J Neurol (1991) 238 : 23-26

Journal of

Neurology
Springer-Verlag1991

Cerebrovascular CO2 reactivity in migraine: assessment by transcranial Doppler ultrasound

C. Hater 1'2 and R. yon Kummer 2

1Department of Neurosonology, The Bowman Gray School of Medicine, Winston-Salem, North Carolina, USA 2Department of Neurology, University of Heidelberg, Heidelberg, Federal Republic of Germany Received January 22, 1990 / Received in revised form June 15, 1990 / Accepted September 17, 1990
Summary. Cerebrovascular reactivity to C O 2 inhalation was studied by transcranial Doppler sonography in 30 patients with classic or common migraine and 39 healthy controls without clinical or ultrasonic signs of arteriosclerosis. Systolic and diastolic Doppler frequencies of the middle cerebral artery were plotted against end-tidal CO2 partial pressure; the reactivity index (I x R) was defined as relative frequency change during a PCO2 increase of 5 m m H g . In the normal subjects, I x R was 20.0 + 6.3 for systolic velocities, and 26.0 ___8.2 for diastolic values. Migraineurs during their headache-free interval had significantly higher I x R values on the affected side (mean: 41.6 systolic, 61.2 diastolic), compared with either controls (P < 0.01) or the contralateral side (mean: 28.3 systolic, 30.8 diastolic; P < 0 . 0 1 ) . During the headache attack, CO2 reactivity was significantly lower than normal only for systolic velocities (mean: 8.3; P < 0.05). Increased CO2 reactivity is thought to be one phenomenon of migraine. Transcranial Doppler CO2 testing of cerebrovascular reactivity is a reliable method that may be of interest for the diagnostic evaluation and management of migraine patients. Key words: Migraine - Transcranial Doppler ultrasound - Cerebrovascular reactivity - Carbon dioxide

Introduction and literature review

Because of the largely unknown pathophysiology of migraine, the array of therapeutic approaches proposed for its prophylactic interval treatment is more remarkable for diversity than for results. Drugs that are used include ergot derivates, [32-receptor blockers, platelet antagonists, Ca channel blockers, and monoamineoxidase inhibitors. The response to these various treatments is Offprint requests to: R. von Kummer, Neurologische Universitfitsklinik, Im Neuenheimer Feld 400, W-6900 Heidelberg 1, Federal Republic of Germany

highly individualized, and the effect of the drugs is difficult to assess. Transcranial ultrasonic (TCD) CO2 testing of cerebrovascular reactivity, first described by Markwalder et al. [8], is a simple, completely non-invasive method for determination of the capacity of the cerebral resistance vessels to react to changes of arterial C02 partial pressure (PaCO2) with dilatation or constriction, giving a measure of their residual autoregulatory capacity. In the literature, there are two concepts for assessing cerebrovascular reactivity by TCD: Ringelstein et al. [9] determined the whole extent of CO2 regulation, whereas Widder et al. [13] scored a "normalized autoregulatory response", defined as relative increase of mean flow velocity during a moderate hypercapnia from 40 to 46.5 m m H g . According to the vascular concept of migraine, the attack itself is associated with changes in the intra- or extracranial arteries. Lauritzen [5, 6] and Lauritzen et al. [7] stated that reactivity to changes of PaCO2 and to mental activation is reduced, whereas blood pressure regulation is normal. During the attack-flee interval, an increased CO2 reactivity has been reported by Sakai and Meyer [10], who presented regional cerebral blood flow (rCBF) measurements in 79 patients, and by Thomas and Harpold (poster presentation at the 1987 meeting of the American Neurological Association, San Francisco) who reported ultrasonic CO2 testing in 10 patients. Thie et al. [11] detected vasospasms during and after the migraine attack in three patients by TCD, without, however, correlating angiographic findings, and with normal response to hyperventilation. The purpose of this study was to determine whether changes in C02 reactivity can be consistently recognized in affected patients by means of transcranial Doppler ultrasound.
Materials and methods

Since a modification of the method suggested by Widder et al. [13] revealed normally distributed reactivity index values in a healthy

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Table 1. Systolic and diastolic reactivity index values (I R) of the middle cerebral arteries ipsi- and contralateral to the headaches of migraine patients and age- and sex-matched controls

it

I R-systolic Mean Standard deviation 14.5 8.4 6.5 4.8 2.4 4.8 Median

I R-diastolic Mean Standard deviation 27.4 6.8 8.3 14.7 4.1 5.1 Median

Between attacks

50 M C A

Ipsilateral Contralateral Controls

During attacks

32 18 32
10 M C A

41.6 28.3 20.6 8.3 14.3 17.1

43 28 19 8 15.6 17.5

61.2 30.8 27.0 17.8 16.5 21.2

48 29.5 26 11.5 17.6 21

lpsilateral Contralateral Controls

7 3 7

population [14], the index of reactivity (I R) was determined in the following way: 1. Continuous insonation of the middle cerebral artery (MCA) at a depth of 50-55 mm through the temporal squama (transcranial ultrasound device TC 2-64, EME, Uberlingen, FRG). 2. Continuous measurement of end-tidal CO2 partial pressure (PETCO2) by infrared analysis (capnometer LB 2 of Sensor Medics, Essen, FRG). 3. Reading of the "normal" PETCO: (PE~CO2N) of the individual patient, and reading of systolic and end-diastolic TCD frequencies (F-0. 4. Induction of moderate hypercapnia by application of Carbogene gas (5% CO2, 95% 02); reading of varied PETCO2 (PErCO2w, R) and varied TCD frequencies (FVAR) after a steady state over five heart and breathing cycles was reached. 5. Control of TCD frequencies and blood pressure in a second normocapnie steady state. 6. Calculation of reactivity index for both systolic and diastolic frequencies. I R = percent increase of TCD frequencies during a PEvC02 increase of 5 mmHg: I R - (500 * (Fv~xR-Fx))/(FN * (PCO2vAR - PCO2x)) We did not measure TCD frequencies during hypocapnia because we found that readings during voluntary hyperventilation are less reliable than those during CO2 breathing [2]. We studied 30 non-treated patients clinically diagnosed as having classic or common migraine. Twenty-five patients (8 males, 17 females; aged 19-56 years, mean 38.8 years) were examined during a headache-free interval (subgroup 1); the other 5 patients (1 male, 4 females); aged 23-54 years, mean 38.8 years) underwent TCD CO2 testing during an acute headache attack (subgroup 2). Extracranial Doppler studies were performed in all patients in order to exclude cerebrovascular obstructive disease. In 18 patients of subgroup 1, who had consistently unilateral headaches, we compared the reactivity of the MCA ipsilateral to the headaches with that of the eontralateral, presumably normal MCA. In both subgroups, 32 (group 1) and 7 (group 2) affected vessels were compared with the MCA of 39 age- and sex-matched healthy controls. Data were statistically analysed by the Wilcoxon signed-rank test.

D u r i n g the a t t a c k - f r e e interval ( T a b l e 1, Fig. 1), the CO2 reactivity o f the i p s i l a t e r a l M C A was 41.6, S D 14.5 ( r a n g e : 1 8 . 3 - 7 8 . 4 ) , a n d 61.2, SD 27.4 ( 2 0 . 4 - 1 2 0 . 5 ) , for systolic a n d diastolic calculations, r e s p e c t i v e l y . T h e cont r a l a t e r a l M C A h a d a r e a c t i v i t y of 28.3, SD 8.4 (systolic f r e q u e n c i e s ) a n d 30.8, SD 6.8 (diastolic values). A n a l y sis by the W i l c o x o n test r e v e a l e d for b o t h systolic a n d diastolic reactivity i n d e x values significant d i f f e r e n c e s b e t w e e n p a t i e n t s a n d c o n t r o l s ( P < 0.01), a n d also b e t w e e n the ipsi- a n d c o n t r a l a t e r a l M C A of the s a m e p a tients ( P < 0.01). D u r i n g the h e a d a c h e a t t a c k ( T a b l e 1, Fig. 2), i n d e x values r a n g e d f r o m 2.7 to 17.7 ( m e a n : 8.3) for systolic r e a d i n g s , a n d f r o m 9.1 to 50.6 ( m e a n : 17.8) for diastolic r e a d i n g s . A significant d i f f e r e n c e b e t w e e n p a t i e n t s a n d c o n t r o l s was o n l y seen for i n d e x values b a s e d o n systolic T C D r e a d i n g s ( P < 0.05). B e c a u s e of the small n u m b e r of p a t i e n t s with u n i l a t e r a l h e a d a c h e s in this g r o u p we w e r e not able to c o m p a r e the ipsi- and the c o n t r a l a t e r a l MCA. T h e u n d e r l y i n g a b s o l u t e D o p p l e r f r e q u e n c i e s a n d the " n o r m a l " PETCO2 values w e r e similar in all p a t i e n t s a n d c o n t r o l s (PCO2: 3 2 . 5 - 4 3 . 8 m m H g ; m e a n : 39.6; systolic diastolic: 1.1/0.5-3.4/1.5 k H z , m e a n 2.6/1.0). A f t e r variation of the CO2 c o n c e n t r a t i o n of the b r e a t h i n g gas PETCO2 and T C D values r e a c h e d a new s t e a d y state after 1 . 5 - 3 . 5 min in b o t h p a t i e n t s a n d controls.
Discussion

Results

In the two c o n t r o l s u b g r o u p s , CO2 r e a c t i v i t y values w e r e 20.0, S D 6.3 ( r a n g e : 6 . 8 - 3 2 . 2 ) for systolic v a l u e s , a n d 26.0, S D 8.2 ( r a n g e : 1 4 . 7 - 4 4 . 2 ) for diastolic values.

O n l y the relative CO2 r e a c t i v i t y is c o n s t a n t in v a r i o u s regions o f the c e n t r a l n e r v o u s system, w h e r e a s t h e absolute r e s p o n s e s are g r e a t e r in b e t t e r p e r f u s e d a r e a s a n d vice versa [3]. T o a v o i d confusion, the CO2 r e a c t i v i t y s h o u l d b e d e t e r m i n e d in r e l a t i o n to a definite C B F o r velocity value [1, 3]. In a f o r m e r study, h o w e v e r , m e a s u r ing a n d calculating with f r e q u e n c i e s at i d e n t i c a l PETCO2 levels, i.e. 40 a n d 45 m m H g in all p a t i e n t s , r e v e a l e d o n l y a p o o r c o r r e l a t i o n with a s t a n d a r d n o r m a l d i s t r i b u t i o n [14]. I n this r e p o r t , CO2 r e a c t i v i t y was d e t e r m i n e d b y relating the h y p e r c a p n i c M C A D o p p l e r f r e q u e n c i e s to t h o s e at the " n o r m a l " PETCO2 of the i n d i v i d u a l p a t i e n t , which p r o v i d e s a n o r m a l d i s t r i b u t i o n in a c o n t r o l p o p u l a tion.

25
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Fig.la, b. Comparison of CO2 reactivity index (I R) of the ipsilateral middle cerebral artery in migraine patients (D) during their headache-free intervals and controls ([]); n = 32 each group. a Systolic reactivity index values, b Diastolic reactivity index values

3.

A c c o r d i n g to o t h e r authors [5-7, 10], we f o u n d a red u c e d responsiveness to changes in arterial b l o o d P C O 2 during the acute attack. This m a y be due to a m a x i m u m dilatation of extra- and intracranial vessels because of an excessive release o f vasodilating agents. T h e patients' blush, their complaints a b o u t worsening of the h e a d a c h e during hypercapnia, and the response to J32-receptor blockers which prevent a vasodilation support this theory. O n the o t h e r hand, the spreading depression of C B F with c o m p e n s a t o r y dilatation o f the intracerebral arterioles, c o m p a r a b l e to the a u t o r e g u l a t o r y vasodilatation

Fig.2a, b. Comparison of CO2 reactivity index (I x R) of the ipsilateral middle cerebral artery in migraine patients (D) during their headache attacks and controls (F1); n = 7 each group, a Systolic reactivity index values, b Diastolic reactivity index values

in cerebrovascular obstructive disease, m a y be the reason for a r e d u c e d CO2 reactivity and m a y explain the event of migrainous stroke. In contrast to Thie et al. [11], w h o interpreted increased flow velocities as vasospastic vessel narrowing, we did not find increased T C D frequencies. T h e fact that angiography, which was p e r f o r m e d in one of their pa-

26 t i e n t s , s h o w e d no vessel a b n o r m a l i t i e s suggests that inc r e a s e d flow v e l o c i t i e s m a y be c a u s e d by h y p e r p e r f u s i o n d u e to d i l a t a t i o n of the r e s i s t a n c e vessels, which w o u l d also e x p l a i n o u r findings o f i m p a i r e d CO2 reactivity. D u r i n g t h e a t t a c k - f r e e i n t e r v a l , h o w e v e r , the CO2 r e a c t i v i t y o f the M C A i p s i l a t e r a l to the h e a d a c h e s was n e a r l y d o u b l e w h e n c o m p a r e d with a c o n t r o l p o p u l a t i o n . O u r results suggest t h a t t h e i n c r e a s e d i n t e r v a l c e r e b r o v a s c u l a r CO2 r e a c t i v i t y is o n e p h e n o m e n o n o f m i g r a i n e , regardless o f what the individual pathophysiological mecha n i s m s are. A l t h o u g h m i g r a i n e u r s h a d an i n c r e a s e d i n t e r v a l CO2 r e a c t i v i t y as a g r o u p , I R values within t h e n o r m a l r a n g e c o u l d be n o t e d in i n d i v i d u a l p a t i e n t s . T h e s e findings i m p l y t h a t the i n c r e a s e d i n t e r v a l CO2 reactivity, ins t e a d o f b e i n g a g e n e r a l p h e n o m e n o n , m a y focus, like n e u r o l o g i c a l s y m p t o m s in " m i g r a i n e a c c o m p a g n d e " , on p a r t i c u l a r b r a i n a r e a s u n r e l a t e d to t h e v a s c u l a r distribution [4]. H o w e v e r , CO2 r e a c t i v i t y m e a s u r e m e n t s of the M C A p r o v i d e an o v e r a l l M C A d i s t r i b u t i o n p a r a m e t e r , r e g a r d l e s s o f t h e b r a i n a r e a s i n v o l v e d in the m i g r a i n e attack. This m a y be o n e r e a s o n for the b r o a d o v e r l a p of ! R values in p a t i e n t s a n d controls. F u r t h e r m o r e , the h e t e r o g e n e o u s s e v e r i t y o f s y m p t o m s in v a r i o u s m i g r a i n e s u b g r o u p s m a y e x p l a i n the high v a r i a n c e . T o o few p a t i e n t s h a v e b e e n s t u d i e d y e t to est a b l i s h CO2 r e a c t i v i t y p a t t e r n s for e a c h s u b g r o u p . W e s p e c u l a t e t h a t a successful p r o p h y l a c t i c t r e a t m e n t w o u l d n o t o n l y i n f l u e n c e the f r e q u e n c y a n d c h a r a c t e r of h e a d a c h e a t t a c k s , b u t also the v a s c u l a r f u n c t i o n a l state. A n o r m a l i z a t i o n of CO2 r e a c t i v i t y m i g h t o c c u r e a r l i e r t h a n the s u b j e c t i v e c e s s a t i o n of h e a d a c h e s . T C D CO2 testing m i g h t t h e n p r o v i d e a f o r e c a s t of the i n d i v i d u a l res p o n s e to i n t e r v a l d r u g t r e a t m e n t [12]. S t u d i e s to e v a l u a t e t h e effect o f t r e a t m e n t on CO2 r e a c t i v i t y are p l a n n e d . M.A. (University of Heidelberg, FRG) for reviewing the manuscript.

References
1. Bishop CR, Powell S, Rutt D, Browse NL (1986) Transcranial Doppler measurement of middle cerebral artery blood flow velocity. A validation study. Stroke 17 : 913-915 2. Harer C. Winter R, Hofmann V (1990) Wie aussagekr~iftig ist die transkraniell dopplersonographische Messung der zerebralen Perfusionsreserve? In: Gebhardt J, Hackel6er J, Klinggr~iff G von, Seitz K (eds) Ultraschalldiagnostik 1989. Springer, Berlin Heidelberg New York (in press) 3. Kummer R von (1984) Local vascular response to change in carbon dioxide tension. Long term observation in the cat's brain by means of the hydrogen clearance technique. Stroke 15:108-114 4. Kummer R von, Schiller EM (1981) Zur Lokalisation der Begleitsymptome bei Migraine accompagn~e. Nervenarzt 52: 172-174 5. Lauritzen M (1984) Long-lasting reduction of cortical blood flow of the brain after spreading depression with preserved autoregulation and impaired CO2-response. J Cereb Blood Flow Metab 4 : 546-554 6. Lauritzen M (1987) Cerebral blood flow in migraine and cortical spreading depression. Acta Neurol Scand [Suppl] 113 : 1-40 7. Lauritzen M, Olsen TS, Lassen NA, Paulson OB (1983) Regulation of regional cerebral blood flow during and between migraine attacks. Ann Neurol 14 : 269-272 8. Markwalder TM, Grolimund P, Seiler RW, Roth F, Aaslid R (1984) Dependency of blood flow velocity in the middle cerebral artery on end-tidal carbon dioxide partial pressure transcranial ultrasound Doppler study. J Cereb Blood Flow Metab 4 : 368-372 9. Ringelstein EB, Sievers C, Ecker S, Schneider PA, Otis SM (1988) Noninvasive assessment of CO2-induced cerebral vasomotor response in normal individuals and patients with internal carotid artery occlusions. Stroke 19 : 963-969 10. Sakai F, Meyer J (1979) Abnormal cerebrovascular reactivity in patients with migraine and cluster headache. Headache 19 : 257-266 11. Thie A, Spitzer K, Lachenmayer L, Kunze K (1988) Prolonged vasospasm in migraine detected by noninvasive transcranial Doppler ultrasound. Headache 28:183-186 12. Thomas D, Harpold G (1988) Alteration of cerebrovascutar reactivity in migraineurs treated with propranolol. Neurology 38 [Suppl 1]: 108 13. Widder B, Paulat K, Hackspacher J, Mayr E (1986) Transcranial Doppler CO2 test for the detection of hemodynamically critical carotid artery stenoses and occlusions. Eur Arch Psychiatry Neurol Sci 236:162-168 14. Winter R, Harer C, Hofmann V (1991) Technical problems of transcranial ultrasonic CO2 testing of cerebrovascular reactivity. Neurosonology (in press)

Acknowledgements. The authors thank the Bowman Gray School

of Medicine (Winston-Salem, N.C., USA) "Neurosonology group" (Drs. Bill Ferrell. William McKinney), the "Neurology Departments of Clinics" (Dr. Larry Pearce, Rick Coburn, P.A.) and Dr. Ralph Winter (Neurology Clinic, University of Heidelberg, FRG) for numerous discussions and for actively supporting our work by referring patients. Dana Meads, Larry Myers (Bowman Gray School of Medicine, Winston-Salem, N.C., USA) and Monika Stegmaier (Neurology Clinic, University of Heidelberg, FRG) performed the extra- and transcranial Doppler studies. Jochen Pilz (University Clinic, Heidelberg, FRG) designed the graphical layout. Last not least, we thank Francis R. Schwartz,