theta, then delta, frequency range
(mean duration, 7.3 2.9 seconds), followed by a period of flattening (8 4.8 seconds) and then culminating with a second slow phase (8.4 3.6 seconds). Loss of consciousness occurred during the first slow phase of EEG. The initial clinical signs of loss of consciousness included loss of postural tone (e.g., head drop, slumping of the shoulders), followed rapidly by brief myoclonic movements. In most patients, the transition from EEG slowing to flattening led to tonic posturing. If the eyes were closed with the loss of postural tone, they opened, often widely, during this transition. Some patients developed tonic flexion or extension of their arms or extension followed by flexion. Head turns, facial grimaces, and conjugate eye deviation also occurred during the flat phase. As the period of EEG flattening transitioned to the second period of slowing, sighing and other vocalizations were observed. Myoclonic movements, lip smacking, righting movements, and grunting noises dominated the second phase of EEG slowing. Myoclonic movements during the second slow phase were more prominent (higher amplitude and longer duration) compared to the first slow phase. The syncope semiologies with slow-only EEG changes had greater variation than with the slow-flat-slow pattern. The loss of postural tone appeared to evolve more gradually and to persist longer compared with the slow-flat-slow group. Convulsive signs such as myoclonic movements occurred but less consistently and, when present, always
G.L. Heyer et al. / Pediatric Neurology 62 (2016) 27e33
FIGURE 3. Most patients with delayed hypotension without syncope had corresponding electroencephalographic (EEG) slowing. The periods of EEG slowing from onset to table lowering exceeded the periods of EEG slowing from onset to loss of consciousness among the patients with syncope (slow-flat-slow and slow-only patterns). The very long relative periods of hypotension with EEG slowing argue against typical presyncope as the cause of hypotension. In addition, the slow-flat-slow group of syncope patients had a significantly briefer interval from EEG slowing to clinical syncope than the slow-only group.
following the loss of postural tone. In most patients (91.2%), the eyes either remained open throughout the event or they opened during the transition from the loss of tone to the onset of convulsive signs. Discussion
In this study, we present detailed descriptions of the clinical and EEG features of tilt-induced reflex syncope and delayed hypotension without syncope from a cohort of young, otherwise healthy patients. Our analysis produced several important findings: First, we describe a form of delayed OH without syncope in youth that has not been well characterized to date; second, we delineate the clinical symptoms that precede syncope and compare symptoms by EEG pattern; and third, we confirm that the clinical signs that correspond with the different EEG patterns during syncope are similar in our youth cohort to those reported from largely adult cohorts.5-13 Hypotension without syncope
OH is defined as a sustained reduction of SBP by 20 mm Hg or diastolic blood pressure 10 mm Hg within 3 minutes of orthostatic challenge.4 Streeten and Anderson15 first described delayed OH in seven patients, aged 15 to 70 years, who developed hypotension during orthostatic challenge, but after 3 minutes. Subsequent studies have shown that delayed OH is not an uncommon phenomenon among symptomatic adults.16,17 Adult patients with delayed OH tend to be younger than those with OH,16 and they appear to
31
be at risk of developing OH over time.18 Even among adults, the clinical features of delayed OH have not been well characterized. Although OH and delayed OH are generally considered disorders of the elderly,4,19 over 15% of our youth cohort developed a delayed onset of marked hypotension with corresponding orthostatic symptoms and signs of mild encephalopathy but without apparent progression to syncope. The higher rate of symptom reporting in these patients compared to patients with syncope may be related to the much longer periods of hypotension and retained consciousness, which probably led to better perception of each distinct symptom.14 Most patients with hypotension only also had periods of EEG slowing which significantly exceeded the slowing intervals leading up to loss of consciousness among patients with syncope, arguing against mere “presyncope” as the cause of this phenomenon. Our patients differed from those reported in adult delayed-OH series in three important ways: they were younger in age, had a relatively abrupt (rather than gradual) onset of hypotension, and were generally in good health without OH risk factors. It is not clear why two patients developed similar degrees of hypotension but did not have EEG slowing, although hypotension without EEG changes has been described.13 Mecarelli et al.20 found that hyperventilation during the baseline (recumbent) EEG induced intermittent rhythmic delta slowing in 40% of their patients who had a history of neurally mediated syncope, but in none of their control subjects without prior syncope. They considered the EEG changes to be different from the common slowing pattern seen with hyperventilation in adults. It is possible that the threshold for EEG changes or the degree of hyperventilation differed between our patients who had EEG changes and those who did not. We propose that the term “juvenile delayed OH” be used when otherwise healthy young patients develop delayed hypotension without syncope during orthostatic challenge. Juvenile delayed OH may represent the poorly defined phenomenon of “near syncope” in some patients. All patients endorsed similarities between the episodes captured during HUT testing and episodes that prompted clinical referral; some patients recognized the episodes to be identical to prior nearfainting spells. Syncope
Two EEG patterns have been described with tilt-induced syncope: slow-flat-slow and slow-only.5-13 We characterized the specific signs that correspond with each EEG phase and compared the orthostatic symptoms reported from each group. Wieling et al.14 regard the slow-only pattern as the first slow phase of slow-flat-slow, where blood flow does not decrease long enough or deep enough to cause a flat phase. The EEG flattens when cerebral perfusion falls beneath a critical value.21 Comparing EEG patterns in our cohort, there was no difference in terms of total duration of EEG abnormalities, but the slow-flat-slow group had a greater rate of asystole and a shorter period from EEG slowing to syncope. Our findings suggest that the degree of diminished cerebral perfusion, but not the duration, predicts the EEG pattern. The slow-flat-slow pattern can occur in some patients without asystole5,7,9,10,14,22; the converse is
32
G.L. Heyer et al. / Pediatric Neurology 62 (2016) 27e33
FIGURE 4. The slow-flat-slow syncope pattern on electroencephalographic (EEG) has distinctive clinical features. Letter headings (A to G) mark each EEG phase. Hypotension is the first clinical sign. (A) Asystole begins. (B) The first phase of EEG slowing begins. (C) Slumping of the shoulders and gaze shifted upward (without substantial head drop) indicate loss of consciousness. This is followed by a single myoclonic jerk. (D) EEG slowing transitions to flattening. There is head and conjugate eye turning to the left, followed rapidly by flexor posturing. The first QRS wave following asystole is seen. (E) EEG flattening transitions to the second slow phase. (F) A series of myoclonic jerks, groaning vocalizations, and lip smacking occurs. These movements are marked, in part, by muscle artifact on EEG. (G) EEG slowing begins to normalize as the patient recovers.
TABLE 2. Clinical Characteristics Compared by Syncope EEG Patterns: SFS Versus Slow-Only
Characteristic
Syncope With Syncope With P SFS (n ¼ 23); Slowing Only Value n (%) (n ¼ 57); n (%)
Age, years Females Nitroglycerin given Asystole Bradycardia (without asystole) EEG laterality (at onset or offset) Right hemisphere Left hemisphere Myoclonic movements Eyes open Facial grimace Vocalizations (includes grunting and sighing) Head drop Gaze deviation Arm extension Arm flexion Deviation of head or neck Gagging
15.2 2.8 19 (82.6) 1 (4.3) 19 (82.6) 2 (8.7)
15.4 2.2 47 (82.5) 3 (5.3) 9 (15.8) 17 (29.8)
0.77 0.98 1 <0.001 0.08
4 (17.4)
11 (19.3)
0.84
Abbreviations: EEG ¼ Electroencephalography SFS ¼ Slow-flat-slow
3 1 21 23 18 15
(13) (4.3) (91.3) (100) (78.3) (65.2)
8 3 26 52 24 16
(14) (5.3) (45.6) (91.2) (42.1) (28.1)
NA NA <0.001 0.14 0.003 0.002
13 13 13 13 8 1
(56.5) (56.5) (56.5) (56.5) (34.8) (4.3)
25 19 14 8 12 4
(43.9) (33.3) (24.6) (14) (21.1) (7)
0.31 0.06 0.006 <0.001 0.2 0.66
also true that asystole can occur without inducing a slowflat-slow pattern. When the slow-flat-slow pattern is present, the semiology of the syncope episode is distinctive, and the clinical signs of convulsion are prominent. Although our patients were much younger (15.3 2.3 versus 46 19.8 years) and we used nitroglycerin to provoke spells much less frequently (5% vs 69.6%), the sequence of clinical signs in our study generally matches the descriptions of van Dijk et al.7 Myoclonic activity only occurs during slow phases when some degree of cortical activity is present.7 EEG flattening represents the absence of cortical activity; tonic posturing during the flat EEG phase is likely generated from a brainstem neural pathway. Mercader et al.13 found left-side predominance of EEG slowing in five of their six syncope patients. A small number of our patients had leftor right-side EEG laterality at the onset or offset of syncope, but the majority of each tracing was generalized. Limitations
We acknowledge several study limitations. First, we used loss of postural tone and loss of responsiveness as our clinical indication that syncope occurred, but it is possible that the burden of symptoms caused some patients to drop their heads or stop responding before the actual loss of consciousness. All had EEG changes during this period.
G.L. Heyer et al. / Pediatric Neurology 62 (2016) 27e33
Second, convulsive movements could have been missed because they were concealed by the tilt-table straps, outside the video frame, aborted by table lowering with loss of consciousness or not detected in real-time. Third, the reading neurophysiologist had access to event videos and was not blinded. She was, however, not aware of the blood pressure data. Fourth, our study patients were highly selected based on their referral to a tertiary care, subspecialty clinic, and milder forms of syncope or hypotension without syncope may be underrepresented in this cohort. Fifth, most patients had mild hyperventilation that preceded hypotension (with or without syncope) or coincided with it, which is normal. However, we did not measure pCO2 and cannot assess how hyperventilation may have affected EEG patterns, especially for the hypotension-only patients. Finally, we relied on recall of prodromal symptoms in some patients who did not report all symptoms in real time which prevented us from documenting symptomonset times.
5. 6.
7.
8. 9.
10.
11.
12.
Conclusion
The present study broadens current knowledge about the clinical and EEG features of syncope and orthostatic intolerance. We characterize a juvenile form of tilt-induced delayed OH that may represent “near syncope” in some patients. We delineate the semiology of tilt-induced syncope in youth and show that orthostatic symptoms vary across the spectrum of syncope and hypotension without syncope. The authors thank Rebecca A. Harvey, RN, for her assistance with data collection and Timothy P. Held, MHA, for his technical assistance. Both deny any industry relations, funding sources, or conflicts of interest related to the present study.
13.
14.
15.
16.
17.
18.
References 1. Ganzeboom KS, Mairuhu G, Reitsma JB, Linzer M, Wieling W, van DN. Lifetime cumulative incidence of syncope in the general population: a study of 549 Dutch subjects aged 35-60 years. J Cardiovasc Electrophysiol. 2006;17:1172-1176. 2. Ganzeboom KS, Colman N, Reitsma JB, Shen WK, Wieling W. Prevalence and triggers of syncope in medical students. Am J Cardiol. 2003;9:1006-1008. 3. Serletis A, Rose S, Sheldon AG, Sheldon RS. Vasovagal syncope in medical students and their first-degree relatives. Eur Heart J. 2006; 27:1965-1970. 4. Freeman R, Wieling W, Axelrod FB, et al. Consensus statement on the definition of orthostatic hypotension, neurally mediated syn-
19.
20.
21. 22.
33
cope and the postural tachycardia syndrome. Clin Auton Res. 2011; 21:69-72. Brenner RP. Electroencephalography in syncope. J Clin Neurophysiol. 1997;14:197-209. Ammirati F, Colivicchi F, Di BG, Garelli FF, Santini M. Electroencephalographic correlates of vasovagal syncope induced by head-up tilt testing. Stroke. 1998;29:2347-2351. van Dijk JG, Thijs RD, van Zwet E, et al. The semiology of tilt-induced reflex syncope in relation to electroencephalographic changes. Brain. 2014;137:576-585. Karp HR, Weissler AM, Heyman A. Vasodepressor syncope: EEG and circulatory changes. Arch Neurol. 1961;5:94-101. Grubb BP, Gerard G, Roush K, et al. Differentiation of convulsive syncope and epilepsy with head-up tilt testing. Ann Intern Med. 1991;115:871-876. Sheldon RS, Koshman ML, Murphy WF. Electroencephalographic findings during presyncope and syncope induced by tilt table testing. Can J Cardiol. 1998;14:811-816. Ladwig S, Ries S, Henning O, Valikovics A, Daffertshofer M, Pohlmann-Eden B. Combined electroencephalography and measurements of transcranial blood flow velocity during orthostatic testingda new approach to assess syncope of unknown origin? Clin Auton Res. 1997;7:305-309. Lempert T, Bauer M, Schmidt D. Syncope: a videometric analysis of 56 episodes of transient cerebral hypoxia. Ann Neurol. 1994;36: 233-237. Mercader MA, Varghese PJ, Potolicchio SJ, Venkatraman GK, Lee SW. New insights into the mechanism of neurally mediated syncope. Heart. 2002;88:217-221. Wieling W, Thijs RD, van DN, Wilde AA, Benditt DG, van Dijk JG. Symptoms and signs of syncope: a review of the link between physiology and clinical clues. Brain. 2009;132:2630-2642. Streeten DH, Anderson Jr GH. The role of delayed orthostatic hypotension in the pathogenesis of chronic fatigue. Clin Auton Res. 1998;8:119-124. Gibbons CH, Freeman R. Delayed orthostatic hypotension: a frequent cause of orthostatic intolerance. Neurology. 2006;67: 28-32. Podoleanu C, Maggi R, Oddone D, et al. The hemodynamic pattern of the syndrome of delayed orthostatic hypotension. J Interv Card Electrophysiol. 2009;26:143-149. Gibbons CH, Freeman R. Clinical implications of delayed orthostatic hypotension: a 10-year follow-up study. Neurology. 2015;85: 1362-1367. Moya A, Sutton R, Ammirati F, et al. Guidelines for the diagnosis and management of syncope (version 2009). Eur Heart J. 2009;30: 2631-2671. Mecarelli O, Pulitano P, Vicenzini E, Vanacore N, Accornero N, De MM. Observations on EEG patterns in neurally-mediated syncope: an inspective and quantitative study. Neurophysiol Clin. 2004; 34:203-207. Astrup J, Siesjo BK, Symon L. Thresholds in cerebral ischemiadthe ischemic penumbra. Stroke. 1981;12:723-725. Martinez-Fernandez E, Garcia FB, Gonzalez-Marcos JR, Peralta AG, Garcia AG, Deya AM. Clinical and electroencephalographic features of carotid sinus syncope induced by internal carotid artery angioplasty. AJNR Am J Neuroradiol. 2008;29: 269-272.
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Original Article
The Clinical and Electroencephalographic Spectrum of Tilt-Induced Syncope and “Near Syncope” in Youth Geoffrey L. Heyer MD a, b, c, *, Caitlin Schmittauer RN d, Monica P. Islam MD a, b, c a
Division of Pediatric Neurology, Nationwide Children’s Hospital, Columbus, Ohio Department of Pediatrics, The Ohio State University, Columbus, Ohio c Department of Neurology, The Ohio State University, Columbus, Ohio d Department of Pediatrics, Nationwide Children’s Hospital, Columbus, Ohio b
abstract BACKGROUND: The aim of the study was to characterize the clinical and electroencephalographic (EEG) patterns associated with tilt-induced reflex syncope and delayed orthostatic hypotension without syncope in youth. METHODS: We conducted a prospective observational study of 95 patients referred to a pediatric neurology clinic for head-upright tilt testing. Clinical signs, symptoms, video EEG, and continuous blood pressure and heart rate were monitored. RESULTS: Eighty patients had reflex syncope, and 15 had delayed-onset hypotension without syncope. The mean age was 15.3 (standard deviation 2.3) years; 75 (78.9%) were female. All patients with hypotension only had corresponding signs and symptoms; 13 (86.7%) had corresponding EEG slowing. The duration of EEG slowing with hypotension far exceeded the presyncope interval from onset of slowing to loss of consciousness among patients with syncope (P < 0.001). Although prior near-syncope and presyncope episodes were reported commonly in both groups, patients with delayed hypotension without syncope were less likely to have experienced loss of consciousness during episodes of orthostatic intolerance (P < 0.001). Patients with syncope had either slow-flat-slow (n ¼ 23) or slow-only (n ¼ 57) EEG patterns. Compared to those with slow-only EEG patterns, patients with the slow-flat-slow pattern had greater rates of asystole (P < 0.001), myoclonic movements (P < 0.001), facial grimace (P ¼ 0.003), vocalizations (P ¼ 0.002), and arm flexion (P < 0.001) or extension (P ¼ 0.006) during tilt-induced syncope. CONCLUSIONS: Among otherwise healthy youth, orthostatic signs and symptoms vary across the spectrum of tilt-induced reflex syncope and delayed hypotension without syncope. Delayed hypotension without syncope may represent the poorly defined phenomenon of “near syncope” in some patients. Keywords: delayed orthostatic hypotension, orthostatic hypotension, pediatric, adolescent, electroencephalography, syncope, near syncope
Pediatr Neurol 2016; 62: 27-33 Ó 2016 Elsevier Inc. All rights reserved.
Introduction
Reflex (neurally mediated) syncope is a common cause of transient loss of consciousness among children and adults, with a lifetime cumulative incidence estimated as high as 35% to 40%.1-3 Syncope ultimately results from insufficient cerebral blood flow, but the precise afferent nerve pathways Article History: Received March 9, 2016; Accepted in final form May 14, 2016 * Communications should be addressed to: Dr. Heyer; Departments of Pediatrics and Neurology; Nationwide Children’s Hospital and The Ohio State University; 700 Children’s Drive, ED-5; Columbus, Ohio 43205. E-mail address: [email protected] 0887-8994/$ e see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2016.05.007
and central nervous system mechanisms underlying the process remain largely unknown.4 Electroencephalography (EEG) allows real-time assessment of dynamic cerebral changes during the syncope episode. Two EEG patterns have been described from predominantly adult studies of tilt-induced reflex syncope: a slow-flat-slow pattern and a slow-only pattern.5-13 The slow-flat-slow pattern represents a greater degree of cerebral hypoperfusion than the slow-only pattern,14 but why two patterns exist is not clear. Prospective studies of otherwise healthy youth with reflex syncope are lacking. We sought to further characterize the clinical and EEG patterns associated with tilt-induced reflex syncope in
28
G.L. Heyer et al. / Pediatric Neurology 62 (2016) 27e33
youth. As part of the research protocol, we asked that patients remain in the tilted position until loss of consciousness occurred. Some patients developed substantial hypotension with corresponding signs and symptoms of imminent syncope, but they did not experience loss of consciousness. These patients were also included in this study. A better understanding of the clinical and physiologic changes that occur with the spectrum of tilt-induced hypotension and syncope may help to elucidate the elusive neural mechanism(s) underlying these common clinical events and to aid clinicians in distinguishing syncope from epileptic seizures and other forms of transient loss of consciousness. Patients and Methods Subjects We conducted a prospective observational study of sequential patients referred to a pediatric neurologyebased clinic for head-upright tilt (HUT) testing between June 2014 and October 2015. Reasons for referral included refractory syncope, transient loss of consciousness of unclear etiology, and persistent orthostatic symptoms (e.g., lightheadedness, blackout spells, “near syncope”) with or without loss of consciousness. Study inclusion criteria were normal cardiac evaluation (minimally including 12-lead electrocardiogram and cardiac examination) and syncope or substantial orthostatic hypotension (OH) during HUT. The protocol allowed for all patient ages given their referral to a pediatric neurologyebased clinic and their ability to tolerate HUT testing. Patients were excluded from study if they had normal HUT tests; if their procedures were aborted prematurely for any reason; if the captured event was consistent with a psychogenic form of collapse; or if the patient had a genetic, autoimmune, metabolic, or neuropathic cause of OH. Patients with typical features of presyncope who requested lowering before loss of consciousness or less than 20 seconds after onset of hypotension were also excluded. To help distinguish delayed hypotension without syncope (see the later discussion) from presyncope, we chose 20 seconds based on our prior experience that most patients with syncope will lose consciousness within 20 seconds of symptomatic hypotension. Syncope was defined as a transient loss of consciousness associated with hypotension, with or without bradycardia. Bradycardia was defined as heart rate slowing 40 bpm for 10 seconds. Asystole was defined as an interval 3 seconds between QRS complexes. We defined
delayed-onset hypotension without syncope as a symptomatic drop in systolic blood pressure (SBP, 20 mm Hg), persisting 20 seconds without loss of consciousness, and occurring beyond three minutes of HUT.
Protocol All medicines that could affect orthostatic tolerance were discontinued 5 half-lives. Video EEG (Comet AS-40; GRASS systems, Warwick, RI) was synchronized with continuous heart rate and blood pressure (Portapres; Finapres Medical Systems, Amsterdam, The Netherlands) monitoring at baseline and during HUT testing. After 30 minutes of recumbency, patients were tilted upright (70 ), up to 45 minutes. Patients with syncope were lowered with onset of loss of consciousness. Patients who developed hypotension without syncope were encouraged to remain upright until symptoms became intolerable. They underwent simple cognitive testing during the hypotensive period (e.g., What is the name of this hospital? Where were you born?). Four patients with syncope were given sublingual nitroglycerin (0.3 mg) as part of their clinical protocol to provoke syncope. Medicine provocation was not given to any patient with hypotension only. Patients were asked to report all symptoms immediately upon symptom onset. Clinical signs were recorded in real time and confirmed by video review. On recovery, several individuals recalled prodromal symptoms that were not reported in real time, so precise timing of symptom onset could not be established. Amnesia of prodromal symptoms did not occur in any patient. EEGs were interpreted by a pediatric neurologist trained in neurophysiology (M.P.I.).
Standard protocol approvals The study was approved by the Institutional Review Board at Nationwide Children’s Hospital. Informed consent (parents and subjects 18 years of age) and assent (subjects 9 to 17 years) were obtained before all testing.
Statistical analysis Descriptive statistics were calculated for clinical and HUT characteristics. Baseline and nadir blood pressure data were calculated using mean values from 20-second epochs for patients with hypotension only. Sustained movement artifacts from convulsions prevented accurate and consistent assessments of nadir blood pressures in syncope patients. One-way analysis of variance with Bonferroni post hoc testing was used to compare variables between the three groups. The chi-square test or
FIGURE 1. Blood pressure changes with delayed orthostatic hypotension without syncope. An abrupt blood pressure drop (greater than 20 mm Hg) occurred at 992 seconds of head-upright tilt and persisted through table lowering at 1087 seconds. Table lowering takes an additional 12 seconds. Corresponding electroencephalographic changes were present for 51 seconds.
G.L. Heyer et al. / Pediatric Neurology 62 (2016) 27e33
29
TABLE 1. Clinical Characteristics of Syncope Versus Delayed Hypotension Without Syncope
Characteristic
Syncope, SFS, and Slow-Only (n ¼ 80); n (%)
Hypotension Without Syncope (n ¼ 15); n (%)
P Value*
Age (years) Females History of prior syncope episodes History of prior near-syncope (or presyncope) episodes Prodromal symptoms related to onset of hypotension Lightheadedness Vision change (dimming, tunnel vision) Nausea Warmth Headachey Hearing changes (diminished hearing, buzzing, ringing) Yawning Chest tightness Dyspnea or shortness of breath Neck pain Sensation of tingling Clinical signs during tilt-table testing Pallor Acrocyanosis Tearfulness (includes recovery period) Tongue biting Urinary incontinence
15.3 2.4 65 (81.3) 64 (80) 76 (95) 80 (100) 77 (96.3) 43 (57.5) 46 (57.5) 53 (65) 10 (12.5) 15 (18.8) 8 (10) 12 (15) 14 (17.5) 12 (15) 11 (13.8) 49 (61.3) 41 (51.2) 12 (15) 2 (2.5) 0 (0) 0 (0)
15.2 1.7 10 (66.7) 5 (33.3) 15 (100) 15 (100) 15 (100) 15 (100) 9 (60) 14 (93.3) 7 (46.7) 7 (46.7) 7 (46.7) 6 (40) 4 (26.7) 3 (20) 3 (20) 5 (33.3) 2 (13.3) 2 (13.3) 1 (6.7) 0 (0) 0 (0)
0.75 0.2 <0.001 1 1 1 0.09 1 0.033 0.002 0.019 <0.001 0.023 0.47 0.7 0.69 0.045 0.009 1 0.41 1 1
* y
Listed characteristics do not differ between slow-flat-slow (SFS) and slow-only groups (data not shown). Patients with chronic daily headache or headache before tilt (n ¼ 6) were excluded.
Fisher exact test was used to compare categorical variables between two groups, and the Student t test or the ManneWhitney U test was used to compare continuous variables between two groups. All statistical analyses were performed using SPSS Version 22 (SPSS Inc, Chicago, IL). The significance threshold was set at 5%.
Results
Our cohort consisted of 95 patients, 80 with neurally mediated syncope and 15 with delayed-onset hypotension without syncope. Patient age ranged from six to 21 years (mean standard deviation, 15.3 2.3 years); 75 (78.9%) were female. Seventy-nine patients evaluated during the study period were excluded from study: 76 did not meet inclusion criteria based on HUT results and three were eligible for study before testing but declined research participation. Hypotension without syncope
Fifteen patients (15.8% of the cohort) experienced an abrupt onset of prolonged hypotension without syncope (Fig 1). The delay in hypotension onset after initiation of tilt (mean, 1053 463 seconds; range, 286 to 1775 seconds) did not differ from the delay in syncope onset among the 80 patients with syncope (mean, 834.3 521 seconds; range, 123 to 2372 seconds), P ¼ 0.51. SBPs dropped by mean values of 34.3 to 71.6 mm Hg (grand mean, 51.5 14.9 mm Hg). Heart rate changes varied during hypotension with mean values from 20-second epochs ranging from 55.2 to 147.8 bpm. Bradycardia with or without asystole did not occur. The clinical features are compared between patients with hypotension without syncope and patients with syncope (Table 1).
Thirteen (86.7%) patients with hypotension only developed high-amplitude EEG slowing (theta and delta frequencies) that corresponded with hypotension, continued in a stuttering or continuous pattern, and resolved upon table lowering (Fig 2). The duration of EEG changes among the hypotension-only group (mean, 35.3 10.6; range, 21 to 55 seconds) exceeded both the intervals from onset of EEG slowing to loss of consciousness (mean, 7.3 4.9; range, 1 to 20 seconds) and the overall durations of EEG changes (mean, 21.5 7; range, four to 42 seconds) in the syncope group, both P < 0.001 (Fig 3). During the hypotensive period, all 15 patients were able to respond to at least one question, but most responses were abnormal because of excessive delays in response, abnormally long pauses between words, incorrect answers, or limited detail. On recovery, all patients remembered at least one of the questions and could correct any errors. All patients confirmed that the captured event was similar to prior episodes of orthostatic intolerance. Ten patients (66.6%) with hypotension only had frequent “near-syncope” spells as the primary reason for clinic referral and had never experienced loss of consciousness. The two patients with hypotension only but without EEG changes had shorter than average periods of hypotension (21 and 28 seconds) before requesting to be lowered. But differences in degree of hypotension (SBP drops of 43.7 and 38.7 mm Hg) or other clinical features were not apparent. Syncope (slow-flat-slow and slow-only EEG patterns)
Among the 80 patients with syncope during testing, 23 had a slow-flat-slow EEG pattern and 57 had a slow-only EEG pattern. Hypotension, with or without heart rate changes, was the first sign of imminent syncope in all cases.
30
G.L. Heyer et al. / Pediatric Neurology 62 (2016) 27e33
FIGURE 2. Electroencephalographic (EEG) slowing during a period of delayed-onset hypotension without syncope. This patient endured a period of hypotension lasting about 70 seconds with corresponding EEG slowing of 48 seconds. She was able to answer three of four questions correctly, but her responses were delayed by several seconds. Upon recovery, she described the period as “like a dream” and identical to past episode where syncope did not occur.
The slow-flat-slow and slow-only groups did not differ in terms of the timing of onset of EEG abnormalities once tilted upright (693 496 vs 891 524 seconds, P ¼ 0.12) or the total duration of EEG abnormalities during the syncope episodes (23.4 7.2 vs 20.7 6.9 seconds, P ¼ 0.11), but loss of consciousness occurred more rapidly once EEG slowing began in the slow-flat-slow group (4.6 2.3 vs 8.3 5.2 seconds, P < 0.001; Fig 3). Several clinical characteristics differed between syncope groups (Table 2). Compared to those with slow-only EEGs, patients with the slow-flat-slow EEG pattern had greater rates of asystole (P < 0.001) and more convulsive features including myoclonic movements (P < 0.001), facial grimace (P ¼ 0.003), vocalizations (P ¼ 0.002), and arm flexion (P < 0.001) or extension (P ¼ 0.006). In both syncope groups, the onset or offset of EEG changes infrequently showed brief lateralizing features (Table 2), which rapidly generalized at onset and rapidly normalized at offset. Patients with the slow-flat-slow EEG pattern exhibited a sequence of clinical signs that corresponded with each EEG phase (Fig 4). Not every patient developed every clinical sign, but the sequence appeared to be distinctive. The onset of asystole (n ¼ 19) preceded the onset of EEG slowing by 3.5 2.1 seconds and preceded the onset of clinical loss of consciousness by 7 3.6 seconds. The first phase of the slow-flat-slow EEG pattern consisted of high amplitude slowing initially in the theta, then delta, frequency range
(mean duration, 7.3 2.9 seconds), followed by a period of flattening (8 4.8 seconds) and then culminating with a second slow phase (8.4 3.6 seconds). Loss of consciousness occurred during the first slow phase of EEG. The initial clinical signs of loss of consciousness included loss of postural tone (e.g., head drop, slumping of the shoulders), followed rapidly by brief myoclonic movements. In most patients, the transition from EEG slowing to flattening led to tonic posturing. If the eyes were closed with the loss of postural tone, they opened, often widely, during this transition. Some patients developed tonic flexion or extension of their arms or extension followed by flexion. Head turns, facial grimaces, and conjugate eye deviation also occurred during the flat phase. As the period of EEG flattening transitioned to the second period of slowing, sighing and other vocalizations were observed. Myoclonic movements, lip smacking, righting movements, and grunting noises dominated the second phase of EEG slowing. Myoclonic movements during the second slow phase were more prominent (higher amplitude and longer duration) compared to the first slow phase. The syncope semiologies with slow-only EEG changes had greater variation than with the slow-flat-slow pattern. The loss of postural tone appeared to evolve more gradually and to persist longer compared with the slow-flat-slow group. Convulsive signs such as myoclonic movements occurred but less consistently and, when present, always
G.L. Heyer et al. / Pediatric Neurology 62 (2016) 27e33
FIGURE 3. Most patients with delayed hypotension without syncope had corresponding electroencephalographic (EEG) slowing. The periods of EEG slowing from onset to table lowering exceeded the periods of EEG slowing from onset to loss of consciousness among the patients with syncope (slow-flat-slow and slow-only patterns). The very long relative periods of hypotension with EEG slowing argue against typical presyncope as the cause of hypotension. In addition, the slow-flat-slow group of syncope patients had a significantly briefer interval from EEG slowing to clinical syncope than the slow-only group.
following the loss of postural tone. In most patients (91.2%), the eyes either remained open throughout the event or they opened during the transition from the loss of tone to the onset of convulsive signs. Discussion
In this study, we present detailed descriptions of the clinical and EEG features of tilt-induced reflex syncope and delayed hypotension without syncope from a cohort of young, otherwise healthy patients. Our analysis produced several important findings: First, we describe a form of delayed OH without syncope in youth that has not been well characterized to date; second, we delineate the clinical symptoms that precede syncope and compare symptoms by EEG pattern; and third, we confirm that the clinical signs that correspond with the different EEG patterns during syncope are similar in our youth cohort to those reported from largely adult cohorts.5-13 Hypotension without syncope
OH is defined as a sustained reduction of SBP by 20 mm Hg or diastolic blood pressure 10 mm Hg within 3 minutes of orthostatic challenge.4 Streeten and Anderson15 first described delayed OH in seven patients, aged 15 to 70 years, who developed hypotension during orthostatic challenge, but after 3 minutes. Subsequent studies have shown that delayed OH is not an uncommon phenomenon among symptomatic adults.16,17 Adult patients with delayed OH tend to be younger than those with OH,16 and they appear to
31
be at risk of developing OH over time.18 Even among adults, the clinical features of delayed OH have not been well characterized. Although OH and delayed OH are generally considered disorders of the elderly,4,19 over 15% of our youth cohort developed a delayed onset of marked hypotension with corresponding orthostatic symptoms and signs of mild encephalopathy but without apparent progression to syncope. The higher rate of symptom reporting in these patients compared to patients with syncope may be related to the much longer periods of hypotension and retained consciousness, which probably led to better perception of each distinct symptom.14 Most patients with hypotension only also had periods of EEG slowing which significantly exceeded the slowing intervals leading up to loss of consciousness among patients with syncope, arguing against mere “presyncope” as the cause of this phenomenon. Our patients differed from those reported in adult delayed-OH series in three important ways: they were younger in age, had a relatively abrupt (rather than gradual) onset of hypotension, and were generally in good health without OH risk factors. It is not clear why two patients developed similar degrees of hypotension but did not have EEG slowing, although hypotension without EEG changes has been described.13 Mecarelli et al.20 found that hyperventilation during the baseline (recumbent) EEG induced intermittent rhythmic delta slowing in 40% of their patients who had a history of neurally mediated syncope, but in none of their control subjects without prior syncope. They considered the EEG changes to be different from the common slowing pattern seen with hyperventilation in adults. It is possible that the threshold for EEG changes or the degree of hyperventilation differed between our patients who had EEG changes and those who did not. We propose that the term “juvenile delayed OH” be used when otherwise healthy young patients develop delayed hypotension without syncope during orthostatic challenge. Juvenile delayed OH may represent the poorly defined phenomenon of “near syncope” in some patients. All patients endorsed similarities between the episodes captured during HUT testing and episodes that prompted clinical referral; some patients recognized the episodes to be identical to prior nearfainting spells. Syncope
Two EEG patterns have been described with tilt-induced syncope: slow-flat-slow and slow-only.5-13 We characterized the specific signs that correspond with each EEG phase and compared the orthostatic symptoms reported from each group. Wieling et al.14 regard the slow-only pattern as the first slow phase of slow-flat-slow, where blood flow does not decrease long enough or deep enough to cause a flat phase. The EEG flattens when cerebral perfusion falls beneath a critical value.21 Comparing EEG patterns in our cohort, there was no difference in terms of total duration of EEG abnormalities, but the slow-flat-slow group had a greater rate of asystole and a shorter period from EEG slowing to syncope. Our findings suggest that the degree of diminished cerebral perfusion, but not the duration, predicts the EEG pattern. The slow-flat-slow pattern can occur in some patients without asystole5,7,9,10,14,22; the converse is
32
G.L. Heyer et al. / Pediatric Neurology 62 (2016) 27e33
FIGURE 4. The slow-flat-slow syncope pattern on electroencephalographic (EEG) has distinctive clinical features. Letter headings (A to G) mark each EEG phase. Hypotension is the first clinical sign. (A) Asystole begins. (B) The first phase of EEG slowing begins. (C) Slumping of the shoulders and gaze shifted upward (without substantial head drop) indicate loss of consciousness. This is followed by a single myoclonic jerk. (D) EEG slowing transitions to flattening. There is head and conjugate eye turning to the left, followed rapidly by flexor posturing. The first QRS wave following asystole is seen. (E) EEG flattening transitions to the second slow phase. (F) A series of myoclonic jerks, groaning vocalizations, and lip smacking occurs. These movements are marked, in part, by muscle artifact on EEG. (G) EEG slowing begins to normalize as the patient recovers.
TABLE 2. Clinical Characteristics Compared by Syncope EEG Patterns: SFS Versus Slow-Only
Characteristic
Syncope With Syncope With P SFS (n ¼ 23); Slowing Only Value n (%) (n ¼ 57); n (%)
Age, years Females Nitroglycerin given Asystole Bradycardia (without asystole) EEG laterality (at onset or offset) Right hemisphere Left hemisphere Myoclonic movements Eyes open Facial grimace Vocalizations (includes grunting and sighing) Head drop Gaze deviation Arm extension Arm flexion Deviation of head or neck Gagging
15.2 2.8 19 (82.6) 1 (4.3) 19 (82.6) 2 (8.7)
15.4 2.2 47 (82.5) 3 (5.3) 9 (15.8) 17 (29.8)
0.77 0.98 1 <0.001 0.08
4 (17.4)
11 (19.3)
0.84
Abbreviations: EEG ¼ Electroencephalography SFS ¼ Slow-flat-slow
3 1 21 23 18 15
(13) (4.3) (91.3) (100) (78.3) (65.2)
8 3 26 52 24 16
(14) (5.3) (45.6) (91.2) (42.1) (28.1)
NA NA <0.001 0.14 0.003 0.002
13 13 13 13 8 1
(56.5) (56.5) (56.5) (56.5) (34.8) (4.3)
25 19 14 8 12 4
(43.9) (33.3) (24.6) (14) (21.1) (7)
0.31 0.06 0.006 <0.001 0.2 0.66
also true that asystole can occur without inducing a slowflat-slow pattern. When the slow-flat-slow pattern is present, the semiology of the syncope episode is distinctive, and the clinical signs of convulsion are prominent. Although our patients were much younger (15.3 2.3 versus 46 19.8 years) and we used nitroglycerin to provoke spells much less frequently (5% vs 69.6%), the sequence of clinical signs in our study generally matches the descriptions of van Dijk et al.7 Myoclonic activity only occurs during slow phases when some degree of cortical activity is present.7 EEG flattening represents the absence of cortical activity; tonic posturing during the flat EEG phase is likely generated from a brainstem neural pathway. Mercader et al.13 found left-side predominance of EEG slowing in five of their six syncope patients. A small number of our patients had leftor right-side EEG laterality at the onset or offset of syncope, but the majority of each tracing was generalized. Limitations
We acknowledge several study limitations. First, we used loss of postural tone and loss of responsiveness as our clinical indication that syncope occurred, but it is possible that the burden of symptoms caused some patients to drop their heads or stop responding before the actual loss of consciousness. All had EEG changes during this period.
G.L. Heyer et al. / Pediatric Neurology 62 (2016) 27e33
Second, convulsive movements could have been missed because they were concealed by the tilt-table straps, outside the video frame, aborted by table lowering with loss of consciousness or not detected in real-time. Third, the reading neurophysiologist had access to event videos and was not blinded. She was, however, not aware of the blood pressure data. Fourth, our study patients were highly selected based on their referral to a tertiary care, subspecialty clinic, and milder forms of syncope or hypotension without syncope may be underrepresented in this cohort. Fifth, most patients had mild hyperventilation that preceded hypotension (with or without syncope) or coincided with it, which is normal. However, we did not measure pCO2 and cannot assess how hyperventilation may have affected EEG patterns, especially for the hypotension-only patients. Finally, we relied on recall of prodromal symptoms in some patients who did not report all symptoms in real time which prevented us from documenting symptomonset times.
5. 6.
7.
8. 9.
10.
11.
12.
Conclusion
The present study broadens current knowledge about the clinical and EEG features of syncope and orthostatic intolerance. We characterize a juvenile form of tilt-induced delayed OH that may represent “near syncope” in some patients. We delineate the semiology of tilt-induced syncope in youth and show that orthostatic symptoms vary across the spectrum of syncope and hypotension without syncope. The authors thank Rebecca A. Harvey, RN, for her assistance with data collection and Timothy P. Held, MHA, for his technical assistance. Both deny any industry relations, funding sources, or conflicts of interest related to the present study.
13.
14.
15.
16.
17.
18.
References 1. Ganzeboom KS, Mairuhu G, Reitsma JB, Linzer M, Wieling W, van DN. Lifetime cumulative incidence of syncope in the general population: a study of 549 Dutch subjects aged 35-60 years. J Cardiovasc Electrophysiol. 2006;17:1172-1176. 2. Ganzeboom KS, Colman N, Reitsma JB, Shen WK, Wieling W. Prevalence and triggers of syncope in medical students. Am J Cardiol. 2003;9:1006-1008. 3. Serletis A, Rose S, Sheldon AG, Sheldon RS. Vasovagal syncope in medical students and their first-degree relatives. Eur Heart J. 2006; 27:1965-1970. 4. Freeman R, Wieling W, Axelrod FB, et al. Consensus statement on the definition of orthostatic hypotension, neurally mediated syn-
19.
20.
21. 22.
33
cope and the postural tachycardia syndrome. Clin Auton Res. 2011; 21:69-72. Brenner RP. Electroencephalography in syncope. J Clin Neurophysiol. 1997;14:197-209. Ammirati F, Colivicchi F, Di BG, Garelli FF, Santini M. Electroencephalographic correlates of vasovagal syncope induced by head-up tilt testing. Stroke. 1998;29:2347-2351. van Dijk JG, Thijs RD, van Zwet E, et al. The semiology of tilt-induced reflex syncope in relation to electroencephalographic changes. Brain. 2014;137:576-585. Karp HR, Weissler AM, Heyman A. Vasodepressor syncope: EEG and circulatory changes. Arch Neurol. 1961;5:94-101. Grubb BP, Gerard G, Roush K, et al. Differentiation of convulsive syncope and epilepsy with head-up tilt testing. Ann Intern Med. 1991;115:871-876. Sheldon RS, Koshman ML, Murphy WF. Electroencephalographic findings during presyncope and syncope induced by tilt table testing. Can J Cardiol. 1998;14:811-816. Ladwig S, Ries S, Henning O, Valikovics A, Daffertshofer M, Pohlmann-Eden B. Combined electroencephalography and measurements of transcranial blood flow velocity during orthostatic testingda new approach to assess syncope of unknown origin? Clin Auton Res. 1997;7:305-309. Lempert T, Bauer M, Schmidt D. Syncope: a videometric analysis of 56 episodes of transient cerebral hypoxia. Ann Neurol. 1994;36: 233-237. Mercader MA, Varghese PJ, Potolicchio SJ, Venkatraman GK, Lee SW. New insights into the mechanism of neurally mediated syncope. Heart. 2002;88:217-221. Wieling W, Thijs RD, van DN, Wilde AA, Benditt DG, van Dijk JG. Symptoms and signs of syncope: a review of the link between physiology and clinical clues. Brain. 2009;132:2630-2642. Streeten DH, Anderson Jr GH. The role of delayed orthostatic hypotension in the pathogenesis of chronic fatigue. Clin Auton Res. 1998;8:119-124. Gibbons CH, Freeman R. Delayed orthostatic hypotension: a frequent cause of orthostatic intolerance. Neurology. 2006;67: 28-32. Podoleanu C, Maggi R, Oddone D, et al. The hemodynamic pattern of the syndrome of delayed orthostatic hypotension. J Interv Card Electrophysiol. 2009;26:143-149. Gibbons CH, Freeman R. Clinical implications of delayed orthostatic hypotension: a 10-year follow-up study. Neurology. 2015;85: 1362-1367. Moya A, Sutton R, Ammirati F, et al. Guidelines for the diagnosis and management of syncope (version 2009). Eur Heart J. 2009;30: 2631-2671. Mecarelli O, Pulitano P, Vicenzini E, Vanacore N, Accornero N, De MM. Observations on EEG patterns in neurally-mediated syncope: an inspective and quantitative study. Neurophysiol Clin. 2004; 34:203-207. Astrup J, Siesjo BK, Symon L. Thresholds in cerebral ischemiadthe ischemic penumbra. Stroke. 1981;12:723-725. Martinez-Fernandez E, Garcia FB, Gonzalez-Marcos JR, Peralta AG, Garcia AG, Deya AM. Clinical and electroencephalographic features of carotid sinus syncope induced by internal carotid artery angioplasty. AJNR Am J Neuroradiol. 2008;29: 269-272.