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Queckenstedt’s Test Headache Response is Associated with Increased Jugular Venous Flow Volume During Migraine Attack
Ultrasound in Med. & Biol., Vol. 37, No. 1, pp. 23–28, 2011 Copyright Ó 2011 World Federation for Ultrasound in Medicine & Biology Printed in the USA. All rights reserved 0301-5629/$ - see front matter
doi:10.1016/j.ultrasmedbio.2010.10.018
d
Original Contribution QUECKENSTEDT’S TEST HEADACHE RESPONSE IS ASSOCIATED WITH INCREASED JUGULAR VENOUS FLOW VOLUME DURING MIGRAINE ATTACK CHI-HSIANG CHOU,*y JONG-LING FUH,zx SHUU-JIUN WANG,zx HAN-HWA HU,zk JAW-CHING WU,*{ and YU-TING CHENG# * Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; y Department of Neurology, Yuan-Shan Veterans Hospital, Yi-Lan, Taiwan; z Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan; x Department of Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan; k Institute of Brain Science, National Yang-Ming University School of Medicine, Taipei, Taiwan; { Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan; and # Department of Statistics, National Chengchi University, Taipei, Taiwan (Received 4 July 2010; revised 11 October 2010; in final form 17 October 2010)
Abstract—Cephalic venous congestion induced by Queckenstedt’s (Q)-test, i.e., transient compression of bilateral internal jugular veins (IJV), can aggravate headache intensity during migraine attacks, especially in patients with throbbing pain. We hypothesized that the IJV flow volume was related to the Q-test response. Ultrasonography was used to measure the flow volume of bilateral IJV in migraine patients during acute attacks and interictal periods and in normal controls. All acute migraine patients underwent Q-test in a supine position. ‘‘Q-test headache response’’ was designated by the changes in headache intensity (0–10 scale) before and 30 s after the Q-test. Thirty-nine acute migraine patients, 20 interictal migraine patients and 23 noxrmal controls completed the study. Acute migraine patients had higher bilateral IJV flow volume than both interictal patients and normal controls (973.4 ± 348.2 vs. 733.8 ± 210.1 vs. 720.3 ± 244.9 mL/min, p 5 0.001). In acute migraine patients, bilateral IJV flow volume was the only independent variable related to the Q-test headache response (adjusted R25 0.422). Thus, the IJV flow volume was increased during migraine attacks and was directly related to the Q-test response. It may be used as a research tool for peripheral sensitization during acute migraine attacks. (E-mail: sjwang@ vghtpe.gov.tw) Ó 2011 World Federation for Ultrasound in Medicine & Biology. Key Words: Queckenstedt’s test, Migraine, Ultrasonography, Internal jugular vein, Throbbing.
headaches (Chou et al. 2004) and is related to throbbing pain but not to brushing allodynia (BA) (Chou et al. 2009), indicating that the Q-test headache response is related to peripheral but not central sensitization (Chou et al. 2009). Although the underlying mechanism of the Q-test headache response is unknown, a transient increase in intracranial pressure has been proposed as one possible cause (Chou et al. 2009). The Q-test hampers venous return in the IJV, resulting in cephalic venous congestion and increased intracranial pressure that can increase headache pain intensity. Therefore, we hypothesized that the IJV flow volume might play a role in migraine aggravation during the Q-test.
INTRODUCTION AND LITERATURE Studies on the contribution of the cerebral venous system to migraine attack symptoms are limited. Previous studies have shown that the transient cephalic venous congestion induced by Queckenstedt’s test (Q-test), i.e., compression of bilateral internal jugular veins (IJV), can aggravate headache intensity during migraine attacks (Doepp et al. 2003; Chou et al. 2004). This Q-test headache response is elicited in the supine position and to a lesser extent in the sitting position (Chou et al. 2004). This is because cerebral venous outflow is mainly through the IJV when the individual is supine but principally through the vertebral venous system when sitting (Valdueza et al. 2000). Previously, we demonstrated that the Q-test headache response is specific to migraine but not to tension-type
MATERIALS AND METHODS Address correspondence to: Dr. Shuu-Jiun Wang, Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, No. 201, Section 2, Shih-Pai Road, Taipei, Taiwan, 112. E-mail: [email protected]
Subjects Three groups of participants were recruited for this study: (1) migraine patients during acute migraine attacks 23
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(‘‘acute migraine patients’’), (2) migraine patients without headaches for at least three days prior to the test (‘‘interictal migraine patients’’) and (3) normal healthy controls without a history of migraine (‘‘normal controls’’). All migraine patients visited the Neurology Outpatient Clinic at Yuan Shan Veterans Hospital or Yi-Lan General Hospital, Yi-Lan, Taiwan. Patients who had an acute migraine but were untreated for the attack were included. Normal controls were either our colleagues (n 5 10) or healthy people who went to Yuan-Shan Veterans Hospital for a routine physical check-up (n 5 13). None of the controls had a history of migraine but they could have infrequent tension-type headaches (,1 day per month). The study protocol was approved by the Institutional Review Board of National Yang-Ming University, Taipei, Taiwan. Prior to enrollment, written informed consent was obtained from each subject. The sex, age, height and weight of each participant were recorded. Previous and current headache characteristics were recorded for the migraine patients, including aura, headache duration, headache frequency, headache intensity (0–10 on a verbal numeric scale), headache laterality, throbbing pain, aggravation by physical activities or not, associated symptoms (nausea, vomiting, photophobia and phonophobia) and analgesic use. Diagnoses of headache The diagnoses of migraine with or without aura were made according to the proposed criteria of the International Classification of Headache Disorders, 2nd edition (ICHD-2), 2004 (Headache Classification Subcommittee of the International Headache Society 2004) (codes 1.1 and 1.2). Patients with chronic migraine, i.e., $15 headache days per month for 3 months with $8 migraine days per month, were excluded (code 1.5.1). Brushing allodynia To evaluate the possible effect of central sensitization, a gauze brushing test (Chou et al. 2009; Ashkenazi and Young 2004; Ashkenazi and Young 2005; Young et al. 2005) was performed to detect BA in the acute migraine patients. A diagonally folded piece of gauze (4 in. 3 4 in.) was used to brush the chins, foreheads and bilateral forearms at approximately 1–2 Hz in frequency for 10 times. Patients were asked if discomfort in addition to a ‘‘brushing’’ sensation was noted (BA1) or not (BA–) during this test. Measurement of the internal jugular venous flow volume A computed sonography system (HP Sonos 7500; Philips Medical Systems, Andover, MA, USA) with an L11-3 broadband linear array probe, which has B-mode, real-time and pulsed Doppler capabilities, was used to examine both patients and controls in the supine
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position. The method of measuring the IJV flow volume was based on the protocol described by M€uller et al. (M€uller et al. 1990). The duplex probe was placed so that the IJV could be visualized at the level of the limbs of the thyroid cartilage and the probe was adjusted to keep the cross-section of the IJV in the center of the scanning field. The probe was turned by 90 to view the longitudinal section of the vessel as much and as horizontally as possible. Pulsed Doppler was used to measure the flow velocity. The Doppler beam was directed through the vessel around the junction site of the midline of both the scan and the vessel and the gate was modified to occupy the whole lumen of the IJV. After stabilization, the time-averaged mean velocity (TAMV, cm s21) was measured for 7–8 s, or for at least one respiratory cycle when the respiration pattern of the patient significantly influenced the Doppler spectrum (Fig. 1). Thereafter, the B-mode, real-time component and probe were used to visualize the IJV in a crosssectional manner. Images of the maximal (Amax) and minimal (Amin) cross-sectional areas of the IJV were recorded for analysis. The areas were calculated and averaged as the mean cross-sectional area of the IJV. The IJV flow volume (mL min21) was calculated from [(Amax1Amin)/2] 3 TAMV 3 60. The bilateral IJV flow volume was calculated as the sum of the right and left IJV flow volumes. The above calculations were all performed off-line. Since the flow volume depends on the averaged cross-sectional area of a vessel lumen, a transient or extreme increase or decrease in diameter may largely influence the results. To address the ‘‘variability’’ of the IJV diameter, we compared the ‘‘variability’’ of the IJV cross-sectional area, which was defined as (AmaxAmin)/[(Amax1Amin)/2] 3 100% in our study. Our rationale was that, if the transient and extreme situations of the IJV differed among the study groups, then the variability of IJV cross-sectional area would differ.
Queckenstedt’s test The Q-test (described in detail in Chou et al. 2004, 2009) was performed on acute migraine patients in the supine position by placing constant and equal manual pressure on both IJVs at the level of the limbs of the thyroid cartilage. These anatomical landmarks were first located by ultrasound. The common carotid artery was avoided as much as possible when the IJVs were compressed. A change in headache intensity was recorded by a 0–10 verbal numerical scale at 10 s intervals for 30 s during and after the Q-test. A change in headache intensity at the 30-s time point during the Q-test was designated as a ‘‘Q-test headache response’’.
Queckenstedt’s test headache response d C.-H. CHOU et al.
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Fig. 1. Measurements of the internal jugular vein (IJV) flow volume and the time-averaged mean velocity of the IJV.
Study procedures After surveying the demographic profiles and prior and current headache profiles of participants followed by at least 5 min of rest, the IJV flow volume was measured for all study participants. Acute migraine patients were also subjected to a gauze brushing test and a Q-test. One trained research technician performed the IJV flow volume and Q-test measurements. Of note, the technician was not blinded since she knew who had a headache. Statistical methods SPSS Version 17.0 for Windows (SPSS Inc., Chicago, IL, USA) was used for all statistical analyses. Student’s t-test was used to compare continuous variables and Pearson’s correlation was used to examine the correlation between continuous variables. One-way analysis of variance with the post-hoc least significant difference test was used to compare the continuous variables between the three study groups. A stepwise multiple regression analysis was used to determine the independent predictors of the Q-test headache response. A p value of ,0.05 in the two-tailed tests was considered to be statistically significant. RESULTS A total of 39 acute migraine patients, 20 interictal migraine patients and 23 normal controls completed the study. The demographic profiles did not differ among
the three study groups and the previous headache profiles of the two migraine groups were comparable (Table 1). The headache characteristics of the current migraine in the acute migraine group were: mean headache duration (from onset to the examination) 23.9 6 24.8 h; mean headache intensity 6.6 6 2.0; aura in four patients (10.3%); unilateral headache in 30 (76.9%); throbbing pain in 32 (82.1%); aggravation by physical activities in 22 (56.4%), nausea in 31 (79.5%); vomiting in six (15.4%); photophobia in 21 (53.8%) and phonophobia in 32 (82.1%). Queckenstedt’s test headache response The Q-test aggravated the headache intensities in acute migraine patients (Fig. 2). The increment of headache intensity was highest at 30 s during the Q-test. Brushing allodynia A total of eight (20.5%) patients had BA in the acute migraine group. Internal jugular venous flow volume Comparisons of the cross-sectional areas, variabilities of the cross-sectional areas and the flow velocities and flow volumes of the IJV are shown in Table 2. The acute migraine group had significantly higher bilateral and left IJV flow volumes than the interictal or control group. A difference in the right IJV flow volume was observed between the acute migraine patients and normal controls but not between the acute and interictal migraine
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Table 1. Demographic data of the acute migraine, interictal migraine, and normal control groups, and past headache profiles in the two migraine groups Acute migraine group
Interictal migraine group
Normal controls
39 10/29 37.9 6 14.7 160.8 6 7.9 60.6 6 10.5 23.4 6 3.3 4 (10.3%) 42.3 6 25.7 6.0 6 4.5 7.7 6 2.3 29 (74.4%) 31 (79.5%) 23 (59.0%) 31 (79.5%) 8 (20.5%) 22 (56.4%) 30 (76.9%)
20 5/15 39.0 6 12.1 160.3 6 8.0 59.5 6 14.1 22.9 6 3.4 1 (5.0%) 33.0 6 27.3 4.5 6 3.7 7.6 6 1.9 17 (85.0%) 16 (80.0%) 6 (30.0%) 17 (85.0%) 2 (10.0%) 13 (65.0%) 16 (80.0%)
23 7/16 41.9 6 12.5 159.5 6 7.5 56.8 6 11.3 22.2 6 2.9
Case number Male/female Age (years) Body height (cm) Body weight (kg) Body mass index Aura Headache duration (h) Headache frequency (days/month) Headache intensity Unilateral location Throbbing pain Aggravation by physical activities Nausea Vomiting Photophobia Phonophobia
p values (ANOVA or t-test) 0.977 0.535 0.813 0.458 0.351 0.653 0.201 0.210 0.879 0.511 1.0 0.054 0.734 0.469 0.585 1.0
ANOVA 5 one-way analysis of variance.
patients. The IJV flow volume did not differ between the interictal migraine patients and normal controls. Of note, the right IJV flow volume was significantly higher than the left IJV flow volume in all three groups. The mean flow velocities and variabilities of the cross-sectional areas of the left or right IJV did not differ among the three study groups (Table 2) and the variabilities of the cross-sectional areas were similar between the left and right IJV in all three study groups (data not shown). The mean cross-sectional area of the left IJV was larger in acute migraine than interictal migraine patients. In the acute migraine patients, the bilateral IJV flow volume did not differ between patients with BA and without BA (1042.7 6 252.2 mL min21 vs. 955.5 6 370.3 mL min21, p 5 0.535). In contrast, patients with throbbing pain had higher bilateral IJV flow volumes
than those without (1043.6 6 333.4 mL min21vs. 652.7 6 218.2 mL min21, p 5 0.005). However, the flow velocity and variability of the cross-sectional area of the left or right IJV did not differ between patients with and without throbbing pain. Correlates of the Q-test headache response In the acute migraine patients, three variables were correlated with the Q-test headache response: the presence of throbbing pain (presence: 0.69 6 1.20, absence: –0.14 6 0.38, p 5 0.003), headache duration (r 5 –0.370, p 5 0.020), and bilateral IJV flow volume (r 5 0.661, p , 0.001). In contrast, BA was not related (BA1: 0.94 6 1.08, BA–: 0.44 6 1.15, p 5 0.272). Multiple regression analyses with the stepwise method showed that the IJV flow volume (beta 5 0.661, t 5 5.36, p , 0.001) was the only independent predictor for the Q-test headache response (adjusted R2 5 0.422). DISCUSSION AND SUMMARY
Fig. 2. Mean headache intensity changes during and after Queckenstedt’s test (Q-test) in patients with acute migraine attack (n 5 39). X-axis: duration in seconds during and after Queckenstedt’s test; Y-axis: mean headache intensity changes.
In this study, we demonstrated an increased IJV flow volume in acute migraine patients compared with interictal migraine patients or normal controls. In addition, the Q-test headache response was closely associated to recordable increases in the IJV flow volume in the acute migraine patients. Since both the Q-test headache response and the IJV flow volume were related to the presence of throbbing pain but not to the presence of BA, an increased IJV flow volume may be associated with peripheral sensitization during migraine attacks. We adopted the ultrasound method proposed by M€uller et al. to measure the flow volumes of the IJV (M€uller et al. 1990). The mean cross-sectional area of the IJV was calculated by averaging the maximal and
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Table 2. Cross-sectional area, variability of cross-sectional areas, flow velocity, and internal jugular venous flow volume in acute migraine, interictal migraine, and normal control groups
2
Smallest cross-sectional area (cm ) Largest cross-sectional area (cm2) Average cross-sectional area (cm2) Variability of cross-sectional area (%) Flow velocity (cm min21) Flow volume (mL min21) Bilateral flow volume (mL min21)
Acute migraine group (N 5 39)
Interictal migraine group (N 5 20)
Normal controls (N 5 23)
p values (ANOVA)
Left: 0.51 6 0.21* Right: 0.49 6 0.24 Left: 0.63 6 0.24* Right: 0.64 6 0.28 Left:0.57 6 0.23* Right: 0.56 6 0.26 Left: 22.7 6 12.2 Right: 28.0 6 14.7 Left: 13.6 6 7.0 Right: 17.9 6 7.1 Left: 424.6 6 222.2*# Right: 548.8 6 201.8# 973.4 6 348.2*#
0.35 6 0.18* 0.44 6 0.22 0.47 6 0.23* 0.58 6 0.22 0.41 6 0.19* 0.51 6 0.24 28.3 6 22.0 29.9 6 17.2 13.1 6 7.1 17.0 6 7.9 269.3 6 128.9* 464.5 6 178.4 733.8 6 210.1*
0.44 6 0.26 0.41 6 0.26 0.58 6 0.30 0.56 6 0.222 0.51 6 0.29 0.49 6 0.23 28.0 6 15.1 34.1 6 27.3 11.8 6 6.1 16.5 6 9.6 295.2 6 128.3# 425.1 6 201.6# 720.3 6 244.9#
0.028 0.469 0.013 0.416 0.018 0.430 0.306 0.502 0.776 0.705 0.003 0.048 0.001
ANOVA 5 one-way analysis of variance. *or #: p , 0.05 by post-hoc least significant difference test. Results are given as means 6 SDs.
minimal cross-sectional areas. The representational quality might be limited in extreme situations such as a short period of small or large fluctuations in areas. Therefore, it might be more accurate to measure the mean values of cross-sectional area changes at more levels. However, since we included interictal migraine and normal controls as comparison groups and since the variability of the cross-sectional areas of the left or right IJV did not differ among the three groups, the chance of this bias was minimal. In addition, the ultrasonographic method was validated by the finding that the results of the normal controls in our study were similar to those reported in previous studies (Valdueza et al. 2000; M€uller et al. 1990). Of note, the value for the right IJV flow volume was higher than the left in our study because the left IJV is commonly smaller than the right anatomically (Lobato et al. 1999; McGee and Mallory 1988). Since the size of the vessel lumen of the venous system is determined passively, flow volume is considered as the determinant for the lumen size. Even though our study showed acute migraine patients had increased flow volumes of the IJV, only left but not right IJV showed significantly increased lumen size. Although some other factors can reportedly change the IJV diameter, such as the body position or weight, Valsalva maneuver and abdominal binder usage (Mortensen et al. 1990; Armstrong et al. 1994), these factors did not differ among our three groups. The reasons for the increment in the IJV flow volume during migraine attacks are unknown. We provide possible explanations. Migraine pain arises from meningeal neurogenic inflammation (Moskowitz 1992), which may, in turn cause arterial vasodilatation and increased cerebral blood flow (Moskowitz 1992; Edvinsson 2001; Edvinsson and Uddman 2005; Waeber and Moskowitz
2005). Some vasoactive substances, such as calcitonin gene-related peptide (CGRP), substance P, neurokinin A (Edvinsson 2001) and pituitary adenylate cyclaseactivating peptide (Edvinsson and Uddman 2005) may be involved. In addition, animal studies and a recent cadaveric study have demonstrated that arteriovenous anastomoses, such as precapillary communicating vessels between arteries and veins, exist in the dura mater (Arulmani et al. 2006; Ishikawa et al. 2007). One experimental animal migraine model showed that intracarotid capsaicin infusion may open these carotidjugular arteriovenous anastomoses (Kapoor et al. 2003). Either arterial vasodilatation or opening of the arteriovenous anastamoses would elevate the dural venous sinus flow and, therefore, result in an increased IJV flow volume. Notably, one animal study showed that CGRP could increase the dural blood flow but not sensitize the meningeal nociceptors (Levy et al. 2005), which excluded the possibility that CGRP links the increased blood flow with peripheral sensitization. Therefore, although our data demonstrated a high correlation between the Q-test headache response and IJV flow volume (r 5 0.661), their causal relationship remains uncertain. By hampering the venous return, the Q-test can induce an increased intracranial pressure, especially in patients with a higher IJV flow volume during migraine attacks (i.e., those with throbbing pain). Combined with the sensitized meninges due to peripheral sensitization, the headache intensity perceived by the patient is increased. Thus, the Q-test combined with IJV flow volume measurement may serve as useful research tools for peripheral sensitization in humans, and may be used to test anti-migraine medications. If tested drugs inhibit or reduce meningeal sensitization, a reduction of the IJV flow volume or Q-test headache response would be
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noted. Such findings would allow the role of the IJV flow volume during migraine attack to be further clarified. There were limitations in our study. First, we performed the test for BA but not for other cutaneous allodynia, such as static mechanical (pressure), heat or cold sensory tests (LoPinto et al. 2006; Greenspan 2001; Klein et al. 2005). The incidence (20.5%) of cutaneous allodynia might, therefore, be underestimated and the absence of a correlation between the IJV flow volume and cutaneous allodynia should be interpreted carefully. Second, the average migraine attack duration (23.9 6 24.8 h) in our acute migraine group was longer than the development of cutaneous allodynia from the onset of the migraine attack (1 h) (Burstein et al. 2000). Third, measurement of the IJV flow volume by ultrasound was operator-dependent. However, only one well-trained technician performed this examination throughout the study, which should have reduced this bias. Fourth, the common carotid artery may have been accidently compressed during the Q-test, aggravating the headache intensity of migraine attack patients. However, since we localized the IJV positions when measuring the IJV flow volume by ultrasonography, we believe this possibility to have been reduced as much as possible. Fifth, since we did not measure the cerebrospinal fluid pressure during the procedure, this pressure cannot be excluded as an underlying mechanism for the throbbing pain. Indeed, increases in the IJV flow volume and cerebrospinal fluid pressure can occur simultaneously. In summary, owing to the IJV flow volume was increased during migraine attacks and was associated with the Q-test headache response, this volume combined with Q-test headache response may be used as a research tool for peripheral sensitization during acute migraine attacks. Acknowledgments—This study was supported in part by grants from the National Science Council of Taiwan (97-2628-B-010-007-MY3), Taipei Veterans General Hospital (V98C1-143), Ministry of Education (Aim for the Top University Plan) and Yuan-Shan Veterans Hospital.
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Volume 37, Number 1, 2011 Ashkenazi A, Young WB. The effects of greater occipital nerve block and trigger point injection on brush allodynia and pain in migraine. Headache 2005;45:350–354. Burstein R, Cutrer MF, Yarnitsky D. The development of cutaneous allodynia during a migraine attack: Clinical evidence for the sequential recruitment of spinal and supraspinal nociceptive neurons in migraine. Brain 2000;123:1703–1709. Chou CH, Chao AC, Lu SR, Hu HH, Wang SJ. Cephalic venous congestion aggravates only migraine-type headaches. Cephalalgia 2004;24: 973–979. Chou CH, Fuh JL, Hu HH, Wu JC, Wang SJ. Throbbing pain is related to Queckenstedt’s test effect in migraine patients. Cephalalgia 2009; 29:373–378. Doepp F, Schreiber SJ, Dreier JP, Einhaupl KM, Valdueza JM. Migraine aggravation caused by cephalic venous congestion. Headache 2003; 43:96–98. Edvinsson L. Sensory nerves in man and their role in primary headaches. Cephalalgia 2001;21:761–764. Edvinsson L, Uddman R. Neurobiology in primary headaches. Brain Res Rev 2005;48:438–456. Greenspan JD. Quantitative assessment of neuropathic pain. Curr Pain Headache Rep 2001;52:107–113. Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia 2004;24(Suppl 1):1–160. Ishikawa T, Sato S, Sasaki T, Matsumoto M, Suzuki K, Itakura T, Kodama N, Hiraiwa K. Histologic study of arteriovenous shunts in the normal dura mater adjacent to the transverse sinus. Surg Neurol 2007;68:272–276. Kapoor K, Arulmani U, Heiligers JP, Garrelds IM, Willems EW, Doods H, Villalon CM, Saxena PR. Effects of the CGRP receptor antagonist BIBN4096BS on capsaicin-induced carotid haemodynamic changes in anaesthetised pigs. Br J Pharmacol 2003;140: 329–338. Klein T, Magerl W, Rolke R, Treede RD. Human surrogate models of neuropathic pain. Pain 2005;115:227–233. Levy D, Burstein R, Strassman AM. Calcitonin gene-related peptide does not excite or sensitize meningeal nociceptors: Implications for the pathophysiology of migraine. Ann Neurol 2005;58: 698–705. Lobato EB, Sulek CA, Moody RL, Morey TE. Cross-sectional area of the right and left internal jugular veins. J Cardiothorac Vasc Anesth 1999;13:136–138. LoPinto C, Young WB, Ashkenazi A. Comparison of dynamic (brush) and static (pressure) mechanical allodynia in migraine. Cephalalgia 2006;26:852–856. McGee WT, Mallory DL. Cannulation of the internal and external jugular veins. Prob Crit Care 1988;2:217–241. Mortensen JD, Talbot S, Burkart JA. Cross-sectional internal diameters of human cervical and femoral blood vessels: relationship to subject’s sex, age, body size. Anat Rec 1990;226:115–124. Moskowitz MA. Neurogenic versus vascular mechanisms of sumatriptan and ergot alkaloids in migraine. Trends Pharmacol Sci 1992; 13:307–311. M€uller HR, Hinn G, Buser MW. Internal jugular venous flow measurement by means of a duplex scanner. J Ultrasound Med 1990;9: 261–265. Valdueza JM, von Munster T, Hoffman O, Schreiber S, Einhaupl KM. Postural dependency of the cerebral venous outflow. Lancet 2000; 355:200–201. Waeber C, Moskowitz MA. Migraine as an inflammatory disorder. Neurology 2005;64(Suppl 2):S9–S15. Young WB, Richardson ES, Shukla P. Brush allodynia in hospitalized headache patients. Headache 2005;45:999–1003.
doi:10.1016/j.ultrasmedbio.2010.10.018
d
Original Contribution QUECKENSTEDT’S TEST HEADACHE RESPONSE IS ASSOCIATED WITH INCREASED JUGULAR VENOUS FLOW VOLUME DURING MIGRAINE ATTACK CHI-HSIANG CHOU,*y JONG-LING FUH,zx SHUU-JIUN WANG,zx HAN-HWA HU,zk JAW-CHING WU,*{ and YU-TING CHENG# * Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; y Department of Neurology, Yuan-Shan Veterans Hospital, Yi-Lan, Taiwan; z Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan; x Department of Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan; k Institute of Brain Science, National Yang-Ming University School of Medicine, Taipei, Taiwan; { Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan; and # Department of Statistics, National Chengchi University, Taipei, Taiwan (Received 4 July 2010; revised 11 October 2010; in final form 17 October 2010)
Abstract—Cephalic venous congestion induced by Queckenstedt’s (Q)-test, i.e., transient compression of bilateral internal jugular veins (IJV), can aggravate headache intensity during migraine attacks, especially in patients with throbbing pain. We hypothesized that the IJV flow volume was related to the Q-test response. Ultrasonography was used to measure the flow volume of bilateral IJV in migraine patients during acute attacks and interictal periods and in normal controls. All acute migraine patients underwent Q-test in a supine position. ‘‘Q-test headache response’’ was designated by the changes in headache intensity (0–10 scale) before and 30 s after the Q-test. Thirty-nine acute migraine patients, 20 interictal migraine patients and 23 noxrmal controls completed the study. Acute migraine patients had higher bilateral IJV flow volume than both interictal patients and normal controls (973.4 ± 348.2 vs. 733.8 ± 210.1 vs. 720.3 ± 244.9 mL/min, p 5 0.001). In acute migraine patients, bilateral IJV flow volume was the only independent variable related to the Q-test headache response (adjusted R25 0.422). Thus, the IJV flow volume was increased during migraine attacks and was directly related to the Q-test response. It may be used as a research tool for peripheral sensitization during acute migraine attacks. (E-mail: sjwang@ vghtpe.gov.tw) Ó 2011 World Federation for Ultrasound in Medicine & Biology. Key Words: Queckenstedt’s test, Migraine, Ultrasonography, Internal jugular vein, Throbbing.
headaches (Chou et al. 2004) and is related to throbbing pain but not to brushing allodynia (BA) (Chou et al. 2009), indicating that the Q-test headache response is related to peripheral but not central sensitization (Chou et al. 2009). Although the underlying mechanism of the Q-test headache response is unknown, a transient increase in intracranial pressure has been proposed as one possible cause (Chou et al. 2009). The Q-test hampers venous return in the IJV, resulting in cephalic venous congestion and increased intracranial pressure that can increase headache pain intensity. Therefore, we hypothesized that the IJV flow volume might play a role in migraine aggravation during the Q-test.
INTRODUCTION AND LITERATURE Studies on the contribution of the cerebral venous system to migraine attack symptoms are limited. Previous studies have shown that the transient cephalic venous congestion induced by Queckenstedt’s test (Q-test), i.e., compression of bilateral internal jugular veins (IJV), can aggravate headache intensity during migraine attacks (Doepp et al. 2003; Chou et al. 2004). This Q-test headache response is elicited in the supine position and to a lesser extent in the sitting position (Chou et al. 2004). This is because cerebral venous outflow is mainly through the IJV when the individual is supine but principally through the vertebral venous system when sitting (Valdueza et al. 2000). Previously, we demonstrated that the Q-test headache response is specific to migraine but not to tension-type
MATERIALS AND METHODS Address correspondence to: Dr. Shuu-Jiun Wang, Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, No. 201, Section 2, Shih-Pai Road, Taipei, Taiwan, 112. E-mail: [email protected]
Subjects Three groups of participants were recruited for this study: (1) migraine patients during acute migraine attacks 23
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(‘‘acute migraine patients’’), (2) migraine patients without headaches for at least three days prior to the test (‘‘interictal migraine patients’’) and (3) normal healthy controls without a history of migraine (‘‘normal controls’’). All migraine patients visited the Neurology Outpatient Clinic at Yuan Shan Veterans Hospital or Yi-Lan General Hospital, Yi-Lan, Taiwan. Patients who had an acute migraine but were untreated for the attack were included. Normal controls were either our colleagues (n 5 10) or healthy people who went to Yuan-Shan Veterans Hospital for a routine physical check-up (n 5 13). None of the controls had a history of migraine but they could have infrequent tension-type headaches (,1 day per month). The study protocol was approved by the Institutional Review Board of National Yang-Ming University, Taipei, Taiwan. Prior to enrollment, written informed consent was obtained from each subject. The sex, age, height and weight of each participant were recorded. Previous and current headache characteristics were recorded for the migraine patients, including aura, headache duration, headache frequency, headache intensity (0–10 on a verbal numeric scale), headache laterality, throbbing pain, aggravation by physical activities or not, associated symptoms (nausea, vomiting, photophobia and phonophobia) and analgesic use. Diagnoses of headache The diagnoses of migraine with or without aura were made according to the proposed criteria of the International Classification of Headache Disorders, 2nd edition (ICHD-2), 2004 (Headache Classification Subcommittee of the International Headache Society 2004) (codes 1.1 and 1.2). Patients with chronic migraine, i.e., $15 headache days per month for 3 months with $8 migraine days per month, were excluded (code 1.5.1). Brushing allodynia To evaluate the possible effect of central sensitization, a gauze brushing test (Chou et al. 2009; Ashkenazi and Young 2004; Ashkenazi and Young 2005; Young et al. 2005) was performed to detect BA in the acute migraine patients. A diagonally folded piece of gauze (4 in. 3 4 in.) was used to brush the chins, foreheads and bilateral forearms at approximately 1–2 Hz in frequency for 10 times. Patients were asked if discomfort in addition to a ‘‘brushing’’ sensation was noted (BA1) or not (BA–) during this test. Measurement of the internal jugular venous flow volume A computed sonography system (HP Sonos 7500; Philips Medical Systems, Andover, MA, USA) with an L11-3 broadband linear array probe, which has B-mode, real-time and pulsed Doppler capabilities, was used to examine both patients and controls in the supine
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position. The method of measuring the IJV flow volume was based on the protocol described by M€uller et al. (M€uller et al. 1990). The duplex probe was placed so that the IJV could be visualized at the level of the limbs of the thyroid cartilage and the probe was adjusted to keep the cross-section of the IJV in the center of the scanning field. The probe was turned by 90 to view the longitudinal section of the vessel as much and as horizontally as possible. Pulsed Doppler was used to measure the flow velocity. The Doppler beam was directed through the vessel around the junction site of the midline of both the scan and the vessel and the gate was modified to occupy the whole lumen of the IJV. After stabilization, the time-averaged mean velocity (TAMV, cm s21) was measured for 7–8 s, or for at least one respiratory cycle when the respiration pattern of the patient significantly influenced the Doppler spectrum (Fig. 1). Thereafter, the B-mode, real-time component and probe were used to visualize the IJV in a crosssectional manner. Images of the maximal (Amax) and minimal (Amin) cross-sectional areas of the IJV were recorded for analysis. The areas were calculated and averaged as the mean cross-sectional area of the IJV. The IJV flow volume (mL min21) was calculated from [(Amax1Amin)/2] 3 TAMV 3 60. The bilateral IJV flow volume was calculated as the sum of the right and left IJV flow volumes. The above calculations were all performed off-line. Since the flow volume depends on the averaged cross-sectional area of a vessel lumen, a transient or extreme increase or decrease in diameter may largely influence the results. To address the ‘‘variability’’ of the IJV diameter, we compared the ‘‘variability’’ of the IJV cross-sectional area, which was defined as (AmaxAmin)/[(Amax1Amin)/2] 3 100% in our study. Our rationale was that, if the transient and extreme situations of the IJV differed among the study groups, then the variability of IJV cross-sectional area would differ.
Queckenstedt’s test The Q-test (described in detail in Chou et al. 2004, 2009) was performed on acute migraine patients in the supine position by placing constant and equal manual pressure on both IJVs at the level of the limbs of the thyroid cartilage. These anatomical landmarks were first located by ultrasound. The common carotid artery was avoided as much as possible when the IJVs were compressed. A change in headache intensity was recorded by a 0–10 verbal numerical scale at 10 s intervals for 30 s during and after the Q-test. A change in headache intensity at the 30-s time point during the Q-test was designated as a ‘‘Q-test headache response’’.
Queckenstedt’s test headache response d C.-H. CHOU et al.
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Fig. 1. Measurements of the internal jugular vein (IJV) flow volume and the time-averaged mean velocity of the IJV.
Study procedures After surveying the demographic profiles and prior and current headache profiles of participants followed by at least 5 min of rest, the IJV flow volume was measured for all study participants. Acute migraine patients were also subjected to a gauze brushing test and a Q-test. One trained research technician performed the IJV flow volume and Q-test measurements. Of note, the technician was not blinded since she knew who had a headache. Statistical methods SPSS Version 17.0 for Windows (SPSS Inc., Chicago, IL, USA) was used for all statistical analyses. Student’s t-test was used to compare continuous variables and Pearson’s correlation was used to examine the correlation between continuous variables. One-way analysis of variance with the post-hoc least significant difference test was used to compare the continuous variables between the three study groups. A stepwise multiple regression analysis was used to determine the independent predictors of the Q-test headache response. A p value of ,0.05 in the two-tailed tests was considered to be statistically significant. RESULTS A total of 39 acute migraine patients, 20 interictal migraine patients and 23 normal controls completed the study. The demographic profiles did not differ among
the three study groups and the previous headache profiles of the two migraine groups were comparable (Table 1). The headache characteristics of the current migraine in the acute migraine group were: mean headache duration (from onset to the examination) 23.9 6 24.8 h; mean headache intensity 6.6 6 2.0; aura in four patients (10.3%); unilateral headache in 30 (76.9%); throbbing pain in 32 (82.1%); aggravation by physical activities in 22 (56.4%), nausea in 31 (79.5%); vomiting in six (15.4%); photophobia in 21 (53.8%) and phonophobia in 32 (82.1%). Queckenstedt’s test headache response The Q-test aggravated the headache intensities in acute migraine patients (Fig. 2). The increment of headache intensity was highest at 30 s during the Q-test. Brushing allodynia A total of eight (20.5%) patients had BA in the acute migraine group. Internal jugular venous flow volume Comparisons of the cross-sectional areas, variabilities of the cross-sectional areas and the flow velocities and flow volumes of the IJV are shown in Table 2. The acute migraine group had significantly higher bilateral and left IJV flow volumes than the interictal or control group. A difference in the right IJV flow volume was observed between the acute migraine patients and normal controls but not between the acute and interictal migraine
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Table 1. Demographic data of the acute migraine, interictal migraine, and normal control groups, and past headache profiles in the two migraine groups Acute migraine group
Interictal migraine group
Normal controls
39 10/29 37.9 6 14.7 160.8 6 7.9 60.6 6 10.5 23.4 6 3.3 4 (10.3%) 42.3 6 25.7 6.0 6 4.5 7.7 6 2.3 29 (74.4%) 31 (79.5%) 23 (59.0%) 31 (79.5%) 8 (20.5%) 22 (56.4%) 30 (76.9%)
20 5/15 39.0 6 12.1 160.3 6 8.0 59.5 6 14.1 22.9 6 3.4 1 (5.0%) 33.0 6 27.3 4.5 6 3.7 7.6 6 1.9 17 (85.0%) 16 (80.0%) 6 (30.0%) 17 (85.0%) 2 (10.0%) 13 (65.0%) 16 (80.0%)
23 7/16 41.9 6 12.5 159.5 6 7.5 56.8 6 11.3 22.2 6 2.9
Case number Male/female Age (years) Body height (cm) Body weight (kg) Body mass index Aura Headache duration (h) Headache frequency (days/month) Headache intensity Unilateral location Throbbing pain Aggravation by physical activities Nausea Vomiting Photophobia Phonophobia
p values (ANOVA or t-test) 0.977 0.535 0.813 0.458 0.351 0.653 0.201 0.210 0.879 0.511 1.0 0.054 0.734 0.469 0.585 1.0
ANOVA 5 one-way analysis of variance.
patients. The IJV flow volume did not differ between the interictal migraine patients and normal controls. Of note, the right IJV flow volume was significantly higher than the left IJV flow volume in all three groups. The mean flow velocities and variabilities of the cross-sectional areas of the left or right IJV did not differ among the three study groups (Table 2) and the variabilities of the cross-sectional areas were similar between the left and right IJV in all three study groups (data not shown). The mean cross-sectional area of the left IJV was larger in acute migraine than interictal migraine patients. In the acute migraine patients, the bilateral IJV flow volume did not differ between patients with BA and without BA (1042.7 6 252.2 mL min21 vs. 955.5 6 370.3 mL min21, p 5 0.535). In contrast, patients with throbbing pain had higher bilateral IJV flow volumes
than those without (1043.6 6 333.4 mL min21vs. 652.7 6 218.2 mL min21, p 5 0.005). However, the flow velocity and variability of the cross-sectional area of the left or right IJV did not differ between patients with and without throbbing pain. Correlates of the Q-test headache response In the acute migraine patients, three variables were correlated with the Q-test headache response: the presence of throbbing pain (presence: 0.69 6 1.20, absence: –0.14 6 0.38, p 5 0.003), headache duration (r 5 –0.370, p 5 0.020), and bilateral IJV flow volume (r 5 0.661, p , 0.001). In contrast, BA was not related (BA1: 0.94 6 1.08, BA–: 0.44 6 1.15, p 5 0.272). Multiple regression analyses with the stepwise method showed that the IJV flow volume (beta 5 0.661, t 5 5.36, p , 0.001) was the only independent predictor for the Q-test headache response (adjusted R2 5 0.422). DISCUSSION AND SUMMARY
Fig. 2. Mean headache intensity changes during and after Queckenstedt’s test (Q-test) in patients with acute migraine attack (n 5 39). X-axis: duration in seconds during and after Queckenstedt’s test; Y-axis: mean headache intensity changes.
In this study, we demonstrated an increased IJV flow volume in acute migraine patients compared with interictal migraine patients or normal controls. In addition, the Q-test headache response was closely associated to recordable increases in the IJV flow volume in the acute migraine patients. Since both the Q-test headache response and the IJV flow volume were related to the presence of throbbing pain but not to the presence of BA, an increased IJV flow volume may be associated with peripheral sensitization during migraine attacks. We adopted the ultrasound method proposed by M€uller et al. to measure the flow volumes of the IJV (M€uller et al. 1990). The mean cross-sectional area of the IJV was calculated by averaging the maximal and
Queckenstedt’s test headache response d C.-H. CHOU et al.
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Table 2. Cross-sectional area, variability of cross-sectional areas, flow velocity, and internal jugular venous flow volume in acute migraine, interictal migraine, and normal control groups
2
Smallest cross-sectional area (cm ) Largest cross-sectional area (cm2) Average cross-sectional area (cm2) Variability of cross-sectional area (%) Flow velocity (cm min21) Flow volume (mL min21) Bilateral flow volume (mL min21)
Acute migraine group (N 5 39)
Interictal migraine group (N 5 20)
Normal controls (N 5 23)
p values (ANOVA)
Left: 0.51 6 0.21* Right: 0.49 6 0.24 Left: 0.63 6 0.24* Right: 0.64 6 0.28 Left:0.57 6 0.23* Right: 0.56 6 0.26 Left: 22.7 6 12.2 Right: 28.0 6 14.7 Left: 13.6 6 7.0 Right: 17.9 6 7.1 Left: 424.6 6 222.2*# Right: 548.8 6 201.8# 973.4 6 348.2*#
0.35 6 0.18* 0.44 6 0.22 0.47 6 0.23* 0.58 6 0.22 0.41 6 0.19* 0.51 6 0.24 28.3 6 22.0 29.9 6 17.2 13.1 6 7.1 17.0 6 7.9 269.3 6 128.9* 464.5 6 178.4 733.8 6 210.1*
0.44 6 0.26 0.41 6 0.26 0.58 6 0.30 0.56 6 0.222 0.51 6 0.29 0.49 6 0.23 28.0 6 15.1 34.1 6 27.3 11.8 6 6.1 16.5 6 9.6 295.2 6 128.3# 425.1 6 201.6# 720.3 6 244.9#
0.028 0.469 0.013 0.416 0.018 0.430 0.306 0.502 0.776 0.705 0.003 0.048 0.001
ANOVA 5 one-way analysis of variance. *or #: p , 0.05 by post-hoc least significant difference test. Results are given as means 6 SDs.
minimal cross-sectional areas. The representational quality might be limited in extreme situations such as a short period of small or large fluctuations in areas. Therefore, it might be more accurate to measure the mean values of cross-sectional area changes at more levels. However, since we included interictal migraine and normal controls as comparison groups and since the variability of the cross-sectional areas of the left or right IJV did not differ among the three groups, the chance of this bias was minimal. In addition, the ultrasonographic method was validated by the finding that the results of the normal controls in our study were similar to those reported in previous studies (Valdueza et al. 2000; M€uller et al. 1990). Of note, the value for the right IJV flow volume was higher than the left in our study because the left IJV is commonly smaller than the right anatomically (Lobato et al. 1999; McGee and Mallory 1988). Since the size of the vessel lumen of the venous system is determined passively, flow volume is considered as the determinant for the lumen size. Even though our study showed acute migraine patients had increased flow volumes of the IJV, only left but not right IJV showed significantly increased lumen size. Although some other factors can reportedly change the IJV diameter, such as the body position or weight, Valsalva maneuver and abdominal binder usage (Mortensen et al. 1990; Armstrong et al. 1994), these factors did not differ among our three groups. The reasons for the increment in the IJV flow volume during migraine attacks are unknown. We provide possible explanations. Migraine pain arises from meningeal neurogenic inflammation (Moskowitz 1992), which may, in turn cause arterial vasodilatation and increased cerebral blood flow (Moskowitz 1992; Edvinsson 2001; Edvinsson and Uddman 2005; Waeber and Moskowitz
2005). Some vasoactive substances, such as calcitonin gene-related peptide (CGRP), substance P, neurokinin A (Edvinsson 2001) and pituitary adenylate cyclaseactivating peptide (Edvinsson and Uddman 2005) may be involved. In addition, animal studies and a recent cadaveric study have demonstrated that arteriovenous anastomoses, such as precapillary communicating vessels between arteries and veins, exist in the dura mater (Arulmani et al. 2006; Ishikawa et al. 2007). One experimental animal migraine model showed that intracarotid capsaicin infusion may open these carotidjugular arteriovenous anastomoses (Kapoor et al. 2003). Either arterial vasodilatation or opening of the arteriovenous anastamoses would elevate the dural venous sinus flow and, therefore, result in an increased IJV flow volume. Notably, one animal study showed that CGRP could increase the dural blood flow but not sensitize the meningeal nociceptors (Levy et al. 2005), which excluded the possibility that CGRP links the increased blood flow with peripheral sensitization. Therefore, although our data demonstrated a high correlation between the Q-test headache response and IJV flow volume (r 5 0.661), their causal relationship remains uncertain. By hampering the venous return, the Q-test can induce an increased intracranial pressure, especially in patients with a higher IJV flow volume during migraine attacks (i.e., those with throbbing pain). Combined with the sensitized meninges due to peripheral sensitization, the headache intensity perceived by the patient is increased. Thus, the Q-test combined with IJV flow volume measurement may serve as useful research tools for peripheral sensitization in humans, and may be used to test anti-migraine medications. If tested drugs inhibit or reduce meningeal sensitization, a reduction of the IJV flow volume or Q-test headache response would be
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noted. Such findings would allow the role of the IJV flow volume during migraine attack to be further clarified. There were limitations in our study. First, we performed the test for BA but not for other cutaneous allodynia, such as static mechanical (pressure), heat or cold sensory tests (LoPinto et al. 2006; Greenspan 2001; Klein et al. 2005). The incidence (20.5%) of cutaneous allodynia might, therefore, be underestimated and the absence of a correlation between the IJV flow volume and cutaneous allodynia should be interpreted carefully. Second, the average migraine attack duration (23.9 6 24.8 h) in our acute migraine group was longer than the development of cutaneous allodynia from the onset of the migraine attack (1 h) (Burstein et al. 2000). Third, measurement of the IJV flow volume by ultrasound was operator-dependent. However, only one well-trained technician performed this examination throughout the study, which should have reduced this bias. Fourth, the common carotid artery may have been accidently compressed during the Q-test, aggravating the headache intensity of migraine attack patients. However, since we localized the IJV positions when measuring the IJV flow volume by ultrasonography, we believe this possibility to have been reduced as much as possible. Fifth, since we did not measure the cerebrospinal fluid pressure during the procedure, this pressure cannot be excluded as an underlying mechanism for the throbbing pain. Indeed, increases in the IJV flow volume and cerebrospinal fluid pressure can occur simultaneously. In summary, owing to the IJV flow volume was increased during migraine attacks and was associated with the Q-test headache response, this volume combined with Q-test headache response may be used as a research tool for peripheral sensitization during acute migraine attacks. Acknowledgments—This study was supported in part by grants from the National Science Council of Taiwan (97-2628-B-010-007-MY3), Taipei Veterans General Hospital (V98C1-143), Ministry of Education (Aim for the Top University Plan) and Yuan-Shan Veterans Hospital.
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